Adoptive cell therapy (ACT) is one of promising immunotherapies for cancer patients by providing a large amount of cancer antigen-specific effector T cells that can be manufactured rapidly by ex vivo gene engineering. To provide antigen-specificity to patients’ autologous T cells in a short-term culture, T-cell receptors (TCRs) or chimeric antigen receptors (CARs) are transduced to bulk T cells. Because of intra- and inter-tumoral heterogeneity in tumor antigen expression, a repertoire of TCR or CAR genes targeting a wide range of tumor antigens are required for a broad and effective treatment by ACT. Here, we characterized immunogenicity of claudin 6 (CLDN6) in ovarian cancer patients and identified specific TCR genes from CD8⁺ and CD4⁺ T cells. CLDN6 protein was frequently expressed on EpCAM⁺ ovarian cancer cells but not CD45⁺ lymphocytes in tumor ascites of ovarian cancer patients. Spontaneous CLDN6-specific CD4⁺ and CD8⁺ T-cell response was detected in peripheral blood mononuclear cells (PBMCs) from 1 out of 17 ovarian cancer patients. HLA-A*02:01 (A2) and DR*04:04 (DR4)-restricted TCR genes were isolated from CLDN6-specific CD8⁺ and CD4⁺ T cells, respectively. T cells that were engineered with A2-restricted TCR gene recognized and killed A2⁺CLDN6⁺ cancer cells. DR4-restricted TCR-transduced T cells directly recognized DR4⁺CLDN6⁺-overexpressed cancer cells. Our results demonstrate that these CLDN6-specific TCR genes are useful as therapeutic genes for ACT to patients with ovarian and other solid tumors expressing CLDN6.
The oncogenic MUC1-C protein drives dedifferentiation of castrate resistant prostate cancer (CRPC) cells in association with chromatin remodeling. The present work demonstrates that MUC1-C is necessary for expression of IFNGR1 and activation of the type II interferon-gamma (IFN-γ) pathway. We show that MUC1-C→ARID1A/BAF signaling induces IFNGR1 transcription and that MUC1-C-induced activation of the NuRD complex suppresses FBXW7 in stabilizing the IFNGR1 protein. MUC1-C and NuRD were also necessary for expression of the downstream STAT1 and IRF1 transcription factors. We further demonstrate that MUC1-C and PBRM1/PBAF are necessary for IRF1-induced expression of (i) IDO1, WARS and PTGES, which metabolically suppress the immune tumor microenvironment (TME), and (ii) the ISG15 and SERPINB9 inhibitors of T cell function. Of translational relevance, we show that MUC1 associates with expression of IFNGR1, STAT1 and IRF1, as well as the downstream IDO1, WARS, PTGES, ISG15 and SERPINB9 immunosuppressive effectors in CRPC tumors. Analyses of scRNA-seq data further demonstrate that MUC1 correlates with cancer stem cell (CSC) and IFN gene signatures across CRPC cells. Consistent with these results, MUC1 associates with immune cell-depleted "cold" CRPC TMEs. These findings demonstrate that MUC1-C integrates chronic activation of the type II IFN-γ pathway and induction of chromatin remodeling complexes in linking the CSC state with immune evasion.
Menin inhibitors constitute a novel class of agents targeting the underlying biology of nucleophosmin (NPM1) mutant and KMT2A (formerly known as MLL1) rearranged (KMT2Ar) acute leukemias. KMT2Ar acute leukemias constitute 5% to 10% of acute leukemias, and NPM1 mutations are identified in 30% of newly diagnosed acute myeloid leukemias (AMLs). In preclinical AML models, small molecule inhibitors of the menin-KMT2A protein-protein interaction induce differentiation, downregulate critical gene expression programs, and confer a survival advantage in patient-derived xenograft models of NPM1 mutant and KMT2Ar AML. Multiple clinical trials evaluating oral menin inhibitors in acute leukemias are ongoing. Preliminary results in relapsed/refractory NPM1 mutant and KMT2Ar AML have shown on-target effects, tolerable toxicity, and promising clinical activity. This review details the current clinical experience of menin inhibitors in AML and discusses how these agents can be successfully integrated into future therapeutic approaches.
