Journal of Cancer Research and Clinical Oncology

Background Previous studies have found variations in cancer types, tumor progression, and disease outcomes between men and women. However, there is limited knowledge of the effect of sex on gastrointestinal neuroendocrine neoplasms (GI-NENs). Methods We identified 1354 patients with GI-NEN from the IQVIA’s Oncology Dynamics database. Patients were derived from four European countries (Germany, France, the United Kingdom (UK), Spain). Clinical and tumor related characteristics including patients' age, tumor stage, tumor grading and differentiation, frequency and sites of metastases, as well as co-morbidities were analyzed as a function of patients´ sex. Results Among the 1354 included patients, 626 were female and 728 were male. The median age was similar between both groups (w: 65.6 years, SD: 12.1 vs. m: 64.7 years; SD: 11.9; p = 0.452). UK was the country with the most patients, however, there was no differences in the sex ratio between the different countries. Among documented co-morbidities, asthma was more often diagnosed in women (7.7% vs. 3.7%), while COPD was more prevalent in men (12.1% vs. 5.8%). The ECOG performance states was comparable between females and males. Of note, the patients´ sex was not associated with tumor origin (e.g., pNET or siNET). Females were overrepresented among G1 tumors (22.4% vs. 16.8%), however, median proliferation rates according to Ki-67 were similar between both groups. In line, no differences in tumor stages was found and rates of metastases as well as the specific sites of metastases were similar between males and females. Finally, no differences in the applied tumor specific treatments between the both sexes became apparent. Conclusion Females were overrepresented among G1 tumors. No further sex-specific differences became apparent, highlighting that sex-related factors might play a rather subordinate role in the pathophysiology of GI-NENs. Such data may help to better understand the specific epidemiology of GI-NEN.

Purpose Immune checkpoint inhibitors (ICIs) have been demonstrated to be effective for unresectable or metastatic hepatocellular carcinoma (HCC) or cholangiocarcinoma (CCA) in prior prospective trials. However, the clinical outcomes of ICIs in patients with combined HCC–CCA (cHCC–CCA) have not been investigated. Accordingly, we retrospectively evaluated the effectiveness and safety of ICIs in patients with unresectable or metastatic cHCC–CCA. Methods Among 101 patients with histologically documented cHCC–CCA who received systemic therapy, 25 received ICIs between January 2015 and September 2021 and were included in the current analysis. Overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were retrospectively evaluated. Results The median age was 64 years (range 38–83) and 84% (n = 21) of patients were males. Most patients had Child–Pugh A liver function (n = 22, 88%) and hepatitis B virus infection (17, 68%). Nivolumab (n = 17, 68%) was the most frequently used ICI, followed by pembrolizumab (n = 5, 20%), atezolizumab plus bevacizumab (n = 2, 8%), and ipilimumab plus nivolumab (n = 1, 4%). All patients, except one, had previously received systemic therapy; median two lines (1–5 lines) of systemic therapy were administered prior to ICIs. With a median follow-up duration of 20.1 months (95% CI 4.9–35.2 months), the median PFS was 3.5 months (95% CI 2.4–4.8 months), and the median OS was 8.3 months (95% CI 6.8–9.8 months). The ORR was 20.0% (n = 5, nivolumab for 2 patients, pembrolizumab for 1, atezolizumab plus bevacizumab for 1, and ipilimumab plus nivolumab for 1) and the duration of response was 11.6 months (95% CI 11.2–12.0 months). Conclusions ICIs displayed clinical anti-cancer effectiveness, aligning with the results of prior prospective studies for HCC or CCA. Further international studies are required to define the optimal strategies for managing unresectable or metastatic cHCC–CCA.

Purpose Rising incidence of pancreatic ductal adenocarcinoma (PDAC) bind with insufficient therapy options showcases a great medical challenge. Further biomarkers are required to identify patients, who will benefit from more aggressive therapy. Methods 320 patients were included by the PANCALYZE study group. Cytokeratin 6 (CK6) immunohistochemical staining as a putative marker for the basal-like subtype of PDAC was performed. The correlation between CK6 expression patterns and survival data, as well as various markers of the (inflammatory) tumor microenvironment, were analyzed. Results We divided the study population based on the expression pattern of CK6. Patients with a high CK6 tumor expression had a significantly shorter survival (p = 0.013), confirmed in a multivariate cox regression model. CK6-expression is an independent marker for a decreased overall survival (HR = 1.655, 95% CI 1.158–2.365, p = 0.006). In addition, the CK6-positive tumors showed significantly less plasma cell infiltration and more cancer-associated fibroblasts (CAFs) expressing Periostin and SMA. Conclusions CK6 could be considered as an independent biomarker for a shorter overall survival. CK6 is a clinically easily accessible biomarker for the identification of the basal-like subtype of PDAC. Therefore, it could be taken into consideration in deciding for the more aggressive therapy regimes. Prospectively, studies addressing the chemosensitive characteristics of this subtype are required.

Purpose Women with BRCA1 and BRCA2 (BRCA1/2) pathogenic/likely pathogenic (P/LP) variants have a higher risk to develop breast and ovarian cancer. In structured high-risk clinics, risk-reducing measures are adopted. This study aimed at characterizing these women and identify factors that may have influenced their choice between risk reduction mastectomy (RRM) and intensive breast surveillance (IBS). Methods This study reviewed retrospectively 187 clinical records of affected and unaffected women with P/LP variants of the BRCA1/2 genes, from 2007 to 2022, of which 50 chose RRM, while 137 chose IBS. The research focused on personal and family history and tumor characteristics and their relation with the preventive option chosen. Results Among women with personal history of breast cancer, a higher proportion opted for RRM compared to those asymptomatic (34.2% vs 21.3%, p = 0.049), with younger age determining the option for RRM (38.5 years vs 44.0 years, p < 0.001). Among women with personal history of ovarian cancer, a higher proportion opted for RRM compared to those without that history (62.5% vs 25.1%, p = 0.033), with younger age determining the option for RRM (42.6 years vs 62.7 years, p = 0.009). Women who had bilateral salpingo-oophorectomy were more likely to choose RRM than those who did not (37.3% vs 18.3%, p = 0.003). Family history was not associated with preventive option (33.3% vs 25.3, p = 0.346). Conclusions The decision for the preventive option is multifactorial. In our study, personal history of breast or ovarian cancer, younger age at diagnosis, and previous bilateral salpingo-oophorectomy were associated with the choice of RRM. Family history was not associated with the preventive option.

Introduction Immune checkpoint blockade (ICB) is a promising strategy for cancer treatment and has generated remarkable clinical results against multiple malignancies. Exploration of new technical approaches to further boost the therapeutic efficacy of ICB is of potential medical importance. In this study, we designed a novel nanotherapeutics for ICB immunotherapy. Methods CTLA-4 aptamers were conjugated to the surface of albumin nanoparticle to construct an aptamer-modified nanostructure (Apt-NP). To improve ICB efficacy, fexofenadine (FEXO), an antihistamine, was encapsulated into Apt-NP to make a drug-loaded nanoparticle (Apt-NP-FEXO). The antitumor efficacies of Apt-NP and Apt-NP-FEXO were evaluated in vitro and in vivo. Results Apt-NP and Apt-NP-FEXO had average diameters of 149 nm and 159 nm, respectively. Similar to free CTLA-4 aptamers, Apt-modified NPs could selectively bind with CTLA-4 positive cells and improve lymphocyte-mediated antitumor cytotoxicity in vitro. In animal studies, compared with free CTLA-4 aptamer, Apt-NP significantly enhanced antitumor immunity. Moreover, Apt-NP-FEXO further improved antitumor efficacy vs. Apt-NP in vivo. Conclusion The results suggest that Apt-NP-FEXO represents a novel strategy to improve ICB outcome and may have application potential in cancer immunotherapy.

Purpose Dysregulated expression of heat shock proteins (HSP) plays a fundamental role in tumor development and progression. Consequently, HSP90 may be an effective tumor target in oncology, including the treatment of gastrointestinal cancers. Methods We carried out a systematic review of data extracted from clinicaltrials.gov and pubmed.gov, which included all studies available until January 1st, 2022. The published data was evaluated using primary and secondary endpoints, particularly with focus on overall survival, progression-free survival, and rate of stable disease. Results Twenty trials used HSP90 inhibitors in GI cancers, ranging from phase I to III clinical trials. Most studies assessed HSP90 inhibitors as a second line treatment. Seventeen of the 20 studies were performed prior to 2015 and only few studies have results pending. Several studies were terminated prematurely, due to insufficient efficacy or toxicity. Thus far, the data suggests that HSP90 inhibitor NVP-AUY922 might improve outcome for colorectal cancer and gastrointestinal stromal tumors. Conclusion It currently remains unclear which subgroup of patients might benefit from HSP90 inhibitors and at what time point these inhibitors may be beneficial. There are only few new or ongoing studies initiated during the last decade.

