Testicular germ cell tumors (TGCTs) belong to the most chemosensitive solid tumors; however, a small proportion of patients fail to be cured with cisplatin-based chemotherapy. Inhibitors of ...PD-1/PD-L1 pathways represent a new class of promising drugs in anticancer therapy. The aim of this study was to evaluate expression and prognostic value of PD-1 and PD-L1 in TGCTs.
Surgical specimens from 140 patients with TGCTs (131 with primary testicular tumor and 9 with extragonadal GCTs) were included into the translational study. PD-1 and PD-L1 expression was detected in the tumor tissue by immunohistochemistry using monoclonal antibodies, scored by the multiplicative quickscore (QS) method, compared with their expression in normal testicular tissue and correlated with clinicopathological characteristics and clinical outcome.
None of the GCTs exhibited PD-1 protein, although expression of PD-L1 was significantly higher in GCTs in comparison with normal testicular tissue (mean QS = 5.29 versus 0.32, P < 0.0001). Choriocarcinomas exhibit the highest level of PD-L1 with decreasing positivity in embryonal carcinoma, teratoma, yolk sac tumor and seminoma. PD-L1 expression was associated with poor prognostic features, including ≥3 metastatic sites, increased serum tumor markers and/or non-pulmonary visceral metastases. Patients with low PD-L1 expression had significantly better progression-free survival hazard ratio (HR) = 0.40, 95% confidence interval (CI) 0.16–1.01, P = 0.008 and overall survival (HR = 0.43, 95% CI 0.15–1.23, P = 0.040) compared with patients with high PD-L1 expression.
In this translational study, we showed, for the first time, the prognostic value of PD-L1 expression in TGCTs and our data imply that the PD-1/PD-L1 pathway could be a novel therapeutic target in TGCTs.
Summary
Background
Germ cell tumors (GCTs) are highly curable diseases; however, not all patients can be cured. Patients in their second relapse have especially poor prognoses. PD-L1 expression is ...significantly higher in GCTs than in normal testicular tissue, and high PD-L1 expression is associated with a poor prognosis. This study aimed to determine the efficacy and safety of avelumab, a PD-L1 inhibitor, in patients with GCTs.
Methods
In this phase 2 study, patients with multiple relapsed and/or refractory GCTs were treated with avelumab at a dose of 10 mg/kg administered biweekly until progression or unacceptable toxicity. The primary endpoint was 12-week progression-free survival (PFS). Fifteen evaluable patients had to be enrolled in the first cohort, and if <8 of 15 patients had 12-week PFS, the study was to be terminated. Here, we report the results of the first stage of the trial.
Results
From November 2017 to January 2018, 8 patients with a median age of 29 years (range, 22 to 52 months) were enrolled. Patients were pretreated with a median of 5 (range, 1 to 6) previous lines of platinum-based therapies; 5 tumors (62.5%) were absolutely refractory to cisplatin, and 5 patients (62.5%) had visceral nonpulmonary metastases. At a median follow-up period of 2.6 months (range, 0.3 to 14.4), all the patients experienced disease progression, and 7 patients (87.5%) died. The twelve-week PFS was 0%, median PFS was 0.9 months (95% CI 0.5–1.9), and median OS was 2.7 months (95% CI 1.0–3.3). Avelumab was well tolerated, and no severe adverse events were observed.
Conclusions
This study failed to achieve its primary endpoint. Our data suggest a lack of avelumab efficacy in unselected multiple relapsed/refractory GCTs.
Summary
Background
Prebiotics have been shown to reduce abdominal symptoms in patients with functional gut disorders, despite that they are fermented by colonic bacteria and may induce gas‐related ...symptoms.
Aim
To investigate changes in the metabolic activity of gut microbiota induced by a recognised prebiotic.