As of September 18th, 2021, global casualties due to COVID-19 infections approach 200 million, several COVID-19 vaccines have been authorized to prevent COVID-19 infection and help mitigate the spread of the virus. Despite the vast majority having safely received vaccination against SARS-COV-2, the rare complications following COVID-19 vaccination have often been life-threatening or fatal. The mechanisms underlying (multi) organ complications are associated with COVID-19, either through direct viral damage or from host immune response (i.e., cytokine storm). The purpose of this manuscript is to review the role of imaging in identifying and elucidating multiorgan complications following SARS-COV-2 vaccination—making clear that, in any case, they represent a minute fraction of those in the general population who have been vaccinated. The authors are both staunch supporters of COVID-19 vaccination and vaccinated themselves as well.
The Great Debate session at the 2021 Melanoma Bridge virtual congress (December 2–4) featured counterpoint views from experts on seven important issues in melanoma. The debates considered the use of adoptive cell therapy versus use of bispecific antibodies, mitogen-activated protein kinase (MAPK) inhibitors versus immunotherapy in the adjuvant setting, whether the use of corticosteroids for the management of side effects have an impact on outcomes, the choice of programmed death (PD)-1 combination therapy with cytotoxic T-lymphocyte-associated antigen (CTLA)-4 or lymphocyte-activation gene (LAG)-3, whether radiation is needed for brain metastases, when lymphadenectomy should be integrated into the treatment plan and then the last debate, telemedicine versus face-to-face. As with previous Bridge congresses, the debates were assigned by meeting Chairs and positions taken by experts during the debates may not have necessarily reflected their respective personal view. Audiences voted both before and after each debate.
Background Aberrant activation of the mammalian Target of Rapamycin (mTOR) pathway has been linked to obesity and endocrine therapy resistance, factors that may contribute to Black-White disparities in breast cancer outcomes. We evaluated associations of race and clinicopathological characteristics with mRNA expression of key mTOR pathway genes in breast tumors. Methods Surgical tumor tissue blocks were collected from 367 newly diagnosed breast cancer patients (190 Black and 177 White). Gene expression of AKT1 , EIF4EBP1 , MTOR , RPS6KB2 , and TSC1 were quantified by NanoString nCounter. Differential gene expression was assessed using linear regression on log2-transformed values. Gene expression and DNA methylation data from TCGA were used for validation and investigation of race-related differences. Results Compared to White women, Black women had relative under-expression of AKT1 (log2 fold-change = − 0.31, 95% CI − 0.44, − 0.18) and RPS6KB2 (log2 fold-change = − 0.11, 95% CI − 0.19, − 0.03). Higher vs. lower tumor grade was associated with relative over-expression of EIF4EBP1 and RPS6KB2 , but with lower expression of TSC1 . Compared to luminal tumors, triple-negative tumors had relative under-expression of TSC1 (log2 fold-change = − 0.42, 95% CI − 0.22, − 0.01). The results were similar in the TCGA breast cancer dataset. Post-hoc analyses identified differential CpG methylation within the AKT1 and RPS6KB2 locus between Black and White women. Conclusions Over-expression of RPS6KB2 and EIF4EBP1 and under-expression of TSC1 might be indicators of more aggressive breast cancer phenotypes. Differential expression of AKT1 and RPS6KB2 by race warrants further investigation to elucidate their roles in racial disparities of treatment resistance and outcomes between Black and White women with breast cancer.
Over the past decade, immunotherapy has become an increasingly fundamental modality in the treatment of cancer. The positive impact of immune checkpoint inhibition, especially anti-programmed death (PD)-1/PD-ligand (L)1 blockade, in patients with different cancers has focused attention on the potential for other immunotherapeutic approaches. These include inhibitors of additional immune checkpoints, adoptive cell transfer (ACT), and therapeutic vaccines. Patients with advanced cancers who previously had limited treatment options available may now benefit from immunotherapies that can offer durable responses and improved survival outcomes. However, despite this, a significant proportion of patients fail to respond to immunotherapy, especially those with less immunoresponsive cancer types, and there remains a need for new treatment strategies. The virtual Immunotherapy Bridge (December 1st–2nd, 2021), organized by the Fondazione Melanoma Onlus, Naples, Italy in collaboration with the Society for Immunotherapy of Cancer addressed several areas of current research in immunotherapy, including lessons learned from cell therapies, drivers of immune response, and trends in immunotherapy across different cancers, and these are summarised here.