This study has demonstrated improved methods for isolating exosomes from non-small lung cancer cells, which address the problems characterized by exosome morphological and chemical methods. To improve the isolation methods, cells from the NCI 1975 cell line were used as the source for exosomes. The isolation processes were carried out using serial isolation techniques in addition to specific preservation tools. The isolated exosomes were characterized using transmission electron microscopy (TEM), and scanning electron microscopy (SEM) was added for further assurance of the investigation results. The statistical analysis results showed that the size distributions of apoptotic vesicles (APV) 450 nm and necrotic bodies (NCB) 280 nm (extracellular vesicles) were significantly different from exosomes (P < 0.001). In contrast, the exosome size distribution was not significantly different from the published exosome sizes, as demonstrated by statistical analysis tools. This study confirmed the improved methods for isolating exosomes that make exosomes accessible for use in the diagnosis and prognosis of non-small cell lung cancer (NSCLC).

Purpose The aim of our study was to explore the impact of the COVID-19 pandemic on reported cancer cases in Bavaria, Germany, by comparing pre-pandemic (March 2019 to February 2020) and pandemic period (March 2020 to February 2021). Methods Data on incident cases were retrieved from the Bavarian Cancer Registry (until 22nd April 2022). We included patients with malignant and in situ neoplasms reported by pathology departments with consistent reporting. We calculated the number of incident cases during the COVID-19 pandemic and the pre-pandemic period with 95% confidence intervals (CI) with Bonferroni correction (α = 0.0018) based on a Poisson approach. We stratified for malignancy (malignant, in situ), tumor site, and month of year. Results Data was available for 30 out of 58 pathology departments (51.7%) from Bavaria. Incident malignant neoplasms dropped from 42,857 cases in the pre-pandemic period to 39,980 cases in the pandemic period (− 6.7%; 95% CI − 8.7%, − 4.7%). Reductions were higher for colon, rectum, skin/melanoma as well as liver (> 10.0% reduction) and less for breast cancer (4.9% reduction). No case reductions were observed for pancreas, esophagus, ovary, and cervix. Percent changes were largest for April 2020 (− 20.9%; 95% CI − 24.7%, − 16.8%) and January 2021 (− 25.2%; 95% CI − 28.8%, − 21.5%) compared to the previous year. Declines tended to be larger for in situ compared to malignant neoplasms. Conclusion Detection and diagnosis of cancer were substantially reduced during the COVID-19 pandemic. Potential effects, e.g. a stage shift of tumors or an increase of cancer mortality, need to be monitored.

Purpose: When more than two tumors are diagnosed in the same person, it is called multiple primary cancer. It is rare to be diagnosed as four primary cancers. Here, we present one elderly male patient suffered from testicular seminoma, gastric cancer, bladder cancer and breast cancer from 1946 to 2019. Methods: When he was about 1.5 years old in 1946, his mother (a doctor) inadvertently found that the left scrotum of the child was enlarged. He performed left testicular resection under general anesthesia and postoperative pathological report: left testicular seminoma. In March 2007 (62 years old), the upper abdomen was distended and uncomfortable after eating, accompanied by hiccups and heartburn. He performed distal subtotal gastrectomy and postoperative pathology report: moderately and poorly differentiated adenocarcinoma of ulcer. In May 2013 (68 years old), he developed no obvious cause of painless gross hematuria. He performed robot-assisted laparoscopic radical cystectomy+pelvic lymph node dissection+bilateral ureterostomy and postoperative pathological report: invasive high-grade urothelial carcinoma at the bottom of the bladder. In February 2017 (72 years old), he found the right breast was developing, and a nodule was palpable under the skin. He performed undergo modified radical surgery in the right breast and postoperative pathological report: Invasive breast cancer. Results: During the past 70 years, he suffered from four types of tumors, all of which underwent surgical treatment. Postoperative pathology confirmed that they were malignant tumors. Genetic tumor gene testing found no pathogenic or suspected pathogenic mutations. The patient's general condition is good, with regular follow-up and no tumor recurrence CONCLUSION: The treatment of multiple primary cancers is different from tumor recurrence. Targeted treatment for different tumors can achieve good therapeutic results. Cancer patients must be followed up regularly. Timely treatment after discovering new tumors is the key to a good prognosis.

Background Vertebroplasty is a minimally invasive outpatient procedure to stabilize compression fractures in the spine. This procedure involves injecting bone cement into the vertebrae that have been cracked or broken, typically due to osteoporosis. The cement hardens inside the bones, providing stability to the fractures and supporting the spine. Additionally, radioactive bone cement and brachytherapy sources have been utilized to suppress tumor growth in the vertebral body. Objective We present a novel brachytherapy technique for treating vertebral body metastases using a liquid form of radioactive sources, Phosphorus-32 and Lutetium-177, separately mixed with bone cement and injected into vertebral body bone prostheses. We also investigated the dose distribution of the radioactive bone cement by theoretically calculating it using GEANT4 Monte Carlo and measuring it using TLD dosimeters for Phosphorus-32 and Lutetium-177 loaded in vertebral bodies. Material and methods CT-scanned images of each vertebral body (L2 and L3) were imported into GEANT4 for simulation purposes. Two simulations were performed to evaluate the possibility of using PLA prostheses in ex vivo measurements, using bone and PLA material as a bone substitute for brachytherapy of Lutetium-177 and Phosphorus-32. The simulations calculated the dose distribution, dose rates, and deposited dose to the spinal cord and aorta. Next, 3D-printed bone prostheses were drilled and separately filled with bone cement, including PMMA-P32 and PMMA-Lu177, in liquid form using the Vertebroplasty technique. The dose to regions of interest was measured using Thermoluminescence dosimeters. Conclusions When comparing the simulated and measured results of dose rates, it was observed that P32 delivers higher doses to normal organs such as the spinal cord and aorta. At the same time, Lu177 has better sparing in these regions of interest. Therefore, while P32 and Lu177 are suitable for radioactive bone cement treatment, Lu177 delivers relatively lower doses to vital organs such as the spinal cord and aorta. Additionally, Lu177 has characteristics such as a shorter range and lower energies of beta particles in tissue and the presence of gamma rays that make it a better choice for the same treatments. It also provides the possibility of SPECT imaging.

Background Gastrointestinal stromal tumors (GIST) are rare mesenchymal tumors. They are most frequently located in the stomach but are also found in the esophagus and the gastroesophageal junction (GEJ). Information regarding the prognostic factors associated with upper gastrointestinal GIST is still scarse. Methods In this study, datasets provided by the German Clinical Cancer Registry Group, including a total of 93,069 patients with malignant tumors in the upper GI tract (C15, C16) between 2000 and 2016 were analyzed to investigate clinical outcomes of GIST in the entire upper GI tract. Results We identified 1361 patients with GIST of the upper GI tract. Tumors were located in the esophagus in 37(2.7%) patients, at the GEJ in 70 (5.1%) patients, and in the stomach in 1254 (91.2%) patients. The incidence of GIST increased over time, reaching 5% of all UGI tumors in 2015. The median age was 69 years. The incidence of GIST was similar between males and females (53% vs 47%, respectively). However, the proportion of GIST in female patients increased continuously with advancing age, ranging from 34.7% (41–50 years) to 71.4% (91–100 years). Male patients were twice as likely to develop tumors in the esophagus and GEJ compared to females (3.4% vs. 1.9% and 6.7% vs. 3.4%, respectively). The median overall survival of upper gastrointestinal GIST was 129 months. The 1-year, 5-year, and 10-year OS was 93%, 79%, and 52% respectively. Nevertheless, tumors located in the esophagus and GEJ were associated with shorter OS compared to gastric GIST (130 vs. 111 months, p = 0.001). The incidence of documented distant metastasis increased with more proximal location of GIST (gastric vs. GEJ vs. esophagus: 13% vs. 16% vs. 27%) at presentation. Conclusion GIST of the esophagus and GEJ are rare soft tissue sarcomas with increasing incidence in Germany. They are characterized by worse survival outcomes and increased risk of metastasis compared to gastric GIST.

Purpose Lack of evidence on the benefit of stereotactic body radiotherapy (SBRT) in combination with lenvatinib for advanced hepatocellular carcinoma (HCC). Our research compared the efficacy and safety of SBRT plus lenvatinib versus SBRT alone in clinical practice for the treatment of advanced HCC. Methods Propensity score matching (PSM) analysis was used to reduce selection bias. Overall survival (OS), progression-free survival (PFS), intrahepatic PFS (IHPFS), and objective response rate (ORR) were compared between the two groups. Additionally, safety profiles were also evaluated in the two groups. Results After PSM, 35 patients from each group were selected and the date was compared. Compared with the SBRT alone group, the median OS, PFS, and IHPFS were significantly prolonged in SBRT plus lenvatinib group (median OS 16.8 vs. 11.0 months, pOS = 0.043; median PFS 9.1 vs. 3.7 months, pPFS < 0.001; median IHPFS 9.5 vs. 4.2 months, pIHPFS = 0.004). The 6- and 12-month OS rates were 91.4% and 68.6% in the combined therapy group and 82.9% and 48.6% in the monotherapy group, respectively. The 6- and 12-month PFS rates were 68.6% and 34.3% in the combined therapy group and 31.4% and 8.6% in the monotherapy group, respectively. Furthermore, a higher ORR was observed in SBRT plus lenvatinib group (54.29% vs. 22.86%, p = 0.007). Subgroup analysis of patients with macroscopic vascular invasion (MVI) also had similar results. Moreover, most adverse events (AEs) were mild-to-moderate and manageable in the SBRT plus lenvatinib group. Conclusion SBRT plus lenvatinib is expected to significantly improve OS, PFS, IHPFS, and ORR for patients with advanced HCC when compared to SBRT alone, with manageable adverse effects.

