[Show abstract][Hide abstract] ABSTRACT: Background:
Plasma miRNAs have the potential as cancer biomarkers but no consolidated guidelines for data mining in this field are available. The purpose of the study was to apply a supervised data analysis strategy in a context where prior knowledge is available, i.e., that of hemolysis-related miRNAs deregulation, so as to compare our results with existing evidence.
We developed a structured strategy with innovative applications of existing bioinformatics methods for supervised analyses including: 1) the combination of two statistical (t- and Anderson-Darling) test results to detect miRNAs with significant fold change or general distributional differences in class comparison, which could reveal hidden differential biological processes worth to be considered for building predictive tools; 2) a bootstrap selection procedure together with machine learning techniques in class prediction to guarantee the transferability of results and explore the interconnections among the selected miRNAs, which is important for highlighting their inherent biological dependences. The strategy was applied to develop a classifier for discriminating between hemolyzed and not hemolyzed plasma samples, defined according to a recently published hemolysis score. We identified five miRNAs with increased expression in hemolyzed plasma samples (miR-486-5p, miR-92a, miR-451, miR-16, miR-22).
We identified four miRNAs previously reported in the literature as hemolysis related together with a new one (miR-22).which needs further investigations. Our findings confirm the validity of the proposed strategy and, in parallel, the hemolysis score capability to be used as pre-analytic hemolysis detector. R codes for implementing the approaches are provided.
Full-text · Article · Nov 2015 · BMC Bioinformatics
[Show abstract][Hide abstract] ABSTRACT: Background: The potential impact of diagnostic delays on patients' outcomes is a debated issue in pediatric oncology and discordant results have been published so far. We attempted to tackle this issue by analyzing a prospective series of 351 consecutive children and adolescents with solid malignancies using innovative statistical tools. Methods: To address the nonlinear complexity of the association between symptom interval and overall survival (OS), a regression tree algorithm was constructed with sequential binary splitting rules and used to identify homogeneous patient groups vis-à-vis functional relationship between diagnostic delay and OS. Results: Three different groups were identified: group A, with localized disease and good prognosis (5-year OS 85.4%); group B, with locally or regionally advanced, or metastatic disease and intermediate prognosis (5-year OS 72.9%), including neuroblastoma, Wilms tumor, nonrhabdomyosarcoma soft tissue sarcoma, and germ cell tumor and group C, with locally or regionally advanced, or metastatic disease and poor prognosis (5-year OS 45%), including brain tumors, rhabdomyosarcoma, and bone sarcoma. The functional relationship between symptom interval and mortality risk differed between the three subgroups, there being no association in group A (hazard ratio [HR]: 0.96), a positive linear association in group B (HR: 1.48), and a negative linear association in group C (HR: 0.61). Conclusions: Our analysis suggests that at least a subset of patients can benefit from an earlier diagnosis in terms of survival. For others, intrinsic aggressiveness may mask the potential effect of diagnostic delays. Based on these findings, early diagnosis should remain a goal for pediatric cancer patients.
Full-text · Article · Nov 2015 · Pediatric Blood & Cancer
[Show abstract][Hide abstract] ABSTRACT: Background:
Patients with metastatic penile squamous cell carcinoma (SCC) have a poor prognosis and treatment options are needed when chemotherapy treatment fails. We present the final results of panitumumab treatment from our original series.
Patients and methods:
Eligibility included patients with unresectable or metastatic penile SCC, Eastern Cooperative Oncology Group performance status of 0 to 2, and failure of at least 1 chemotherapy regimen. Patients received panitumumab 6.0 mg/kg every 2 weeks until disease progression or unacceptable toxicity. Response was assessed by clinical examination or Response Evaluation Criteria in Solid Tumors version 1.1 criteria every 6 weeks, when applicable. Descriptive statistics were calculated and univariable Cox proportional hazards regression analysis was conducted.
Between October 2010 and July 2013, 11 patients were treated. After a median of 5 panitumumab administrations (range, 1-11), we recorded 1 case of Grade 3 cutaneous toxicity and diarrhea each, and 2 cases of Grade 3 mucositis. One patient discontinued treatment because of skin toxicity. Two patients had a complete remission of skin nodules and of skin and nodal metastases, respectively. One patient had a partial regression of skin metastases, and 2 patients stable disease (clinical benefit: 45.5%). Median progression-free survival was 1.9 months (interquartile range [IQR], 0.9-3.0 months) and median overall survival (OS) was 9.5 months (IQR, 4.9-12.6). The presence of visceral metastases showed a trend for association with worse OS (P = .098).
Panitumumab was active and safe in patients with highly pretreated penile SCC. The design of combination or sequential strategies with chemotherapy and in an earlier disease stage is warranted.