Ibrutinib is effective in the treatment of relapsed/refractory (R/R) marginal zone lymphoma (MZL) with an overall response rate (ORR) of 48%. However, factors associated with response (or lack thereof) to ibrutinib in R/R MZL in clinical practice are largely unknown. To answer this question, we performed a multicenter (25 US centers) cohort study and divided the study population into three groups: “ibrutinib responders”—patients who achieved complete or partial response (CR/PR) to ibrutinib; “stable disease (SD)”; and “primary progressors (PP)”—patients with progression of disease as their best response to ibrutinib. One hundred and nineteen patients met the eligibility criteria with 58%/17% ORR/CR, 29% with SD, and 13% with PP. The median PFS and OS were 29 and 71.4 months, respectively, with no difference in PFS or OS based on the ibrutinib line of therapy or type of therapy before ibrutinib. Patients with complex cytogenetics had an inferior PFS (HR = 3.08, 95% CI 1.23–7.67, p = 0.02), while those with both complex cytogenetics (HR = 3.00, 95% CI 1.03–8.68, p = 0.04) and PP (HR = 13.94, 95% CI 5.17–37.62, p < 0.001) had inferior OS. Only primary refractory disease to first-line therapy predicted a higher probability of PP to ibrutinib (RR = 3.77, 95% CI 1.15–12.33, p = 0.03). In this largest study to date evaluating outcomes of R/R MZL treated with ibrutinib, we show that patients with primary refractory disease and those with PP on ibrutinib are very high-risk subsets and need to be prioritized for experimental therapies.
Objectives We sought to define the optimal threshold for anemia in North American head and neck cancer patients and evaluate its role as a prognostic biomarker. Materials and Methods A single-institution database was queried for patients with head and neck cancer who underwent chemoradiation from January 2005 to April 2021. An optimal threshold of hemoglobin (Hgb) level was defined based on maximum log-rank test statistic. Cox multivariable analysis (MVA), Kaplan-Meier, and propensity score matching were performed to evaluate treatment outcomes. Results A total of 496 patients were identified. Threshold for Hgb was determined to be 11.4 for both overall survival (OS) and progression-free survival (PFS). Low Hgb was associated with worse OS (adjusted hazards ratio [aHR] 2.41, 95 % confidence interval [CI] 1.53–3.80, p < 0.001) and PFS (aHR 2.01, 95 % CI 1.30–3.11, p = 0.002). Similar findings were observed among 39 matched pairs for OS (5-year OS 22.3 % vs 49.0 %; HR 2.22, 95 % CI 1.23–4.03, p = 0.008) and PFS (5-year PFS 24.3 % vs 39.1 %; HR 1.78, 95 % CI 1.02–3.12, p = 0.04). Among those with HPV-negative tumors, low Hgb was associated with worse OS (aHR 13.90, 95 % CI 4.66–41.44, p < 0.001) and PFS (aHR 5.24, 95 % CI 2.09–13.18, p < 0.001). However, among those with HPV-positive tumors, low Hgb was not associated with both OS (aHR 1.75, 95 % CI 0.60–5.09, p = 0.31) and PFS (aHR 1.13, 95 % CI 0.41–3.14, p = 0.82). Conclusion and relevance Low Hgb below 11.4 was an independent adverse prognostic factor for worse survival. It was also prognostic among patients with HPV-negative tumors, but not for HPV-positive tumors.