Background Bacillus Calmette–Guerin (BCG) maintenance therapy is the standard adjuvant treatment of high- and intermediate-risk non-muscle-invasive bladder cancer (NMIBC). However, the problems of shortages and the adverse effects, both local and systemic, that it causes lead to the search for alternatives with devices that improve the penetration of intravesical chemotherapeutics. Materials and methods Prospective observational study was conducted from August 2018 to August 2022. Patients diagnosed with intermediate and high-risk NMIBC without CIS who received one of the following three treatments were included: BCG in induction protocol with six weekly instillations and maintenance with three weekly instillations at months 3, 6, and 12. MMC was applied by Physionizer® 30 device with a current of 20 mA for 30 min was used in an induction protocol of 6 weekly instillations followed by 6 monthly instillations as maintenance (EMDA group). MMC was applied by COMBAT BRS System V2.0 device at 43 ± 0.5 ℃ for 60 min was used in an induction protocol of 6 weekly instillations followed by 6 monthly instillations as maintenance (HIVEC group). The primary objective was to compare the 24-month recurrence-free rate between the three groups. The secondary objectives were to evaluate the rate free of progression at 24 months and the degree of toxicity of the treatments. Results One hundred and eighty-three patients divided into a HIVEC group with sixty-one patients, EMDA group with fifty-nine patients, and BCG group with sixty-three patients. After a mean follow-up of 25 months (IQR 13–36), the 24-month recurrence-free rate was 82.1% for HIVEC, 80% for EMDA, and 84.6% for BCG (p > 0.05), and a progression-free rate at 24 months of 95.6% for HIVEC, 98.3% for EMDA, and 92.9% for BCG (p > 0.05). No statistically significant differences were found between the three groups with respect to the degree of reported adverse events. Conclusion Adjuvant treatment with BCG or MMC applied with COMBAT or EMDA does not present differences in the recurrence-free rate and progression at 24 months in our population of patients with intermediate- and high-risk NMBC without CIS.

Parasites and cancers have some common antigens. Much scientific evidence in the human population, animal models, and in vitro experiments exhibit that parasites have significant anti-cancer effects. The larval stage of the tapeworm Echinococcusgranulosus, Toxoplasmagondii, Trypanosomacruzy, Plasmodium’s, and Trichinellaspiralis are among the parasites that have been subjects of anti-cancer research in the last decades. Anti-tumor effects of parasites may be due to the direct impact of the parasites per se or indirectly due to the immune response raised against common antigens between malignant cells and parasites. This manuscript reviews the anti-cancer effects of parasites and possible mechanisms of these effects. Options for using parasites or their antigens for cancer treatment in the future have been discussed. Graphical abstract

Background Radiation-induced oral mucositis (OM) largely impairs the quality of life (QoL) of patients with head and neck cancer (HNC). Few choices with limited efficacy are available to prevent this adverse effect. This randomized trial was conducted to compare the efficacy of benzydamine (standard) and a new combination (sumac and rose water) in preventing radiation-induced OM. Methods This was a phase II, triple-blind, active-controlled, randomized trial. The primary endpoint was OM, and the secondary endpoints were oral pain and QoL. Besides, the possible variables defining the outcomes were analyzed using the chi-squared test (univariate analysis) and binomial regression model (multivariate analysis). Results Sumac-rose group had fewer high-grade OM (33% vs. 63%, odds ratio [OR] 0.28, 95% confidence interval [CI 95%] 0.08–0.93, P = 0.03) and better QoL (P < 0.05). Multivariate analysis confirmed these findings. Sumac-rose rinsing could also postpone the start of oral pain (hazard ratio [HR] 0.02, CI 95% 0.001–0.32, P = 0.001) and high-grade OM (HR 0.28, P = 0.03) compared with benzydamine. Conclusions The sumac-rose group had a lower OM rate and grade and higher QoL than the benzydamine group. In addition, the experimental group developed high-grade OM and oral pain later during the radiotherapy course. Further studies need to be conducted to assess the role of sumac and rose water in reducing grade 3–4 mucositis in patients who undergo chemoradiation for head and neck cancer. Graphical abstract

As immune checkpoint inhibitors (ICIs) are widely used, a series of immune-related adverse events (irAEs) have been reported, including immune checkpoint inhibitor-related pneumonitis (ICI-pneumonitis). The incidence of ICI-pneumonitis is higher in reality than in clinical trials. The diagnosis is challenging, mainly based on clinical and imaging features, and requires the exclusion of other causes. The data on the biological mechanisms of ICI-pneumonitis are scarce, resulting in little knowledge of the best treatment for ICI-pneumonitis. Bronchoalveolar lavage (BAL) may be helpful to identify the biological differences or find predictive biomarkers, and may in turn help to develop phenotype-specific targeted drugs to treat ICI-pneumonitis. Herein, we outline the characterization of immunomodulatory factors and cells in bronchoalveolar lavage fluid for ICI-pneumonitis. Through careful sorting and literature review, we find crosstalk between pathogenic Th17/Th1 cells (i.e., Th17.1) and pro-inflammatory monocytes, and activation of Th17(/Th1)/IL-17A (/IFN-γ) pathways may play a key role in the pathogenesis of ICI-pneumonitis. Disruption of the interaction between pathogenic Th17/Th1 cells and pro-inflammatory monocytes (such as, anti-IL-23) may be a potential treatment for ICI-pneumonitis. We first describe the possible pathophysiological mechanisms of ICI-pneumonitis, hoping to contribute to the optimization of diagnosis and treatment, as well as provide readers with research inspiration.

Purpose/aim The international standard for patients with large inoperable stage III NSCLC is durvalumab consolidation after concurrent chemoradiotherapy (CRT). In this single centre observational study based on individual data, we prospectively evaluated the role of concurrent/sequential versus sequential immune checkpoint inhibition (ICI). Methods and patients In total, 39 stage III NSCLC patients were prospectively enrolled, 11 (28%) patients were treated with simultaneous and consolidation therapy with PD-1 inhibition (nivolumab) (SIM-cohort) and 28 (72%) patients received PD-L1 inhibition (durvalumab) as consolidation treatment up to 12 months after the end of CRT (SEQ-cohort). Results For the entire cohort, median progression-free survival (PFS) was 26.3 months and median survival (OS), locoregional recurrence-free survival and distant metastasis-free survival were not reached. For the SIM-cohort, median OS was not reached and PFS was 22.8 months, respectively. In the SEQ-cohort, neither median PFS nor OS were reached. After propensity score matching, PFS at 12/24 months were 82/44% in the SIM-cohort and 57/57% in the SEQ-cohort (p = 0.714), respectively. In the SIM-cohort, 36.4/18.2% of patients showed grade II/III pneumonitis; in the SEQ-cohort 18.2/13.6% after PSM (p = 0.258, p = 0.55). Conclusion Both concurrent/sequential and sequential ICI show a favorable side effect profile and promising survival in treated patients with inoperable large stage III NSCLC. Concurrent ICI showed a numerical non-significant improvement regarding 6- and 12-months PFS and distant control compared to sequential approach in this small study. However, concurrent ICI to CRT was associated with a non-significant moderate increase in grade II/III pneumonitis.

Purpose Lung adenocarcinoma (LUAD) is a malignant tumor with a high lethality rate. Immunotherapy has become a breakthrough in cancer treatment and improves patient survival and prognosis. Therefore, it is necessary to find new immune-related markers. However, the current research on immune-related markers in LUAD is not sufficient. Therefore, there is a need to find new immune-related biomarkers to help treat LUAD patients. Methods In this study, a bioinformatics approach combined with a machine learning approach screened reliable immune-related markers to construct a prognostic model to predict the overall survival (OS) of LUAD patients, thus promoting the clinical application of immunotherapy in LUAD. The experimental data were obtained from The Cancer Genome Atlas (TCGA) database, including 535 LUAD and 59 healthy control samples. Firstly, the Hub gene was screened using a bioinformatics approach combined with the Support Vector Machine Recursive Feature Elimination algorithm; then, a multifactorial Cox regression analysis by constructing an immune prognostic model for LUAD and a nomogram to predict the OS rate of LUAD patients. Finally, the regulatory mechanism of Hub genes in LUAD was analyzed by ceRNA. Results Five genes, ADM2, CDH17, DKK1, PTX3, and AC145343.1, were screened as potential immune-related genes in LUAD. Among them, ADM2 and AC145343.1 had a good prognosis in LUAD patients (HR < 1) and were novel markers. The remaining three genes screened were associated with poor prognosis in LUAD patients (HR > 1). In addition, the experimental results showed that patients in the low-risk group had better OS rates than those in the high-risk group (P < 0.001). Conclusion In this paper, we propose an immune prognostic model to predict OS rate in LUAD patients and show the correlation between five immune genes and the level of immune-related cell infiltration. It provides new markers and additional ideas for immunotherapy in patients with LUAD.