Methods
Healthy subjects (n = 20) were given a prebiotic (2.8 g/day HOST‐G904, HOST Therabiomics, Jersey, Channel Islands) for 3 weeks. During 3‐day periods immediately before, at the beginning and at the end of the administration subjects were put on a standard diet (low fibre diet supplemented with one portion of high fibre foods) and the following outcomes were measured: (i) number of daytime gas evacuations for 2 days by means of an event marker; (ii) volume of gas evacuated via a rectal tube during 4 h after a test meal; and (iii) microbiota composition by faecal Illumina MiSeq sequencing.
Results
At the beginning of administration, HOST‐G904 significantly increased the number of daily anal gas evacuations (18 ± 2 vs. 12 ± 1 pre‐administration; P < 0.001) and the volume of gas evacuated after the test meal (236 ± 23 mL vs. 160 ± 17 mL pre‐administration; P = 0.006). However, after 3 weeks of administration, these effects diminished (11 ± 2 daily evacuations, 169 ± 23 mL gas evacuation). At day 21, relative abundance of butyrate producers (Lachnospiraceae) correlated inversely with the volume of gas evacuated (r = −0.52; P = 0.02).
Conclusion
The availability of substrates induces an adaptation of the colonic microbiota activity in bacterial metabolism, which produces less gas and associated issues. Clinical trials.gov NCT02618239.
Linked ContentThis article is linked to Staudacher paper. To view this article visit https://doi.org/10.1111/apt.13976.
Cytokines are involved in cancer invasion and metastasis. Circulating tumor cells (CTCs) play key role in tumor dissemination and are an independent survival predictor in breast cancer patients. The ...aim of this study was to assess correlation between CTCs and plasma cytokines in primary breast cancer (PBC) patients.
This study included 147 chemotherapy naïve PBC patients. Peripheral blood mononuclear cells (PBMC) were depleted of hematopoetic cells using RossetteSep™ negative selection kit. RNA extracted from CD45-depleted PBMC was interrogated for expression of EMT (Twist1, Snail1, Slug, Zeb1) and epithelial (Ck19) gene transcripts by qRT-PCR. The concentrations of 51 plasma cytokines were measured using multiplex bead arrays.
CTCs were detected in 25.2% patients. CTCs exhibiting only epithelial markers (CTC_EP) and only EMT markers (CTC_EMT) were present evenly in 11.6% patients, while CTCs co-expressing both markers were detected in 2.0% patients. Patients with presence of CTC_EP in peripheral blood had significantly elevated levels of plasma IFN-α2, IL-3, MCP-3, β-NGF, SCF, SCGF-β, TNF-β and SDF-1 compared to patients without CTC_EP. CTC_EP exhibited overexpression of SDF-1 receptor and CXCR4, but not other corresponding cytokine receptor, and in multivariate analysis SDF-1 was independently associated with CTC_EP. There was an inverse correlation between CTC_EMT and plasma cytokines CTACK, β-NGF and TRAIL, while presence of either subtype of CTCs was associated with increased level of TGF-β2.
Using cytokine profiling, we identified cytokines associated with CTCs subpopulations in peripheral blood of PBC. Our data suggest that CXCR4-SDF-1 axis is involved in mobilization and trafficking of epithelial CTCs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Survivors of germ-cell tumors (GCT) may suffer from long-term adverse consequences. Our study was conducted to assess a long-term sexual functioning in GCT survivors.
GCT survivors (N = 170) from the ...National Cancer Institute in Slovakia completed a Sexual Function Questionnaire that was modified from PROMIS Sexual Function and Satisfaction Questionnaire 9-year median follow up (range 5-32) as a primary exploratory aim. Study groups consisted of 17 survivors (10%) who had active surveillance (AS, controls), and 153 (90%) survivors who received treatment beyond orchiectomy (Tx), including cisplatin-based chemotherapy (CT, N = 132; 78%), radiotherapy to the retroperitoneal lymph nodes (RT, N = 12; 7%) or both (CTRT, N = 9; 5%).