Introduction There is mixed evidence as to whether nicotine vaping products (NVPs) can help adults who smoke transition away from cigarettes. This study investigated if self-reported attempts to quit smoking and smoking cessation, over a period of either 18 or 24 months, differed between respondents who initiated nicotine vaping versus those who did not. Outcome comparisons were made between those who: (1) initiated vaping vs. those who did not; (2) initiated daily or non-daily vaping vs. those who did not; and (3) initiated daily or non-daily vaping between surveys and continued to vape at follow-up (daily or non-daily) vs. those who did not initiate vaping. Methods This cohort study included 3516 respondents from the ITC Four Country Smoking and Vaping Surveys (Australia, Canada, England, United Sates), recruited at Wave 1 (2016) or 2 (2018) and followed up at Wave 2 (18 months) and/or 3 (2020, 24 months). Adults who smoked daily at baseline and did not have a history of regular vaping were included. Initiation of vaping was defined as beginning to vape at least monthly between surveys. Respondents indicated whether they made an attempt to quit smoking between surveys. Smoking cessation was defined as those who self-reported no longer smoking cigarettes at follow-up. Results Relative to those who did not initiate vaping, initiation of any daily vaping between surveys was associated with a greater likelihood of smokers making a cigarette quit attempt (p < 0.001) and quitting smoking (p < 0.001). Among smokers who attempted to quit smoking, initiation of daily vaping was associated with a greater likelihood of being abstinent from smoking at follow-up (p = 0.001). Respondents who initiated vaping between surveys and were vaping daily at follow up were significantly more likely to have attempted to quit smoking (p < 0.001) and to have quit smoking (p < 0.001) than those who did not initiate vaping. Respondents who initiated non-daily vaping did not differ significantly from those who did not initiate vaping on any of the outcome measures. Conclusions Daily NVP use was associated with increased attempts to quit smoking and abstinence from smoking cigarettes. These findings are consistent with the concept that complete cigarette substitution may be more likely to be achieved when smokers vape nicotine daily.
Innate lymphoid cells 2 (ILC2) play a significant role in the tumorigenesis of pancreatic ductal adenocarcinoma (PDAC). An important aspect of ILC2-mediated tumorigenesis is the expansion of the resident ILC2 and simultaneous recruitment of the peripheral ILC2. Here, we describe a protocol for isolation, enrichment, and DiD labeling of ILC2 for in vivo tracking of ILC2s in the mouse. Further, we describe steps for the adoptive transfer of ILC2 to a recipient mouse model of PDAC. For complete details on the use and execution of this protocol, please refer to Alam et al. (2022).
Minichromosome maintenance proteins (Mcm2‐7) form a hexameric complex that unwinds DNA ahead of a replicative fork. The deficiency of Mcm proteins leads to replicative stress and consequent genomic instability. Mice with a germline insertion of a Cre cassette into the 3′UTR of the Mcm2 gene (designated Mcm2Cre) have decreased Mcm2 expression and invariably develop precursor T‐cell lymphoblastic leukemia/lymphoma (pre‐T LBL), due to 100–1000 kb deletions involving important tumor suppressor genes. To determine whether mice that were protected from pre‐T LBL would develop non‐T‐cell malignancies, we used two approaches. Mice engrafted with Mcm2Cre/Cre Lin−Sca‐1+Kit+ hematopoietic stem/progenitor cells did not develop hematologic malignancy; however, these mice died of hematopoietic stem cell failure by 6 months of age. Placing the Mcm2Cre allele onto an athymic nu/nu background completely prevented pre‐T LBL and extended survival of these mice three‐fold (median 296.5 vs. 80.5 days). Ultimately, most Mcm2Cre/Cre;nu/nu mice developed B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL). We identified recurrent deletions of 100–1000 kb that involved genes known or suspected to be involved in BCP‐ALL, including Pax5, Nf1, Ikzf3, and Bcor. Moreover, whole‐exome sequencing identified recurrent mutations of genes known to be involved in BCP‐ALL progression, such as Jak1/Jak3, Ptpn11, and Kras. These findings demonstrate that an Mcm2Cre/Cre hypomorph can induce hematopoietic dysfunction via hematopoietic stem cell failure as well as a “deletor” phenotype affecting known or suspected tumor suppressor genes.
Nuclear power plants are deeply integrated into our society. They possess substantial risk for major disasters. Two of the worst-categorized nuclear power plant disasters were Chernobyl and Fukushima, emitting large amounts of radioactive materials and required mass evacuations in neighboring areas. This is a rapid review of the literature. We searched PUBMED and Medline for original studies of all large nuclear power plant disaster information documented in literature. Eighty-three publications were identified in the review. The results are summarized in categories based on direct health effects such as immediate health effects, indirect health effects related to evacuation, cancer, behavioral effects and environmental effects like proliferation of wildlife and other infectious diseases. Nuclear power plant disasters have a great impact on human health including increased rates of cancer, behavioral and psychosocial problems, and evacuation related problems. These disasters can lead to major environmental impact, specifically on wildlife, resulting in unanticipated health consequences for local populations. In this review, we describe these consequences of nuclear power plant disasters as they apply to local health care workers.