No preview · Article · Sep 2015 · Clinical Genitourinary Cancer
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND AND AIM:
Solid demonstrations of superior efficacy of drug-eluting beads trans-arterial chemoembolization with respect to conventional chemoembolization in hepatocellular carcinoma patients are lacking. Aim of the study was to compare these two techniques in two large cohorts of unresectable hepatocellular carcinoma patients.
A single Center series of 249 early/intermediate hepatocellular carcinoma patients who underwent "on demand" chemoembolization in the period 2007-2011 was analyzed. Overall survival, time to progression, tumor response rate and safety were compared between 104 patients who underwent conventional chemoembolization and 145 who underwent drug-eluting beads chemoembolization. Time-to-event data were analyzed using the Cox univariate and multivariate regression.
The two cohorts resulted balanced for liver function and tumor stages. Objective response rate was 85.3% after conventional and 74.8% after drug-eluting beads chemoembolization (p = 0.039), and median time to progression was 17 [95% confidence interval: 14-21] vs. 11 months (9-12), respectively (p < 0.001). Treatment regimen was the sole independent predictor of progression at multivariate analysis [hazard ratio = 2.01; 1.45-2.80; p < 0.001]. Median survival was 39 (32-47) and 32 (24-39) months in the two groups, respectively (hazard ratio = 1.33; 0.94-1.87; p = 0.10) but conventional chemoembolization was significantly associated with a survival advantage in patients with bilobar neoplasia, portal hypertension and alpha-fetoprotein above normal limits. No significant differences in severe adverse events were found.
In a large series of Western hepatocellular carcinoma patients, drug-eluting beads chemoembolization with 100-300 µm particles did not seem to improve survival in comparison to conventional chemoembolization, which in turn provided better tumor responses and time to progression.
No preview · Article · Sep 2015 · Journal of Gastroenterology and Hepatology
[Show abstract][Hide abstract] ABSTRACT: Background:
In patients with metastatic seminoma, designing a risk-adapted strategy that may help personalize the burden of treatment and follow-up is required.
Patients and methods:
Patients who were administered cisplatin, etoposide, and bleomycin (PEB) were staged at baseline with computed tomography (CT), positron emission tomography (PET), and serum tumor markers. Restaging was then performed with PET after 2 cycles of PEB (PET2) and with CT after 3 to 4 cycles of treatment. The 20% cutoff of maximal standardized uptake value (SUVmax) changes and Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) criteria were applied to define the response. The Wilcoxon rank sum test was used to analyze the association between metabolic response and the shrinkage of target lesions.
Between February 2009 and November 2013, 37 patients were enrolled. After 2 cycles of PEB, 27 patients (72.9%; 95% confidence interval [CI], 55.8-86.2) had a metabolic complete response (CR) and 10 patients had a partial response (PR; 27%; 95% CI, 13.8-44.1). A significant association was found between PET2 response and baseline (P = .003), final diameter (P < .001), and percentage of tumor shrinkage (P = .014) of target lesions. After 18 months' (interquartile range [IQR], 13-23) median follow-up, 2 patients with PET2 PR had relapsed disease; none of those with a CR had relapsed disease.
A significant association was found between early metabolic response and tumor shrinkage in patients with advanced seminoma. Patients achieving a PET2 CR could be predicted not to need additional treatment after PEB, and simplifying their follow-up should be an end point. PET2 might also identify difficult to treat cases at an early stage.
No preview · Article · Sep 2015 · Clinical Genitourinary Cancer
[Show abstract][Hide abstract] ABSTRACT: Transsphenoidal endoscopic surgery has gained popularity in the last 2 decades and is becoming a standard technique for resection of pituitary adenomas. In contrast to their ENT colleagues, neurosurgical residents have practically no endoscopic experience when they reach the training stage for transsphenoidal procedures. We have developed an affordable method for repetitive training in endoscopic (and microscopic) work in a narrow channel, allowing training of the basic movements needed for resection of pituitary adenoma.
In collaboration with colleagues in the ENT Department, Cantonal Hospital St. Gall, and the Technical University of Zurich, a three-dimensional model of the nasal cavity was developed and patented. The Egghead model consists of a 3D synthetic reconstruction of the head nasal cavity and sphenoid sinus. A boiled egg represents the sella. For validation, 17 neurosurgical residents from the Department of Neurosurgery, University Hospital of Basel, and Department of Neurosurgery, Cantonal Hospital of St. Gall, St. Gall, Switzerland, and two experts performed a standardized procedure mimicking a transsphenoidal pituitary procedure by dissecting a corridor to the egg yolk and resecting it, respecting the surrounding egg white. This procedure was performed under both microscopic and video-endoscopic visualization. A score for the precision and speed of the surgical performance was developed and used.