Purpose Chemotherapy induced peripheral neuropathy (CIPN) is a debilitating condition that is a direct consequence of receiving cancer treatment. The molecular aetiology of CIPN is not well understood, and it is theorised that there may be a genetic component. Genetic polymorphisms in Glutathione-S Transferase (GST) genes, including GSTT1, GSTM1 and GSTP1, encode for enzymes known to metabolise drugs used in chemotherapy, and have been theorised to be associated with CIPN. This study aimed to investigate four markers in these genes for an association in a mixed cancer cohort in relation to CIPN (n = 172). Methods CIPN was measured using the neuropathy item from the Patient Reported Outcome Common Terminology Criteria for Adverse Event (PRO-CTCAE) assessment. Genotyping for all samples was performed using PCR for the GSTM1 and GSTT1 null variants and restriction fragment length polymorphisms for the GSTP1 and GSTM1 polymorphisms. Results No associations were found for the GST gene markers in relation to CIPN within our study, or CIPN severity. Longitudinal stratification of the CIPN phenotypes to examine links for neuropathy, identified nominally significant protective associations with the GSTM* null allele (p-value = 0.038, OR = 0.55) and the presence of pain at month 2 of treatment, as well as a risk factor for pain related month 2 of treatment for individuals with the GSTT1*null allele (p-value = 0.030, OR = 1.64). Higher severity of pain in patients with CIPN persisted at each time-point compared to those without CIPN. Conclusion No significant results for an association between CIPN with polymorphisms in GSTM1, GSTT1 and GSTP1 were identified. However, associations for the GSTM1¬-null and GSTT1-null polymorphisms with pain at month 2 following chemotherapy were identified.

Purpose Molecular Profiling of solid tumours is extensively used for prognostic, theranostic, and risk prediction. Next generation sequencing (NGS) has emerged as powerful method for molecular profiling. The present study was performed to identify molecular alterations present in solid tumours in Indian tertiary cancer centre. Methods Study included 1140 formalin Fixed paraffin embedded samples. NGS was performed using two targeted gene panels viz. Ampliseq Focus panel and Sophia Solid Tumor Plus Solution. Data was analyzed using Illumina’s Local Run Manager and SOPHiA DDM software. Variant interpretation and annotations were done as per AMP/ACMG guidelines. Results Total 896 cases were subjected to NGS after excluding cases with suboptimal nucleic acid quality/quantity. DNA alterations were detected in 64.9% and RNA fusions in 6.9% cases. Among detected variants, 86.7% were clinically relevant aberrations. Mutation frequency among different solid tumours was 70.8%, 67.4%, 64.4% in non-small cell lung (NSCLC), lung squamous cell carcinomas and head neck tumours respectively. EGFR, KRAS, BRAF, ALK and ROS1were commonly altered in NSCLC. Gastrointestinal tumours showed mutations in 63.6% with predominant alterations in pancreatic (88.2%), GIST (87.5%), colorectal (78.7%), cholangiocarcinoma (52.9%), neuroendocrine (45.5%), gall bladder (36.7%) and gastric adenocarcinomas (16.7%). The key genes affected were KRAS, NRAS, BRAF and PIK3CA. NGS evaluation identified co-occurring alterations in 37.7% cases otherwise missed by conventional assays. Resistance mutations were detected in progressive lung tumours (39.5%) against EGFR TKIs and ALK/ROS inhibitors. Conclusion This is the largest Indian study on molecular profiling of solid tumours providing extensive information about mutational signatures using NGS.

PurposeNeoantigens produced from mutations in tumors are important targets of T-cell-based immunotherapy and immune checkpoint blockade has been approved for treating multiple solid tumors. We investigated the potential benefit of adoptive neoantigen-reactive T (NRT) cells in combination with programmed cell death protein 1 inhibitor (anti-PD1) for treating lung cancer in a mouse model.MethodsNRT cells were prepared by co-culturing T cells and neoantigen-RNA vaccine-induced dendritic cells. Then, adoptive NRT cells in combination with anti-PD1 were administered to tumor-bearing mice. Pre- and post-therapy cytokine secretion, antitumor efficacy, and tumor microenvironment (TME) changes were determined both in vitro and in vivo.ResultsWe successfully generated NRT cells based on the 5 neoantigen epitopes identified in this study. NRT cells exhibited an enhanced cytotoxic phenotype in vitro and the combination therapy led to attenuated tumor growth. In addition, this combination strategy downregulated the expression of the inhibitory marker PD‐1 on tumor-infiltrating T cells and promoted the trafficking of tumor-specific T cells to the tumor sites.Conclusion The adoptive transfer of NRT cells in association with anti-PD1 therapy can exert an antitumor effect on lung cancer, and is a feasible, effective, and novel immunotherapy regimen for treating solid tumors.

Purpose Molecularly targeted therapy has revolutionized the therapeutic landscape and is emerging as the first-line treatment option for ALK-rearranged non-small-cell lung cancer (NSCLC). In this study, the highly informative and robust biomarkers based on pre-treatment CT images and clinicopathologic features will be developed and validated to predict the prognosis for ALK-inhibitor therapy in NSCLC patients. Methods A total of 161 ALK-positive NSCLC patients treated with ALK inhibitors were retrospectively collected as training, validation and test sets from multi-center institutions. Cox proportional hazard regression (CPH) penalized by LASSO and random survival forest (RSF) coupled with recursive feature elimination (RFE) were used for radiomics and clinical features identification and model construction. An overlapping post-processing method was extra added to training process to investigate the stronger biomarker on the whole set. Results 123 of the collected cases progressed after a median follow-up of 15.5 months (IQR, 8.3–25.3). The T and M staging, pericardial effusion, age and ALK inhibitor-alectinib were determined as significant predictors in the survival analysis. Furthermore, we visualized the finally retained 4 radiomics feature. The RSF models built from overlapping-processed clinical and radiomics features respectively reached the maximum C-index of 0.68 and 0.75,but the combination of them,radioclinical signature, improved the score to 0.78. The model on the validation and external test datasets yielded the C-index of 0.73 and 0.79, with the iAUC of 0.76 and 0.83, the IBS of 0.119 and 0.112. Conclusion With respect to a simple selection strategy of overlapping optimal radiomics and clinical features from different survival models may promote better progression-free survival(PFS) prediction than conventional survival analysis, which provides a potential method for guiding personalized pre-treatment options of NSCLC.

Multiple myeloma (MM) is the second most common hematological cancer that has no cure. Although currently there are several novel drugs, most MM patients experience drug resistance and disease relapse. The results of previous studies suggest that aberrant mitochondrial function may contribute to tumor progression and drug resistance. Mitochondrial DNA mutations and metabolic reprogramming have been reported in MM patients. Several preclinical and clinical studies have shown encouraging results of mitochondria-targeting therapy in MM patients. In this review, we have summarized our current understanding of mitochondrial biology in MM. More importantly, we have reviewed mitochondrial targeting strategies in MM treatment.

Purpose Gastrointestinal (GI) microbiome modulators, such as fecal microbiome transplants (FMTs), are being considered as supplements to standard immune checkpoint inhibitor (ICI) treatment to improve efficacy. This systematic review aims to assess the study design and outcomes of clinical trials that use FMTs to enhance ICI treatment. Methods Systematic literature searches were conducted on PubMed and Embase using search terms that included names of ICIs and gastrointestinal microbiome. A first search identified interventional trials, and the second search identified interventional, retrospective, and observational studies. Results The search for interventional trials produced 205 articles, 3 of which met the inclusion criteria. All studies had sample sizes ranging between 10 and 30 participants. 2 of the studies were single-arm studies with no control arm. One study reported an overall response rate (ORR) of 3 out of 15 (20%), a median progression-free survival (PFS) of 3 months, and a median overall survival (OS) of 7 months. The second study reported 1 complete response out of 10 (10%) and 2 partial responses out of 10 (20%). The third study reported an ORR of 58% vs. 20%, a median PFS of 12.7 months vs. 2.5 months in patients receiving nivolumab–ipilimumab plus CBM588 compared with patients receiving nivolumab–ipilimumab alone respectively, and an undefined median OS. Conclusion Current studies on the microbiome modulators with ICI use are limited in study design. Future clinical trials should be randomized, use larger sample sizes, and use an appropriate control arm to better ascertain the clinical effect of the GI microbiome on ICI treatment.