Upon chronic antigen exposure, CD8 ⁺ T cells become exhausted, acquiring a dysfunctional state correlated with the inability to control infection or tumor progression. In contrast, stem-like CD8 ⁺ T progenitors maintain the ability to promote and sustain effective immunity. Adenovirus (Ad)–vectored vaccines encoding tumor neoantigens have been shown to eradicate large tumors when combined with anti–programmed cell death protein 1 (αPD-1) in murine models; however, the mechanisms and translational potential have not yet been elucidated. Here, we show that gorilla Ad vaccine targeting tumor neoepitopes enhances responses to αPD-1 therapy by improving immunogenicity and antitumor efficacy. Single-cell RNA sequencing demonstrated that the combination of Ad vaccine and αPD-1 increased the number of murine polyfunctional neoantigen-specific CD8 ⁺ T cells over αPD-1 monotherapy, with an accumulation of Tcf1 ⁺ stem-like progenitors in draining lymph nodes and effector CD8 ⁺ T cells in tumors. Combined T cell receptor (TCR) sequencing analysis highlighted a broader spectrum of neoantigen-specific CD8 ⁺ T cells upon vaccination compared to αPD-1 monotherapy. The translational relevance of these data is supported by results obtained in the first 12 patients with metastatic deficient mismatch repair (dMMR) tumors vaccinated with an Ad vaccine encoding shared neoantigens. Expansion and diversification of TCRs were observed in post-treatment biopsies of patients with clinical response, as well as an increase in tumor-infiltrating T cells with an effector memory signature. These findings indicate a promising mechanism to overcome resistance to PD-1 blockade by promoting immunogenicity and broadening the spectrum and magnitude of neoantigen-specific T cells infiltrating tumors.
Aims: To examine whether poly-use of cigarettes and other smoked products (poly-smoking) is predictive of quit attempts and quit success. Design: A prospective multi-country cohort design. Setting: Australia, Canada, England and the US. Participants: 3983 adult daily cigarette smokers were surveyed in 2016 (Wave 1 of data collection) and were recontacted in 2018 (Wave 2) (i.e., Wave 1-Wave 2 cohort) in the International Tobacco Control Four Country Smoking and Vaping (ITC 4CV) Surveys; and 3736 smokers were surveyed in 2018 and recontacted in 2020 (Wave 3) (i.e., Wave 2-Wave 3 cohort). Measurements: Participants were asked about their cigarette smoking and use of cigars, cigarillos, pipes, and waterpipes. Outcomes were quit attempts between two survey waves and success, defined as having quit smoking all the combustible tobacco at the subsequent survey for 1 month or more. Findings: Levels of poly-smoking were 12.7% in the Wave 1-Wave 2 cohort and 10.5% for the Wave 2-Wave 3 cohort. Compared with cigarette-only smokers, poly-smokers were more likely to attempt between Waves 1 and 2 (54.9% vs. 42.7%, adjusted odds ratio (aOR)=1.37, 95% confidence interval [CI] 1.08-1.74, p<0.01), but not between Waves 2 and 3 (43.8% vs. 40.1%, aOR=0.94, 95%CI 0.72-1.22). Poly-smoking predicted reduced likelihood of success in both cohorts among attempters and the overall samples. Between Waves 2 and 3 there were significantly more transitions to non-daily smoking among the poly-smokers (12.4% vs. 5.3%, 2 =40.4, p<0.001). Conclusions: There is a consistent association between poly-smoking (use of cigarettes along with other smoked products) and reduced quit success for combustible tobacco, but it is likely due to increased likelihood of transitioning to non-daily use rather than complete cessation.