The model allows repetitive training of the resection of the egg yolk under sparing of the egg white after careful opening of the shell. The validation data showed a steeper learning curve using the endoscopic technique than performing the same task using the microscope. After three repetitions, the quality of resection was better with the endoscopic technique.
Our model, the Egghead, is affordable, offers tactile feedback and allows infinite repetitions in basic training for pituitary surgery. It can be used for training of advanced neurosurgical residents, who thus far have very few possibilities of acquiring endoscopic experience.
Full-text · Article · Aug 2015 · Acta Neurochirurgica
[Show abstract][Hide abstract] ABSTRACT: Hope is crucial for patients with cancer. We explored the determinants of hope in patients with cancer using a questionnaire administered over the course of 1 day to an unselected sample of patients at an Italian cancer center.
A team of oncologists, statisticians, and chaplains developed a questionnaire with medical, psychological, spiritual, and religious content. A cross-sectional study was conducted on 320 patients who answered the questionnaire.
In the group of participants, 92.8% had a religious belief. Women, patients with limited formal education, and believers were more hopeful. Patients placed trust in God, their partners and children, scientific research, and doctors. On univariate and multivariate analysis, hope was found sensitive to patients' sharing their experiences with others (including family and friends), their positive perception of the people around them, and their relationship with doctors and nurses.
If validated in further studies, these results support the notion that a patient with cancer's sense of hope is sensitive to the quality of relationships with caregivers. This may be important to health care organization and resource allocation.
[Show abstract][Hide abstract] ABSTRACT: A correlation between osteopontin, E-cadherin, β-catenin, and cyclooxygenase 2 overexpression and poor clinicopathological features and prognosis has been previously suggested in gastric cancer. This translational study was aimed at assessing the correlation of these immunohistochemical biomarkers with outcome in patients with radically resected gastric cancer. We analyzed osteopontin, E-cadherin, β-catenin, and cyclooxygenase 2 expression by immunohistochemistry in 346 primary gastric tumor tissue samples from patients enrolled in the ITACA-S trial. This phase III study randomized patients with radically resected gastric cancer to receive adjuvant chemotherapy with either 5-fluorouracil and leucovorin or a sequential regimen of infusional 5-fluorouracil and leucovorin plus irinotecan followed by cisplatin and docetaxel. High expression of osteopontin was correlated with high histological grade, diffuse histotype, and peritoneal relapse, but not with TNM stage. Moreover, osteopontin overexpression was associated with higher risk of tumor recurrence and metastases, and was an independent prognostic factor for both relapse-free and overall survival of gastric cancer patients following adjuvant chemotherapy. Abnormal E-cadherin expression and abnormal β-catenin expression were correlated with more advanced disease stage, and as a consequence, with poor outcome. Our results suggest that osteopontin overexpression is a valuable independent predictor of tumor recurrence and survival in patients with radically resected gastric cancer.
[Show abstract][Hide abstract] ABSTRACT: The mutation status of KIT or PDGFRA notoriously affects the response of advanced gastrointestinal stromal tumors (GISTs) to tyrosine kinase inhibitors. Conversely, it is currently still unclear whether mutation status impinges on the prognosis of localized, untreated GISTs. Hence, at present, this variable is not included in decision making for adjuvant therapy. A series of 451 primary localized GISTs were analyzed for KIT, PDGFRA, and BRAF mutations. Univariable and multivariable analyses and a backward selection procedure were used to assess the impact of mutation status on overall survival and to identify prognostically homogenous groups. Mutation was a significant prognostic indicator of overall survival in naive, localized GISTs (P<0.001): KIT-mutated patients had a worse outcome than PDGFRA-mutated or triple-negative (KIT, PDGFRA, BRAF wild-type) cases. Multivariable Cox regression models allowed us to identify 3 molecular risk groups: group I exhibited the best outcome and included PDGFRA exon 12, BRAF, and KIT exon 13-mutated cases; group II, of intermediate clinical phenotype (HR=3.06), included triple-negative, KIT exon 17, PDGFRA exon 18 D842V, and PDGFRA exon 14-mutated cases; group III displayed the worst outcome (hazard ratio=4.52), and comprised KIT exon 9 and exon 11 and PDGFRA exon 18 mutations apart from D842V. This study highlights the prognostic impact of mutation status on the natural course of GIST and suggests that the molecular prognostic grouping may complement the conventional clinicopathologic risk stratification criteria in decision making for adjuvant therapy.
No preview · Article · Apr 2015 · The American journal of surgical pathology
[Show abstract][Hide abstract] ABSTRACT: Background
The prognostic impact of early metabolic response by [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) after 2 cycles of first-line chemotherapy is still unrecognized in metastatic transitional cell carcinoma (TCC).