Background Dysregulation of Long Non-coding RNAs (lncRNAs) emerges to be a hallmark of cancers. Metastatic prostate cancer and localized disease that recurs after treatment are clinical challenges, it remains unclear how lncRNA plays a role in those processes. Methods From previous RNA-Seq data on 65 prostate cancer and adjacent normal tissues. We identified a novel lncRNA ENST00000503625 down-regulated in prostate cancer and correlated with tumor progression characteristics. Public datasets were examined for associations between ENST00000503625 expression and clinical parameters and prognoses. Subsequently, we constructed and externally validated a nomogram for predicting biochemical recurrence (BCR). Finally, in vitro experiments were carried out to determine how ENST00000503625 functions biologically in prostate cancer. Results Low ENST00000503625 in tumor was associated with poor clinical features and prognoses. TCGA pan-cancer analysis found that ENST00000503625 was deregulated in a variety of tumors and correlated with overall survival, disease-specific survival, and progression-free survival. The nomogram for predicting BCR was constructed using TCGA data, which exhibited excellent accuracy in external validation with Chinese Prostate Cancer Genome and Epigenome Atlas data. Gene Ontology and KEGG pathway analysis found that genes related to ENST00000503625 were enriched in multiple tumor progression related pathways. When ENST00000503625 was knocked down in vitro, the epithelial-mesenchymal transition was induced, by which cancer cells migrated and invaded more readily. Conclusion Our data suggested that ENST00000503625 may serve as a potential prognostic marker or a therapeutic target for prostate cancer metastases.

Purpose The aim of the study was to evaluate the baseline data of women with breast cancer (BC) undergoing treatment in an intercontinental comparison. Methods This study included 99,571 women with BC from Europe (70,834), Asia (18,208), and Latin America (10,529) enrolled between 2017 and 2021, based on data from IQVIA’s Oncology Dynamics database. This source is supplied with information by means of a cross-sectional partially retrospective survey collecting anonymized data on inpatients and outpatients treated by a representative panel of oncologists. A multivariable logistic regression model was used to investigate the probability of metastases. Results The data available in Asia (98%) and Latin America (100%) were hospital data, while in Europe, patients were treated both in hospitals and in office-based practices (62%, 38%). The mean age in Asia and Latin America (57 ± 13) was lower than in Europe (61 ± 13; p < 0.001). Lobular BC was diagnosed twice as often in Europe compared to Asia and Latin America (15.2%, 9.8%, 8.0%). The number of patients with metastasized hormone receptor-positive (HR +) BC was significantly higher in Europe and Latin America than in Asia (76%, 68%; p < 0.001). The highest number of women with metastasized BC was reported in Europe (26% compared to 14% and 20%, respectively, in Asia and Latin America). Across the continents, the percentage of women with BC who experienced metastases was 51–61% for bone, 30–39% for lung and 25–32% for liver, followed by 3–6% for skin and 3% for brain. Conclusion Women with BC treated in Europe tend to be significantly older and more likely to develop metastases than women in Asia and Latin America, except for lung metastases.

Purpose The aim of this study was to estimate the Italian burden of incident breast cancer (BC) by subtypes, according to the distribution of hormonal receptor (HR) status and expression of human epidermal growth factor 2 (HER2). Methods Female breast cancers incidence in the Romagna Unit of the Emilia-Romagna registry (n. 10,711) were grouped into: HR+ /HER2–, HR+ /HER2+ , HR–/HER2+ , HR–/HER2– and missing, and by age: < 50, 50–69 and 70+ years. Data were compared with other published Italian population-bases series before using them for national estimates. We used national and regional numbers of expected breast cancers published by the Italian network of cancer registries considering the age- and geographic-specific variation of the Italian population. Results Overall, 70.7% of incident BC cases are expected to be HR+ /HER2-, 8.5% HR+ /HER2+ , 7.5% HR-/HER2-, 4.1% HR-/HER2+ and 9.3% missing. The global ranking is similar across age-groups but with age-specific differences. The proportion of missing was around 3-times lower than in the other Italian published population-based series and similar to the SEER one. In Italy, are estimated 38,841 HR+ /HER2- breast cancer cases, 4665 HR+ /HER2+ , 4098 HR-/HER2-, 2281 HR-/HER2+ , and 5092 not specified. Numbers by age-group were provided. Conclusions The present estimates relied on high-quality population-based data and provide a clinically relevant information on the burden of breast cancer subtypes. These data will support the planning of therapy needs for oncologists, decision-makers, and all other stakeholders.

Background Artificial intelligence (AI) is influencing our society on many levels and has broad implications for the future practice of hematology and oncology. However, for many medical professionals and researchers, it often remains unclear what AI can and cannot do, and what are promising areas for a sensible application of AI in hematology and oncology. Finally, the limits and perils of using AI in oncology are not obvious to many healthcare professionals. Methods In this article, we provide an expert-based consensus statement by the joint Working Group on “Artificial Intelligence in Hematology and Oncology” by the German Society of Hematology and Oncology (DGHO), the German Association for Medical Informatics, Biometry and Epidemiology (GMDS), and the Special Interest Group Digital Health of the German Informatics Society (GI). We provide a conceptual framework for AI in hematology and oncology. Results First, we propose a technological definition, which we deliberately set in a narrow frame to mainly include the technical developments of the last ten years. Second, we present a taxonomy of clinically relevant AI systems, structured according to the type of clinical data they are used to analyze. Third, we show an overview of potential applications, including clinical, research, and educational environments with a focus on hematology and oncology. Conclusion Thus, this article provides a point of reference for hematologists and oncologists, and at the same time sets forth a framework for the further development and clinical deployment of AI in hematology and oncology in the future.

Artificial intelligence (AI) has been available in rudimentary forms for many decades. Early AI programs were successful in niche areas such as chess or handwriting recognition. However, AI methods had little practical impact on the practice of medicine until recently. Beginning around 2012, AI has emerged as an increasingly important tool in healthcare, and AI-based devices are now approved for clinical use. These devices are capable of processing image data, making diagnoses, and predicting biomarkers for solid tumors, among other applications. Despite this progress, the development of AI in medicine is still in its early stages, and there have been exponential technical advancements since 2022, with some AI programs now demonstrating human-level understanding of image and text data. In the past, technical advances have led to new medical applications with a delay of a few years. Therefore, now we might be at the beginning of a new era in which AI will become even more important in clinical practice. It is essential that this transformation is humane and evidence based, and physicians must take a leading role in ensuring this, particularly in hematology and oncology.

Objectives: Cag A+ Helicobacter pylori chronic infection cause malignant transformation of the human gastric mucosa. N6-methyladenosine (m6A) modifications are the most common and abundant mRNA modifications and one of the pathways affecting tumorigenicity and tumor progression. However, the role of m6A modification in the process of chronic H. pylori infection leading to malignant transformation of gastric mucosa is unclear. Methods: In this study, we used Cag A- and Cag A+H. pylori chronic infection to establish cellular models in GES-1 cells and analyzed the cellular morphology, proliferation, apoptosis, invasiveness and tumorigenicity of gastric mucosal epithelial cells. The m6A expression levels of GES-1 cells after chronic infection with Cag A- and Cag A+H. pylori were examined, and modifying effect of FTO (the fat mass and obesity-associated protein) on CD44 was verified by MeRIP-qPCR. Finally, the FTO expression changes and m6A expression levels were further validated in clinical gastric cancer tissues. Results: Chronic Cag A+H. pylori-infected GES-1 cells exhibit altered cell morphology, apoptosis inhibition, abnormal proliferation, enhanced migration, colony formation, and increased stem cell-like properties. Meanwhile, FTO and CD44 expression was enhanced, and FTO may induce malignant transformation of gastric mucosa by regulating CD44 mRNA m6A methylation modifications. Conclusions: We verified the effect of chronic stimulation of Cag A+H. pylori on malignant transformation of gastric mucosal epithelium. revealing the possibility of FTO in promoting malignant transformation of gastric mucosa by modifying CD44 mRNA methylation, suggesting that FTO expression is a potential molecule for malignant transformation of gastric mucosal epithelial cells.

Objectives The study aimed to analyze the poor prognosis of microcalcification in breast cancer (BC), including the pathological complete response (pCR) to neoadjuvant chemotherapy (NACT) and the risk of bone metastases. Materials and methods 313 breast cancer patients received NACT to evaluate pCR and 1182 patients from a multicenter database to assess bone metastases were retrospectively included. Two groups were divided according to the presence or absence of mammography microcalcification. Clinical data, image characteristics, neoadjuvant treatment response, bone involvement, and follow-up information were recorded. The pCR and bone metastases were compared between subgroups using the Mann–Whitney and χ² tests and logistic regression, respectively. Results Mammographic microcalcification was associated with a lower pCR than uncalcified BC in the NACT cohort (20.6% vs 31.6%, P = 0.029). Univariate and multivariate analysis suggested that calcification was a risk factor for poor NACT response [OR = 1.780, 95%CI (1.065–2.974), P = 0.028], [OR = 2.352, 95%CI (1.186–4.667), P = 0.014]. Microcalcification was more likely to be necrosis on MRI than those without microcalcification (53.0% vs 31.7%, P < 0.001), multivariate analysis indicated that tumor necrosis was also a risk factor for poor NACT response [OR = 2.325, 95%CI (1.100–4.911), P = 0.027]. Age, menopausal status, breast density, mass, molecular, and pathology type were not significantly associated with non-pCR risk assessment. In a multicenter cohort of 1182 patients with pathologically confirmed BC, those with microcalcifications had a higher proportion of bone metastases compared to non-calcified BC (11.6% vs 4.9%, P < 0.001). Univariate and multivariate analysis showed that microcalcification was an independent risk factor for bone metastasis [OR = 2.550, 95%CI (1.620–4.012), P < 0.001], [OR = 2.268(1.263–4.071), P = 0.006)]. Osteolytic bone metastases predominated but there was no statistical difference between the two groups (78.9% vs 60.7%, P = 0.099). Calcified BC was mainly involved in axial bone, but was more likely to involve the whole-body bone than non-calcified BC (33.8% vs 10.7%, P = 0.021). Conclusion This study provides important insights into the poor prognosis of microcalcification, not only in terms of poor response to NACT but also the risk factor of bone metastases.