MDM2 and MDM4 proteins are key negative regulators of tumor suppressor p53. MDM2 and MDM4 interact via their RING domains and form a heterodimer polyubiquitin E3 ligase essential for p53 degradation. MDM4 also forms heterodimer E3 ligases with MDM2 isoforms that lack p53-binding domains, which regulate p53 and MDM4 stability. We are working to identify small-molecule inhibitors targeting the RING domain of MDM2-MDM4 (MMRi) that can inactivate the total oncogenic activity of MDM2-MDM4 heterodimers. Here, we describe the identification and characterization of MMRi62 as an MDM4-degrader and apoptosis inducer in leukemia cells. Biochemically, in our experiments, MMRi62 bound to preformed RING domain heterodimers altered the substrate preference toward MDM4 ubiquitination and promoted MDM2-dependent MDM4 degradation in cells. This MDM4-degrader activity of MMRi62 was found to be associated with potent apoptosis induction in leukemia cells. Interestingly, MMRi62 effectively induced apoptosis in p53 mutant, multidrug-resistant leukemia cells and patient samples in addition to p53 wild-type cells. In contrast, MMRi67 as a RING heterodimer disruptor and an enzymatic inhibitor of the MDM2-MDM4 E3 complex lacked MDM4-degrader activity and failed to induce apoptosis in these cells. In summary, this study identifies MMRi62 as a novel MDM2-MDM4-targeting agent and suggests that small molecules capable of promoting MDM4 degradation may be a viable new approach to killing leukemia cells bearing non-functional p53 by apoptosis.
Breast cancer is more common on the left side than the right side. We aim to evaluate differences in clinicopathological and genomic characteristics based on laterality. We analyzed survival outcomes and clinical characteristics of 881,320 patients recorded by the Surveillance, Epidemiology, and End Results (SEER) program. The Cancer Genome Atlas (TCGA) was used to explore genomic and clinical features from 1,062 patients. Gene expression data was used to quantitate cytolytic activity and hallmark gene-sets were used for gene set enrichment analysis. An institutional retrospective review was conducted on 155 patients treated with neoadjuvant chemotherapy (NACT). Patient characteristics were summarized by pathological complete response (pCR). Left sided tumors were found to be more prevalent than right sided tumors. No major clinicopathological differences were noted by laterality. Left sided breast cancer demonstrated poorer outcomes versus right sided tumors (HR 1.05, 95% CI 1.01–1.08; p = 0.011). Cell proliferation gene sets, including E2F Targets, G2M Checkpoint, Mitotic spindle, and MYC Targets, were enriched on the left side compared to the right. Left sided tumors had lower pCR rates versus right sided tumors (15.4% versus 29.9%, p = 0.036). Our findings suggest that left sided breast cancer is associated with aggressive biology and worse outcomes compared to right sided breast cancer.
Clustering data is a challenging problem in unsupervised learning where there is no gold standard. Results depend on several factors, such as the selection of a clustering method, measures of dissimilarity, parameters, and the determination of the number of reliable groupings. Stability has become a valuable surrogate to performance and robustness that can provide insight to an investigator on the quality of a clustering, and guidance on subsequent cluster prioritization. This work develops a framework for stability measurements that is based on resampling and OB estimation. Bootstrapping methods for cluster stability can be prone to overfitting in a setting that is analogous to poor delineation of test and training sets in supervised learning. Stability that relies on OB items from a resampling overcomes these issues and does not depend on a reference clustering for comparisons. Furthermore, OB stability can provide estimates at the level of the item, cluster, and as an overall summary, which has good interpretive value. This framework is extended to develop stability estimates for determining the number of clusters (model selection) through contrasts between stability estimates on clustered data, and stability estimates of clustered reference data with no signal. These contrasts form stability profiles that can be used to identify the largest differences in stability and do not require a direct threshold on stability values, which tend to be data specific. These approaches can be implemented using the R package bootcluster that is available on the Comprehensive R Archive Network.
Proviral integration of Moloney virus 2 (PIM2) is a pro‑survival factor of cancer cells and a possible therapeutic target in hematological malignancies. However, the attempts at inhibiting PIM2 have yielded underwhelming results in early clinical trials on hematological malignancies. Recently, a novel pan‑PIM inhibitor, JP11646, was developed. The present study examined the utility of targeting PIM2 in multiple solid cancers and investigated the antitumor efficacy and the mechanisms of action of JP11646. When PIM2 expression was compared between normal and cancer tissues in publicly available datasets, PIM2 was found to be overexpressed in several types of solid cancers. PIM2 ectopic overexpression promoted tumor growth in in vivo xenograft breast cancer mouse models. The pan‑PIM inhibitor, JP11646, suppressed in vitro cancer cell proliferation in a concentration‑dependent manner in multiple types of cancers; a similar result was observed with siRNA‑mediated PIM2 knockdown, as well as an increased in cell apoptosis. By contrast, another pan‑PIM inhibitor, AZD1208, suppressed the expression of downstream PIM2 targets, but not PIM2 protein expression, corresponding to no apoptosis induction. As a mechanism of PIM2 protein degradation, it was found that the proteasome inhibitor, bortezomib, reversed the apoptosis induced by JP11646, suggesting that PIM2 degradation by JP11646 is proteasome‑dependent. JP11646 exhibited significant anticancer efficacy with minimal toxicities at the examined doses and schedules in multiple in vivo mice xenograft solid cancer models. On the whole, the present study demonstrates that PIM2 promotes cancer progression in solid tumors. JP11646 induces apoptosis at least partly by PIM2 protein degradation and suppresses cancer cell proliferation in vitro and in vivo. JP11646 may thus be a possible treatment strategy for multiple types of solid cancers.