In univariate analysis, treatment of any type resulted in difficulty to maintain erection during sexual intercourse compared to patients treated with AS (P = 0.04). Survivors who received CTRT had lower ability to achieve orgasm during sexual activities (P = 0.04) and they reported disappointment with their overall quality of sex life (P = 0.002). The number of attempts to initiate sexual intercourse did not differ. Sexual relationships caused none or mild anxiety and the desire to be sexually active was higher after CTRT (P = 0.05). Multivariable analysis confirmed that orgasmic dysfunction after ≥400 mg/m
of cisplatin and issues in maintaining erection after Tx were independent of retroperitoneal lymph-node dissection (P = 0.03 and P = 0.04, respectively). Survivors were disappointed with the quality of sex life and had stronger desire to be sexually active independent of age, (P = 0.01 and P = 0.05, respectively).
This study identified an impairment in sexual function may represent an issue for long-term GCT survivors. Treatment with chemotherapy plus radiotherapy were associated with disappointment and stronger sexual desire, while a higher cumulative dose of cisplatin may be responsible for orgasmic dysfunction.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Testicular germ cell tumours (GCTs) are the only universally curable solid malignancy. The long‐term cure rate of >95% is attributed to the extraordinary sensitivity to cisplatin‐based ...treatment but a proportion of patients die due to a progression of the chemotherapy‐refractory disease. While treatment of a variety of solid cancers was significantly improved with recent immune therapies, the immunology and immunotherapy remained underinvestigated in GCTs.
Objectives
In this narrative review, we summarize evidence about immune‐related mechanisms and possible immune therapies in GCTs and provide insights and implications for future research and clinical practice.
Materials and methods
We performed a comprehensive search of PubMed/MEDLINE to identify original and review articles reporting on immune mechanisms and immunotherapy in GCTs. Review articles were further searched for additional original articles.
Results
Clear link of immune surveillance and the presence of GCT have been identified with several novel immune‐related prognostic biomarkers published recently. Several case reports, case series, and preliminary results from phase I‐II studies are emerging to report on the efficacy of immune checkpoint inhibitors.
Discussion
Newly discovered immune biomarkers provide an evidence supporting the role of immune environment in the GCT biology. While these discoveries provide only an initial insight into the immunobiology, strong correlation with prognosis is evident. This provided a premise to investigate the treatment efficacy of novel immunotherapy. Some efficacy of these treatments has been reported in clinical setting; however, the results of published studies with immune checkpoint inhibitor monotherapy seem to be disappointing.
Conclusion
Immune‐related mechanisms and efficacy of immune checkpoint blockade in GCTs should be further investigated in preclinical and clinical studies.
Background
Multiple relapsed/refractory germ cell tumor (GCT) patients have extremely poor prognosis. Cisplatin resistant testicular GCTs overexpress aldehyde-dehydrogenase (ALDH) isoforms and ...inhibition of ALDH activity by disulfiram is associated with reconstitution of cisplatin sensitivity in vitro as well as in animal model. This study aimed to determine the efficacy and toxicity of ALDH inhibitor disulfiram in combination with cisplatin in patients with multiple relapsed/refractory GCTs.
Methods
Disulfiram was administered at a dose of 400 mg daily until progression or unacceptable toxicity, cisplatin was administered at dose 50 mg/m
2
day 1 and 2, every 3 weeks. Twelve evaluable patients had to be enrolled into the first cohort, and if 0 of 12 patients had treatment response, the study was to be terminated. The results of the first stage of the trial are presented in this report.
Results
Twelve patients with multiple relapsed/refractory GCTs were enrolled in the phase II study from May 2019 to September 2021. Median number of treatment cycles was 2 (range 1–6). None of patients achieved objective response to treatment, therefore the study was terminated in first stage. Median progression-free survival was 1.4 months, 95% CI (0.7–1.5 months), and median overall survival was 2.9 months 95% CI (1.5–4.7 months). Disease stabilization for at least 3 months was observed in 2 (16.7%) patients. Treatment was well tolerated, however, 5 (41.7%) of patients experienced grade 3/4 fatigue, 4 (33.3%) thrombocytopenia, 3 (25.0%) anemia, while 2 (16.7%) experienced neutropenia, nausea and infection.