Introduction: Gynecological cancers account for a large number of cancer-related deaths in women. Endometrial cancer is the most prevalent, while ovarian cancer is the deadliest gynecological cancer worldwide. To overcome the clinical need for easy and rapid testing, there is a growing interest in cancer detection in non-invasive modalities. With a growing field of liquid biopsy, urine became interesting source of cancer biomarkers. Objectives: The aim of this manuscript is to provide an overview on the origin, analysis and the clinical significance of urine microRNAs in gynecological cancers, with a focus on ovarian and endometrial cancer. MicroRNAs, a class of small non-coding nucleic acids, are emerging as a non-invasive biomarkers due to the feasibility and the extreme stability in body fluids. Specific miRNA expression signatures have been previously identified in ovarian and endometrial cancer. Results: The aim of this manuscript is to provide an overview on the origin, analysis and the clinical significance of urine microRNAs in gynecological cancers, with the focus on ovarian and endometrial cancer. CONCLUSION: The advantages and limitations of urine microRNA utility and technologies are discussed. Previously detected microRNA from urine of the patients are summarized to evaluate their potential as non-invasive clinical biomarkers in gynecological oncology.

Background There are limited studies on the association between angiogenesis-related genes (ARGs) and the predictive risk of melanoma, even though angiogenic factors, which are essential for tumor growth and metastasis, might be secreted by angiogenesis-related protein in skin cutaneous melanoma (SKCM). To forecast patient outcomes, this study attempts to develop a predictive risk signature linked to angiogenesis in cutaneous melanoma. Methods In 650 patients with SKCM, the expression and mutation of ARGs were examined, and this information was related to the clinical prognosis. SKCM patients were split into two groups based on how well they performed on the ARG. The link between ARGs, risk genes, and immunological microenvironment was examined using a range of algorithmic analysis techniques. Based on these five risk genes, an angiogenesis risk signature was created. We developed a nomogram and examined the sensitivity of antineoplastic medications to help the proposed risk model's clinical applicability. Results The risk model developed by ARGs revealed that the prognosis for the two groups was significantly different. The predictive risk score was negatively connected with memory B cells, activated memory CD4 + T cells, M1 macrophages, and CD8 + T cells, and favorably correlated with dendritic cells, mast cells, and neutrophils. Conclusions Our findings offer fresh perspectives on prognostic evaluation and imply that ARG modulation is implicated in SKCM. Potential medications for the treatment of individuals with various SKCM subtypes were predicted by drug sensitivity analysis.

Adipocytes are crucial components of breast cancer and are involved in regulating the progression, therapeutic efficacy, and prognosis of breast cancer patients. Characterized by storing energy and producing a variety of secretory factors, adipocytes are responsible for inducing obesity and regulating the tumor immune activity. Adipocytes communicate with tumor infiltrating immune cells through the secreted adipokines, cytokines, and exosomes in the breast cancer TIME, which shapes the tumor supporting environment to facilitate the immune escape of tumor cells. In-depth studies of the crosstalk between adipocytes and TIME can not only provide a more comprehensive regulatory landscape of TIME, but also be conducive to screening novel targets for future precision targeted therapy. The aim of this review is to discuss recent studies for understanding the role of crosstalk between adipocytes and immune cells in shaping the breast cancer immune microenvironment.

Background Poor pulmonary function and chronic obstructive pulmonary disease (COPD) are associated with poorer overall survival (OS) in non-small-cell lung cancer (NSCLC) patients. Few studies have investigated the association between pulmonary function and OS in small-cell lung cancer (SCLC) patients. We compared the clinical characteristics of extensive disease SCLC (ED-SCLC) with or without moderately impaired diffusion capacity for carbon monoxide (DLco) and investigated the factors associated with survival in ED-SCLC patients. Methods This retrospective single-center study was performed between January 2011 and December 2020. Of the 307 SCLC patients who received cancer therapy during the study, 142 with ED-SCLC were analyzed. The patients were divided into DLco < 60% group and DLco ≥ 60% groups. OS and predictors of poor OS were analyzed. Results The median OS of the 142 ED-SCLC patients was 9.3 months and the median age was 68 years. In total, 129 (90.8%) patients had a history of smoking, and 60 (42.3%) had COPD. Thirty-five (24.6%) patients were assigned to the DLco < 60% group. Multivariate analysis revealed that DLco < 60% (odds ratio [OR], 1.609; 95% confidence interval [CI], 1.062–2.437; P = 0.025), number of metastases (OR, 1.488; 95% CI, 1.262–1.756; P < 0.001), and < 4 cycles of first-line chemotherapy (OR, 3.793; 95% CI, 2.530–5.686; P < 0.001) were associated with poor OS. Forty (28.2%) patients received < 4 cycles of first-line chemotherapy; the most common reason for this was death (n = 22, 55%) from grade 4 febrile neutropenia (n = 15), infection (n = 5), or massive hemoptysis (n = 2). The DLco < 60% group had a shorter median OS than the DLco ≥ 60% group (10.6 ± 0.8 vs. 4.9 ± 0.9 months, P = 0.003). Conclusions In this study, approximately one quarter of the ED-SCLC patients had DLco < 60%. Low DLco (but not forced expiratory volume in 1 s or forced vital capacity), a large number of metastases, and < 4 cycles of first-line chemotherapy were independent risk factors for poor survival outcomes in patients with ED-SCLC.

Purpose We aim to explore the predictive value of neuroendocrine differentiation (NED) in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving abiraterone or docetaxel as first-line therapy. Methods We retrospectively analyzed data of 262 mCRPC patients receiving abiraterone or docetaxel as first-line mCRPC treatment. NED was evaluated using prostate biopsy samples at the time of mCRPC by immunohistochemical staining. Kaplan–Meier curves and Cox regression were used to assess the association between NED and treatment outcomes including PSA progression-free survival (PSA-PFS), radiographic progression-free survival (rPFS), and overall survival (OS). Results NED was confirmed in 100/262 (38.2%) mCRPC patients, with 76/100 (76.0%) and 24/100 (24.0%) men harboring NED < 10% and NED ≥ 10%, respectively. 203/262 (77.5%) and 59/262 (22.5%) patients received abiraterone and docetaxel, respectively. In abiraterone treatment, NED was associated with a significantly shorter median PSA-PFS (mPSA-PFS, 7.5 vs. 10.3-Mo, P < 0.001), median rPFS (mrPFS, 15.9 vs. 19.5-Mo, P = 0.010), and median OS (mOS, 23.2 vs. 34.3-Mo, P = 0.014)). Likewise, for mCRPC patients receiving docetaxel, the positive detection of NED also predicted shorter mPSA-PFS (3.8 vs. 5.9-Mo, P = 0.052), mrPFS (8.4 vs. 20.4-Mo, P = 0.016) and mOS (13.6 vs. 29.0-Mo, P = 0.033). The adverse prognostic trait of NED is consistent in most subgroups. Additionally, patients’ survival outcomes deteriorated as the NED proportion grew in both therapies. After propensity score matching, NED-positive patients showed comparable prognosis in abiraterone and docetaxel therapy. Conclusion For mCRPC patients receiving abiraterone or docetaxel, NED and its proportion were critical predictive factors. NED detection at mCRPC might aid in predicting patients’ outcomes and optimizing treatment decisions.

Purpose This study aims to evaluate the value of tissue inhibitors of MMPs-2 (TIMP-2) to indicate 5-Fluorouracil (5-Fu) resistance status in colorectal cancer. Methods The 5-Fu resistance of colorectal cancer cell lines was detected using Cell-Counting Kit-8 (CCK-8) and calculated using IC50. Enzyme-linked immunosorbent assay (ELISA) and real time-quantitative polymerase chain reaction (RT-qPCR) were used to detect TIMP-2 expression level in the culture supernatant and serum. Twenty-two colorectal cancer patients' TIMP-2 levels and clinical characteristics were analyzed before and after chemotherapy. Additionally, the patient-derived xenograft (PDX) model of 5-Fu resistance was used to evaluate the feasibility of TIMP-2 as a predictive biomarker of 5-Fu resistance. Results Our experimental results display that TIMP-2 expression is elevated in colorectal cancer drug-resistant cell lines, and its expression level is closely related to 5-Fu resistance. Moreover, TIMP-2 in colorectal cancer patient serum undergoing 5-Fu-based chemotherapy could indicate their drug resistance status, and its efficacy is higher than CEA and CA19-9. Finally, PDX model animal experiments reveal that TIMP-2 can detect 5-Fu resistance in colorectal cancer earlier than tumor volume. Conclusion TIMP-2 is a good indicator of 5-Fu resistance in colorectal cancer. Monitoring the serum TIMP-2 level can help the clinician identify 5-Fu resistance in colorectal cancer patients earlier during chemotherapy.