Importance: Sentinel lymph node (SLN) biopsy is a standard staging procedure for cutaneous melanoma. Regional disease control is a clinically important therapeutic goal of surgical intervention, including nodal surgery. Objective: To determine how frequently SLN biopsy without completion lymph node dissection (CLND) results in long-term regional nodal disease control in patients with SLN metastases. Design, setting, and participants: The second Multicenter Selective Lymphadenectomy Trial (MSLT-II), a prospective multicenter randomized clinical trial, randomized participants with SLN metastases to either CLND or nodal observation. The current analysis examines observation patients with regard to regional nodal recurrence. Trial patients were aged 18 to 75 years with melanoma metastatic to SLN(s). Data were collected from December 2004 to April 2019, and data were analyzed from July 2020 to January 2022. Interventions: Nodal observation with ultrasonography rather than CLND. Main outcomes and measures: In-basin nodal recurrence. Results: Of 823 included patients, 479 (58.2%) were male, and the mean (SD) age was 52.8 (13.8) years. Among 855 observed basins, at 10 years, 80.2% (actuarial; 95% CI, 77-83) of basins were free of nodal recurrence. By univariable analysis, freedom from regional nodal recurrence was associated with age younger than 50 years (hazard ratio [HR], 0.49; 95% CI, 0.34-0.70; P < .001), nonulcerated melanoma (HR, 0.36; 95% CI, 0.36-0.49; P < .001), thinner primary melanoma (less than 1.5 mm; HR, 0.46; 95% CI, 0.27-0.78; P = .004), axillary basin (HR, 0.61; 95% CI, 0.44-0.86; P = .005), fewer positive SLNs (1 vs 3 or more; HR, 0.32; 95% CI, 0.14-0.75; P = .008), and SLN tumor burden (measured by diameter less than 1 mm [HR, 0.39; 95% CI, 0.26-0.60; P = .001] or less than 5% area [HR, 0.36; 95% CI, 0.24-0.54; P < .001]). By multivariable analysis, younger age (HR, 0.57; 95% CI, 0.39-0.84; P = .004), thinner primary melanoma (HR, 0.40; 95% CI, 0.22-0.70; P = .002), axillary basin (HR, 0.55; 95% CI, 0.31-0.96; P = .03), SLN metastasis diameter less than 1 mm (HR, 0.52; 95% CI, 0.33-0.81; P = .007), and area less than 5% (HR, 0.58; 95% CI, 0.38-0.88; P = .01) were associated with basin control. When looking at the identified risk factors of age (50 years or older), ulceration, Breslow thickness greater than 3.5 mm, nonaxillary basin, and tumor burden of maximum diameter of 1 mm or greater and/or metastasis area of 5% or greater and excluding missing value cases, basin disease-free rates at 5 years were 96% (95% CI, 88-100) for patients with 0 risk factors, 89% (95% CI, 82-96) for 1 risk factor, 86% (95% CI, 80-93) for 2 risk factors, 80% (95% CI, 71-89) for 3 risk factors, 61% (95% CI, 48-74) for 4 risk factors, and 54% (95% CI, 36-72) for 5 or 6 risk factors. Conclusions and relevance: This randomized clinical trial was the largest prospective evaluation of long-term regional basin control in patients with melanoma who had nodal observation after removal of a positive SLN. SLN biopsy without CLND cleared disease in the affected nodal basin in most patients, even those with multiple risk factors for in-basin recurrence. In addition to its well-validated value in staging, SLN biopsy may also be regarded as therapeutic in some patients. Trial registration: ClinicalTrials.gov Identifier: NCT00297895.
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