Patients and Methods
Patients with metastatic TCC receiving the modified combination of methotrexate, vinblastine, doxorubucin, and cisplatin (MVAC), according to Institutional protocol, underwent computed tomography (CT) and FDG-PET at baseline, a restaging with PET after 2 cycles only (PET2), and a CT (± FDG-PET) at the end of treatment and during follow up. Progression-free (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method; univariable (UVA) and multivariable (MVA) Cox models were fitted. Pre-specified variables were the presence of visceral metastases, nodal or soft tissue disease, and early PET response.
In the time-frame 05/2010-10/2012, 31 patients with ECOG-PS 0 received the modified MVAC regimen, every 3 weeks. Six patients (19.3%) had a complete (CR) and 17 (54.8%) a partial metabolic response (PR), 4 had stable disease (SD), 4 progressed. PET2 responders had a median (95% confidence interval [CI]) progression-free survival (PFS) of 8 (7-11) months compared to 3 (2-5) months of patients without response (p=0.024). They also had a significant benefit in 8-month PFS (p<0.001 at Klein test) and 15-month overall survival (OS, p=0.016). PET2 response was significant for PFS in both UVA and MVA (p=0.027 and p=0.023, respectively).
PET response after 2 cycles of first-line chemotherapy was associated with longer PFS and OS in advanced TCC and warrants further investigation in the field, compared to early CT.
No preview · Article · Dec 2014 · Clinical Genitourinary Cancer
[Show abstract][Hide abstract] ABSTRACT: Objective
The results achieved through the Enhanced Recovery After Surgery (ERAS) approach in the gastrointestinal surgery has led to its enthusiastic acceptance also in pancreatic surgery. However the ERAS programme also involves an early oral feeding that is not always feasible after pancreatoduodenectomy. We investigated in the literature whether the difficulty with an early oral feeding was adequately balanced by a perioperative enteral or parenteral nutritional support as recommended by the ESPEN Guidelines in these patients or whether these recommendations have lost value in the “bundle” of the ERAS.
We reanalyzed both ESPEN guidelines and literature regarding ERAS programme in surgical pancreatic patients.
There was a high prevalence of malnutrition (and consequently of postoperative complications) in pancreatic cancer patients, and there is evidence that many of these patients should be candidate for a perioperative nutritional support according to the ESPEN guidelines. The start of oral fluid and solid feeding was quite variable in literature reporting the use of ERAS in pancreatic cancer surgery, with consistent gap between the recommended and the effective start of both the feedings. The use of nasogastric/jejunal tube or of a needle-catheter jejunostomy was discouraged by the ERAS guidelines but their use can prove beneficial in patients who are recognized at high risk for postoperative complications according to the scores available in literature.
The current practice of the ERAS programme in these patients appears to neglect some ESPEN recommendations. On the contrary both ESPEN and ERAS recommendations could combine together with a supplemental benefit for the patient.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
To explore patterns of failure and postrelapse outcome of patients with retroperitoneal sarcoma primarily treated by extended resection.
All consecutive patients with primary retroperitoneal sarcoma, treated between January 2002 and December 2011 at two European sarcoma centers were included. Five-year overall survival (OS) and crude cumulative incidence (CCI) of local recurrence (LR) and distant metastases (DM) were calculated. Multivariate analyses for OS and CCI of LR and DM were performed. Postrelapse OS was investigated.
A total of 377 patients were identified. Median follow-up from the time of primary surgery was 44 months [interquartile range (IQR) 27-82]. Five-year OS was 64 % [95 % confidence interval (CI) 0.588, 0710]. CCI of LR and DM were 23.6 % (95 % CI 18.9, 29.4) and 21.9 % (95 % CI 17.6, 27.3), respectively. OS, CCI of LR and DM were 87, 18 % and 0 for well-differentiated liposarcoma; 54, 44 and 9 % for grade II dedifferentiated liposarcoma; 41,33, and 44 % for grade III dedifferentiated liposarcoma; 58, 5, and 55 % for leiomyosarcoma; and 85, 4, and 17 % for solitary fibrous tumor, respectively. Seventy-six patients developed LR. Median postrelapse follow-up was 27 months (IQR 10-58). Twenty-one patients (27 %) underwent a second surgical resection (complete in 18), while 55 (73 %) did not (22 multifocal, 17 inoperable, 16 other causes). Median postrelapse OS was 17 months (IQR 7-31). Well-differentiated liposarcoma histology and disease-free interval predicted postrelapse OS, while surgical resection did not.
When primary extended surgery limits LR, histologic subtype and grade determine the outcome. At recurrence, a second surgery is of limited benefit.
Full-text · Article · Oct 2014 · Annals of Surgical Oncology