Purpose Cisplatin is the core chemotherapeutic drug used for first-line treatment of advanced non-small cell lung cancer (NSCLC). However, drug resistance is severely hindering its clinical efficacy. This study investigated the circumvention of cisplatin resistance by repurposing non-oncology drugs with putative histone deacetylase (HDAC) inhibitory effect. Methods A few clinically approved drugs were identified by a computational drug repurposing tool called “DRUGSURV” and evaluated for HDAC inhibition. Triamterene, originally indicated as a diuretic, was chosen for further investigation in pairs of parental and cisplatin-resistant NSCLC cell lines. Sulforhodamine B assay was used to evaluate cell proliferation. Western blot analysis was performed to examine histone acetylation. Flow cytometry was used to examine apoptosis and cell cycle effects. Chromatin immunoprecipitation was conducted to investigate the interaction of transcription factors to the promoter of genes regulating cisplatin uptake and cell cycle progression. The circumvention of cisplatin resistance by triamterene was further verified in a patient-derived tumor xenograft (PDX) from a cisplatin-refractory NSCLC patient. Results Triamterene was found to inhibit HDACs. It was shown to enhance cellular cisplatin accumulation and potentiate cisplatin-induced cell cycle arrest, DNA damage, and apoptosis. Mechanistically, triamterene was found to induce histone acetylation in chromatin, thereby reducing the association of HDAC1 but promoting the interaction of Sp1 with the gene promoter of hCTR1 and p21. Triamterene was further shown to potentiate the anti-cancer effect of cisplatin in cisplatin-resistant PDX in vivo. Conclusion The findings advocate further clinical evaluation of the repurposing use of triamterene to overcome cisplatin resistance.

CXC chemokine receptor type 4 (CXCR4) is a member of the G protein-coupled receptors (GPCRs) superfamily and is specific for CXC chemokine ligand 12 (CXCL12, also known as SDF-1), which makes CXCL12/CXCR4 axis. CXCR4 interacts with its ligand, triggering downstream signaling pathways that influence cell proliferation chemotaxis, migration, and gene expression. The interaction also regulates physiological processes, including hematopoiesis, organogenesis, and tissue repair. Multiple evidence revealed that CXCL12/CXCR4 axis is implicated in several pathways involved in carcinogenesis and plays a key role in tumor growth, survival, angiogenesis, metastasis, and therapeutic resistance. Several CXCR4-targeting compounds have been discovered and used for preclinical and clinical cancer therapy, most of which have shown promising anti-tumor activity. In this review, we summarized the physiological signaling of the CXCL12/CXCR4 axis and described the role of this axis in tumor progression, and focused on the potential therapeutic options and strategies to block CXCR4.

Background The bridging integrator 1 (BIN1) protein was originally identified as a pro-apoptotic tumor suppressor that binds to and inhibits oncogenic MYC transcription factors. BIN1 has complex physiological functions participating in endocytosis, membrane cycling, cytoskeletal regulation, DNA repair deficiency, cell-cycle arrest, and apoptosis. The expression of BIN1 is closely related to the development of various diseases such as cancer, Alzheimer's disease, myopathy, heart failure, and inflammation.PurposeBecause BIN1 is commonly expressed in terminally differentiated normal tissues and is usually undetectable in refractory or metastatic cancer tissues, this differential expression has led us to focus on human cancers associated with BIN1. In this review, we discuss the potential pathological mechanisms of BIN1 during cancer development and its feasibility as a prognostic marker and therapeutic target for related diseases based on recent findings on its molecular, cellular, and physiological roles.ConclusionBIN1 is a tumor suppressor that regulates cancer development through a series of signals in tumor progression and microenvironment. It also makes BIN1 a feasible early diagnostic or prognostic marker for cancer.

Purpose: It was reported that individual heterogeneity among malignancies (IHAM) might correlate well to the prognosis of lung cancer; however, seldom radiomic study is on this field. Standard deviation (SD) in statistics could scale average amount of variability of a variable; therefore, we used SD of CT feature (FeatureSD) among primary tumor and malignant lymph nodes (LNs) in an individual to represent IHAM, and its prognostic ability was explored. Methods: The enrolled patients who had accepted PET/CT scans were selected from our previous study (ClinicalTrials.gov, NCT03648151). The patients had primary tumor and at least one LN, and standardized uptake value of LN higher than 2.0 and 2.5 were enrolled as the cohort 1 (n = 94) and 2 (n = 88), respectively. FeatureSD from the combined or thin-section CT were calculated among primary tumor and malignant LNs in each patient, and were separately selected by the survival XGBoost method. Finally, their prognostic ability was compared to the significant patient characteristics identified by the Cox regression. Results: In the univariate and multi-variate Cox analysis, surgery, target therapy, and TNM stage were significantly against OS in the both cohorts. In the survival XGBoost analysis of the thin-section CT dataset, none FeatureSD could be repeatably ranked on the top list of the both cohorts. For the combined CT dataset, only one FeatureSD ranked in the top three of both cohorts, but the three significant factors in the Cox regression were not even on the list. Both in the cohort 1 and 2, C-index of the model composed of the three factors could be improved by integrating the continuous FeatureSD; furthermore, that of each factor was obviously lower than FeatureSD. Conclusion: Standard deviation of CT features among malignant foci within an individual was a powerful prognostic factor in vivo for lung cancer patients.

Introduction: NR2F6 (nuclear receptor subfamily 2 group F member 6, also called Ear-2) is known to be an orphan nuclear receptor that has been characterized as an intracellular immune checkpoint in effector T cells and, therefore, may control tumor development and growth. The prognostic impact of NR2F6 in endometrial cancers is evaluated in this study. Materials and methods: Expression analysis of NR2F6 in 142 endometrial cancer patients was performed by immunohistochemistry of primary paraffin‑embedded tumor samples. Staining intensity of positive tumor cells was automatically assessed semi-quantitatively, and results were correlated with clinicopathological characteristics and survival. Results: Forty five of 116 evaluable samples (38.8%) showed an overexpression of NR2F6. This leads to an improvement of the overall survival (OS) and progression-free survival (PFS). In NR2F6-positive patients, the estimated mean OS was 156.9 months (95% confidence interval (CI) 143.1-170.7) compared to 106.2 months in NR2F6-negative patients (95% CI 86.2-126.3; p = 0.022). The estimated PFS differed by 63 months (152 months (95% CI 135.7-168.4) vs. 88.3 months (95% CI 68.5-108.0), p = 0.002). Furthermore, we found significant associations between NR2F6 positivity, MMR status, and PD1 status. A multivariate analysis suggests NR2F6 to be an independent factor influencing the OS (p = 0.03). Conclusion: In this study, we could demonstrate that there is a longer progression-free and overall survival for NR2F6-positive patients with endometrial cancer. We conclude that NR2F6 might play an essential role in endometrial cancers. Further studies are required to validate its prognostic impact.

Purpose: The WHO 2016 re-classification of myeloproliferative neoplasms resulted in a separation of essential thrombocythemia (ET) from the pre-fibrotic and fibrotic (overt) phases of primary myelofibrosis (MF). This study reports on a chart review conducted to evaluate the real life approach regarding clinical characteristics, diagnostic assessment, risk stratification and treatment decisions for MPN patients classified as ET or MF after implementation of the WHO 2016 classification. Methods: In this retrospective chart review, 31 office-based hematologists/oncologists and primary care centers in Germany participated between April 2021 and May 2022. Physicians reported available data obtained from patient charts via paper-pencil based survey (secondary use of data). Patient features were evaluated using descriptive analysis, also including diagnostic assessment, therapeutic strategies and risk stratification. Results: Data of 960 MPN patients diagnosed with essential thrombocythemia (ET) (n = 495) or myelofibrosis (MF) (n = 465) after implementation of the revised 2016 WHO classification of myeloid neoplasms was collected from the patient charts. While they met at least one minor WHO-criteria for primary myelofibrosis, 39.8% of those diagnosed with ET did not have histological BM testing at diagnosis. 63.4% of patients who were classified as having MF, however, did not obtain an early prognostic risk assessment. More than 50% of MF patients showed characteristics consistent with the pre-fibrotic phase, which was emphasized by the frequent use of cytoreductive therapy. Hydroxyurea was the most frequently used cytoreductive medication in 84.7% of ET and 53.1% of MF patients. While both ET and MF cohorts showed cardiovascular risk factors in more than 2/3 of the cases, the use of platelet inhibitors or anticoagulants varied between 56.8% in ET and 38.1% in MF patients. Conclusions: Improved histopathologic diagnostics, dynamic risk stratification including genetic risk factors for cases of suspected ET and MF are recommended for precise risk assessment and therapeutic stratification according to WHO criteria.

