Highlights • Probiotics reduced grade 3–4 diarrhea after irinotecan based chemotherapy. • Probiotics reduced all grades of diarrhea and enterocolitis compared to placebo. • Patients on probiotics ...used less antidiarrheal drugs compared to placebo. • Probiotics could reduce gastrointestinal toxicity of irinotecan based therapy.
Testicular germ cell tumors (TGCTs) are nearly universally curable malignancies. Nevertheless, standard cisplatin-based chemotherapy is not curative in a small subgroup of patients. Previously, we ...showed that PD-L1 overexpression is associated with worse prognosis in TGCTs, while tumor infiltrating lymphocytes (TILs) are prognostic in different types of cancer. This study aimed to evaluate the prognostic value of PD-1 and PD-L1 expressing TILs in TGCTs.
PD-L1 positive TILs were found significantly more often in seminomas (95.9% of patients) and embryonal carcinomas (91.0%) compared to yolk sac tumors (60.0%), choriocarcinomas (54.5%) or teratomas (35.7%) (All p < 0.05). TGCTs patients with high infiltration of PD-L1 positive TILs (HS ≥ 160) had significantly better progression-free survival (HR = 0.17, 95% CI 0.09 - 0.31, p = 0.0006) and overall survival (HR = 0.08, 95% CI 0.04 - 0.16, p = 0.001) opposite to patients with lower expression of PD-L1 (HS < 150). PD-1 expressing TILs were not prognostic in TGCTs.
Surgical specimens from 240 patients with primary TGCTs were included into this translational study. The PD-1 and PD-L1 expression on tumor and TILs were detected by immunohistochemistry using anti-PD-1 and anti-PD-L1 monoclonal antibody. Scoring was performed semiquantitatively by weighted histoscore (HS) method.
The prognostic value of PD-L1 expressing TILs in TGCTs was demonstrated for the first time.
WNT/βcatenin (WNTβ) pathway is activated in early stages of embryonic development. We aimed to evaluate the significance of βcatenin in germ cell tumors (GCTs) and explore associations with the ...inflamed environment.
Surgical specimens from 247 patients were analyzed. Βcatenin expression was detected in the tumor tissue by immunohistochemistry and correlated with clinical characteristics, outcome, PD-L1 expression and systemic immune-inflammation index (SII). The Ingenuity Pathway Analysis (IPA) was used to investigate the immune-cell related effects of βcatenin and PD-L1 encoding genes.
βcatenin was expressed in 86.2% of GCTs. The expression in seminomas was significantly lower compared to all subtypes of non-seminoma (all P < 0.0001). A high expression (weighted histoscore > 150) was associated with primary mediastinal non-seminoma (P = 0.035), intermediate/poor risk disease (P = 0.033) and high tumor markers (P = 0.035). We observed a positive correlation with the PD-L1 in tumor and an inverse correlation with the SII. IPA uncovered relationships of CTNNB (βcatenin) and CD274 (PD-L1) genes and their effects on differentiation, proliferation and activation of lymphocyte subtypes.
Herein, we showed that βcatenin is associated with male adult GCT characteristics as well as supressed immune environment.