Purpose: To investigate the value of 18F-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) in the differential diagnosis of lymphoma in patients with fever of unknown origin (FUO) accompanied by lymphadenopathy and to develop a simple scoring system to distinguish lymphoma from other etiologies. Methods: A prospective study was conducted on patients with classic FUO accompanied by lymphadenopathy. After standard diagnostic procedures, including PET/CT scan and lymph-node biopsy, 163 patients were enrolled and divided into lymphoma and benign groups according to the etiology. The diagnostic utility of PET/CT imaging was evaluated, and beneficial parameters that could improve diagnostic effectiveness were identified. Results: The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of PET/CT in diagnosing lymphoma in patients with FUO accompanied by lymphadenopathy were 81.0, 47.6, 59.3, and 72.7%, respectively. The lymphoma prediction model combining high SUVmax of the "hottest" lesion, high SUVmax of the retroperitoneal lymph nodes, old age, low platelet count, and low ESR had an area under the curve of 0.93 (0.89-0.97), a sensitivity of 84.8%, a specificity of 92.9%, a PPV of 91.8%, and an NPV of 86.7%. There was a lower probability of lymphoma for patients with a score < 4 points. Conclusions: PET/CT scans show moderate sensitivity and low specificity in diagnosing lymphoma in patients with FUO accompanied by lymphadenopathy. The scoring system based on PET/CT and clinical parameters performs well in differentiating lymphoma and benign causes and can be used as a reliable noninvasive tool. Registration number: This study on FUO was registered on http://www. Clinicaltrials: gov on January 14, 2014, with registration number NCT02035670.

Purpose: Exosomes are membrane-derived nano-vesicles upregulated in pathological conditions like cancer. Therefore, inhibiting their release is a potential strategy for the development of more efficient combination therapies. Neutral sphingomyelinase 2 (nSMase2) is a key component in exosome release; however, a clinically safe yet efficient nSMase2 inhibitor remains to be used discovered. Accordingly, we made an effort to identify potential nSMase2 inhibitor(s) among the approved drugs. Methods: Virtual screening was performed and aprepitant was selected for further investigation. To evaluate the reliability of the complex, molecular dynamics were performed. Finally, using the CCK-8 assay in HCT116 cells, the highest non-toxic concentrations of aprepitant were identified and the nSMase2 activity assay was performed to measure the inhibitory activity of aprepitant, in vitro. Results: To validate the screening results, molecular docking was performed, and the retrieved scores were in line with the screening results. The root-mean-square deviation (RMSD) plot of aprepitant-nSMase2 showed proper convergence. Following treatment with different concentrations of aprepitant in both cell-free and cell-dependent assays, nSMase2 activity was remarkably decreased. Conclusion: Aprepitant, at a concentration as low as 15 µM, was able to inhibit nSmase2 activity in HCT116 cells without any significant effects on their viability. Aprepitant is therefore suggested to be a potentially safe exosome release inhibitor.

Purpose: Plasmalemma vesicle-associated protein (PLVAP) is involved in many immune‑related signals; however, its role in stomach adenocarcinoma (STAD) remains to be elucidated. This study investigated PLVAP expression in tumor tissues and defined the value in STAD patients. Methods: A total of 96 patient paraffin-embedded STAD specimens and 30 paraffin-embedded adjacent non-tumor specimens from the Ninth Hospital of Xi'an were consecutively recruited in analyses. All RNA‑sequence data were available from the Cancer Genome Atlas database (TCGA). PLVAP protein expression was detected using immunohistochemistry. Microbial community analysis was performed by 16S rRNA gene sequencing using Illumina MiSeq. PLVAP mRNA expression was explored with the Tumor Immune Estimation Resource (TIMER), GEPIA, and UALCAN databases. The effect of PLVAP mRNA on prognosis was analyzed via GEPIA, and Kaplan-Meier plotter database. GeneMANIA and STRING databases were used to predict gene/protein interactions and functions. The relationships between PLVAP mRNA expression and tumor-infiltrated immune cells were analyzed via the TIMER and GEPIA databases. Results: Significantly elevated transcriptional and proteomic PLVAP expressions were found in STAD samples. Increased PLVAP protein and mRNA expression were significantly associated with advanced clinicopathological parameters and correlated with shorter disease-free survival (DFS) and overall survival (OS) in TCGA (P < 0.001). The microbiota in the PLVAP-rich (3+) group was significantly different from that in the PLVAP-poor (1+) group (P < 0.05). The results from TIMER showed that high PLVAP mRNA expression had significant positive correlations with CD4 + T cell (r = 0.42, P < 0.001). Conclusion: PLVAP is a potential biomarker to predict the prognosis of patients with STAD, and the high level of PLVAP protein expression was closely related to bacteria. The relative abundance of Fusobacteriia was positvely associated with the level of PLVAP. In conclusion, positive staining for PLVAP was useful for predicting the poor prognosis of STAD with Fusobacteriia infection.

Purpose: To develop and validate a user-friendly model to predict the risk of in-hospital mortality in solid cancer patients admitted to the ICU with sepsis. Methods: Clinical data of critically ill patients with solid cancer and sepsis were obtained from Medical Information Mart for Intensive Care-IV database and randomly assigned to the training cohort and validation cohort. The primary outcome was in-hospital mortality. The least absolute shrinkage and selection operator (LASSO) regression and logistic regression analysis were used to feature selection and model development. The performance of the model was validated and a dynamic nomogram was developed to visualize the model. Results: A total of 1584 patients were included in this study, of whom 1108 were assigned to the training cohort and 476 to the validation cohort. The LASSO regression and logistic multivariable analysis showed that nine clinical features were associated with in-hospital mortality and enrolled in the model. The area under the curve of the model was 0.809 (95% CI 0.782-0.837) in the training cohort and 0.770 (95% CI 0.722-0.819) in the validation cohort. The model exhibited satisfactory calibration curves and Brier scores in the training set and validation set were 0.149 and 0.152, respectively. The decision curve analysis and clinical impact curve of the model presented good clinical practicability in both the two cohorts. Conclusion: This predictive model could be used to assess the in-hospital mortality of solid cancer patients with sepsis in the ICU, and a dynamic online nomogram could facilitate the sharing of the model.

Purpose: Spread through air spaces (STAS) is a crucial invasive mode of lung cancer and has been shown to be associated with early recurrence and metastasis. We aimed to develop a prognostic risk assessment model for stage I lung adenocarcinoma based on STAS and other pathological features and to explore the potential relationship between CXCL-8, Smad2, Snail, and STAS. Methods: 312 patients who underwent surgery at Harbin Medical University Cancer Hospital with pathologically diagnosed stage I lung adenocarcinoma were reviewed in the study. STAS and other pathological features were identified by H&E staining, and a prognostic risk assessment model was established. The expression levels of CXCL8, Smad2, and Snail were determined by immunohistochemistry. Results: The nomogram was established based on age, smoking history, STAS, tumor lymphocyte infiltration, tissue subtype, nuclear grade, and tumor size. The C-index for DFS was (training set 0.84 vs validation set 0.77) and for OS was (training set 0.83 vs validation set 0.78). Decision curve analysis showed that the model constructed has a better net benefit than traditional reporting. The prognostic risk score validated the risk stratification value for stage I lung adenocarcinoma. STAS was an important prognostic factor associated with stronger invasiveness and higher expression of CXCL8, Smad2, and Snail. CXCL8 was associated with poorer DFS and OS. Conclusions: We developed and validated a survival risk assessment model and the prognostic risk score formula for stage I lung adenocarcinoma. Additionally, we found that CXCL8 could be used as a potential biomarker for STAS and poor prognosis, and its mechanism may be related to EMT.

Purpose Polypharmacy is a significant problem in patients with incurable cancer and a method to optimize pharmacotherapy in this patient group is lacking. Therefore, a drug optimization tool was developed and tested in a pilot test. Methods A multidisciplinary team of health professionals developed a “Tool to Optimize Pharmacotherapy in Patients with Incurable Cancer” (TOP-PIC) for patients with a limited life expectancy. The tool consists of five sequential steps to optimize medications, including medication history, screening for medication appropriateness and drug interactions, a benefit–risk assessment using the TOP-PIC Disease-based list, and shared decision-making with the patient. For pilot testing of the tool, 8 patient cases with polypharmacy were analyzed by 11 oncologists before and after training with the TOP-PIC tool. Results TOP-PIC was considered helpful by all oncologists during the pilot test. The median additional time required to administer the tool was 2 min per patient (P < 0.001). For 17.4% of all medications, different decisions were made by using TOP-PIC. Among possible treatment decisions (discontinuation, reduction, increase, replacement, or addition of a drug), discontinuation of medications was the most common. Without TOP-PIC, physicians were uncertain in 9.3% of medication changes, compared with only 4.8% after using TOP-PIC (P = 0.001). The TOP-PIC Disease-based list was considered helpful by 94.5% of oncologists. Conclusions TOP-PIC provides a detailed, disease-based benefit–risk assessment with recommendations specific for cancer patients with limited life expectancy. Based on the results of the pilot study, the tool seems practicable for day-to-day clinical decision-making and provides evidence-based facts to optimize pharmacotherapy.