Abstract Background Testicular germ cell tumors (TGCTs) represent a highly curable disease; however, a small proportion of patients develop disease recurrence. Loss of the tumor-suppressor gene ...phosphatase and tensin homolog marks the transition from intratubular germ cell neoplasia to invasive GCT and is correlated with disease progression. Inactivation of phosphatase and tensin homolog is associated with deregulation of the PI3K/Akt pathway and increased mammalian target of rapamycin signaling. This study aimed to determine the efficacy and toxicity of a mammalian target of rapamycin inhibitor, everolimus, in patients with refractory TGCTs. Methods From December 2011 to February 2015, 15 patients with refractory GCTs were enrolled in the phase II study. All patients were pretreated with at least 2 cisplatin-based therapies; 4 tumors (26.7%) were absolutely refractory to cisplatin and 9 patients (60.0%) had visceral nonpulmonary metastases. Everolimus was administered at a dose of 10 mg daily until progression or unacceptable toxicity. The primary end point was the objective response rate, according to Response Evaluation Criteria in Solid Tumors. Results No objective response was observed, but 6 patients (40.0%) achieved 12-week progression-free survival. During a median follow-up period of 3.6 months (range: 1–35.1 mo), all patients experienced disease progression and 11 patients (80.0%) died. Median progression-free survival was 1.7 months (95% CI: 1.1–4.0 mo) and median overall survival was 3.6 months (95% CI: 2.0–11.0 mo). Conclusions This study failed to achieve its primary end point and our data suggest limited efficacy of everolimus against unselected heavily pretreated refractory TGCTs. Condensed abstract Everolimus showed limited efficacy in unselected heavily pretreated refractory TGCTs. Prolonged disease stabilization could be achieved in selected patients.
PURPOSE To evaluate the safety, maximum tolerated dose (MTD), and pharmacokinetics of patupilone administered once every 3 weeks with proactive standardized diarrhea management in patients with ...resistant or refractory ovarian, fallopian, or peritoneal cancer. PATIENTS AND METHODS Patients received patupilone (6.5 to 11.0 mg/m(2)) every 3 weeks via 20-minute infusion. Adverse events, dose-limiting toxicities (DLT), MTD, and tumor response were determined. The tumor response was measured by Response Evaluation Criteria in Solid Tumors (RECIST) and cancer antigen 125 levels. Results Forty-five patients were enrolled. Adverse events were mild to moderate in intensity, and grade 3 diarrhea (13%) was the most commonly reported serious adverse event. Grade 3 peripheral neuropathy was noted in two patients (4%). Diarrhea, peripheral neuropathy, and fatigue were the most common DLTs; however, these were uncommon in the first cycle and the MTD was therefore not reached in this study. Overall response (OR; complete and partial responses; median cycles, 8) per RECIST in patients with measurable disease (n = 36) was 19.5%. Median duration of disease stabilization (complete and partial responses and stable disease) was 15.8 months. These results appear improved from a previous study in a similar patient population using a weekly schedule (2.5 mg/m(2)/week; N = 53; OR, 5.7%). CONCLUSION Patupilone once every 3 weeks was well-tolerated at doses up to 11.0 mg/m(2). Patupilone demonstrated promising antitumor activity in patients with drug-resistant/refractory disease. An ongoing phase III study in this patient population is testing the 10.0 mg/m(2) dose.
The objectives of this phase III trial were to compare the time to progressive disease (TtPD), overall response rate (ORR), overall survival, and toxicity of gemcitabine, epirubicin, and paclitaxel ...(GET) versus fluorouracil (FU), epirubicin, and cyclophosphamide (FEC) as first-line therapy in patients with metastatic breast cancer (MBC).
Female patients aged 18 to 75 years with stage IV and measurable MBC were enrolled and randomly assigned to either gemcitabine (1,000 mg/m(2), days 1 and 4), epirubicin (90 mg/m(2), day 1), and paclitaxel (175 mg/m(2), day 1) or FU (500 mg/m(2), day 1), epirubicin (90 mg/m(2), day 1), and cyclophosphamide (500 mg/m(2), day 1). Both regimens were administered every 21 days for a maximum of eight cycles.
Between October 1999 and November 2002, 259 patients (GET, n = 124; FEC, n = 135) were enrolled. Baseline characteristics were well balanced across treatment arms. After a median of 20.4 months of follow-up, median TtPD was 9.1 months and 9.0 months in the GET and FEC arms, respectively (P = .557). The ORR was 62.3% in the GET arm (n = 114) and 51.2% in the FEC arm (n = 129; P = .093). Grade 3 and 4 toxicities, including neutropenia, thrombocytopenia, anemia, stomatitis, neurosensory toxicity, and allergy, occurred significantly more often in the GET arm.
No significant differences in terms of TtPD and ORR were observed between the two treatment arms. Treatment-related toxicity was higher in the GET arm.
We evaluated systemic immune-inflammation index (SII) and its association with patient outcome in germ-cell tumours (GCTs).
Two independent cohorts of patients were analysed; the discovery set ...(n=171) from a single institution and the validation set (n=181) previously included in a study evaluating PD-L1 in GCTs. The SII was calculated using platelet (P), neutrophil (N) and lymphocyte (L) counts before chemotherapy and correlated with survival using regression analyses and Kaplan-Meier method.
In the discovery cohort, the SII was associated with poor risk clinical features. Patients with low SII had significantly longer progression-free survival (HR=0.22, 95% CI 0.12-0.41, P<0.001) and overall survival (OS) (HR=0.16, 95% CI 0.08-0.32, P<0.001) compared to high SII. This index was independent of International Germ Cell Cancer Collaborative Group criteria in multivariable Cox regression analysis for OS and was validated in an independent cohort. When combining PD-L1 expression on tumour infiltrating lymphocytes (TILs) and SII, we identified three distinctive prognostic groups.
High SII was associated with poor outcome in GCTs. Combination of PD-L1 positive TILs and SII could further refine prognosis in GCTs.
Background WNT/betacatenin (WNTbeta) pathway is activated in early stages of embryonic development. We aimed to evaluate the significance of betacatenin in germ cell tumors (GCTs) and explore ...associations with the inflamed environment. Methods Surgical specimens from 247 patients were analyzed. #206;catenin expression was detected in the tumor tissue by immunohistochemistry and correlated with clinical characteristics, outcome, PD-L1 expression and systemic immune-inflammation index (SII). The Ingenuity Pathway Analysis (IPA) was used to investigate the immune-cell related effects of betacatenin and PD-L1 encoding genes. Results betacatenin was expressed in 86.2% of GCTs. The expression in seminomas was significantly lower compared to all subtypes of non-seminoma (all P 0.0001). A high expression (weighted histoscore 150) was associated with primary mediastinal non-seminoma (P = 0.035), intermediate/poor risk disease (P = 0.033) and high tumor markers (P = 0.035). We observed a positive correlation with the PD-L1 in tumor and an inverse correlation with the SII. IPA uncovered relationships of CTNNB (betacatenin) and CD274 (PD-L1) genes and their effects on differentiation, proliferation and activation of lymphocyte subtypes. Conclusion Herein, we showed that betacatenin is associated with male adult GCT characteristics as well as supressed immune environment. Keywords: betacatenin, WNTbeta pathway, PD-L1, Systemic-immune inflammation, Tumor infiltrating lymphocytes
Germ cell tumors (GCTs) are extraordinarily sensitive to cisplatin (CDDP)-based chemotherapy. DNA damage represents one of the most important factors contributing to toxic effects of CDDP-based ...chemotherapy. This study was aimed to evaluate the prognostic value of DNA damage level in peripheral blood lymphocytes (PBLs) from chemo-naïve GCT patients. PBLs isolated from 59 chemotherapy-naïve GCT patients were included into this prospective study. DNA damage levels in PBLs were evaluated by the Comet assay and scored as percentage tail DNA by the Metafer-MetaCyte analyzing software. The mean ± SEM (standard error of the mean) of endogenous DNA damage level was 5.25 ± 0.64. Patients with DNA damage levels lower than mean had significantly better progression free survival (hazard ratio HR = 0.19, 95% CI (0.04 - 0.96), P = 0.01) and overall survival (HR = 0.00, 95% CI (0.00 - 0.0), P < 0.001) compared to patients with DNA damage levels higher than mean. Moreover, there was significant correlation between the DNA damage level and presence of mediastinal lymph nodes metastases, IGCCCG (International Germ Cell Cancer Collaborative Group) risk group, and serum tumor markers level. These data suggest that DNA damage levels in PBLs of GCT patients may serve as an important prognostic marker early identifying patients with poor outcome.
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