Conclusions
This study failed to achieve its primary endpoint and our data suggest limited efficacy of disulfiram in restoring sensitivity to cisplatin in multiple relapsed/refractory GCTs.
Background
We have shown that a galactooligosaccharide prebiotic administration (HOST‐G904) initially increased intestinal gas production and this increase declined back to baseline after 2 week ...administration. Our aim was to determine the mechanism of microbiota adaptation; i.e., to determine whether the net reduction is due to decreased overall production or increased gas consumption.
Methods
In 10 healthy subjects, intestinal gas production and intraluminal disposal was measured before, at the beginning and after 2 week of HOST‐G904 prebiotic administration. Anal gas was collected for 4 hour after a probe meal. Paired studies were performed without and with high‐rate infusion of exogenous gas (24 mL/min) into the jejunum to wash‐out the endogenous gas produced by bacterial fermentation. The exogenous gas infused was labeled (5% SF6) to calculate the proportion of endogenous gas evacuated.
Key Results
The volume of intestinal gas produced i.e., endogenous gas washed‐out, increased by 37% at the beginning of HOST‐G904 administration (P=.049 vs preadministration) and decreased down to preadministration level after 2 week administration (P=.030 vs early administration). The proportion of gas eliminated from the lumen before reaching the anus tended to increase after 2‐week administration (87±3% vs 78±5% preadministration; P=.098).
Conclusions & Inferences
Adaptation to regular consumption of HOST‐G904 prebiotic involves a shift in microbiota metabolism toward low‐gas producing pathways, with a non‐significant increase in gas‐consuming activity. Hence, regular consumption of HOST‐G904 regulates intestinal gas metabolism: less gas is produced and a somewhat larger proportion of it is consumed.
Effect of HOST‐G904 administration on the volume of gas evacuated. Anal evacuation of endogenous gas (produced by bacterial fermentation) 2‐4 hours after a probe meal with and without gaseous wash‐out measured before, at the beginning and after 2 week administration (n=10). With gaseous wash‐out, most endogenous gas produced by colonic fermentation was flushed out and evacuated per anus: gas production increased in the early administration phase and returned back to baseline. Without wash‐out, a large proportion of the gas produced by bacterial fermentation was eliminated from the lumen before reaching the anus and the proportion tended to increase during HOST‐G904 administration.
View the podcast on this paper at the following sites: iTunes: https://itunes.apple.com/gb/podcast/neurogastroenterology-motility-september-2017/id1257018975 Youtube: https://youtu.be/YDdDPaSnzuc
Colonic content: effect of diet, meals, and defecation Bendezú, R. A.; Mego, M.; Monclus, E. ...
Neurogastroenterology & motility/Neurogastroenterology and motility,
February 2017, Letnik:
29, Številka:
2
Journal Article, Publication
Recenzirano
Odprti dostop
Background
The metabolic activity of colonic microbiota is influenced by diet; however, the relationship between metabolism and colonic content is not known. Our aim was to determine the effect of ...meals, defecation, and diet on colonic content.
Methods
In 10 healthy subjects, two abdominal MRI scans were acquired during fasting, 1 week apart, and after 3 days on low‐ and high‐residue diets, respectively. With each diet, daily fecal output and the number of daytime anal gas evacuations were measured. On the first study day, a second scan was acquired 4 hours after a test meal (n=6) or after 4 hours with nil ingestion (n=4). On the second study day, a scan was also acquired after a spontaneous bowel movement.
Results
On the low‐residue diet, daily fecal volume averaged 145 ± 15 mL; subjects passed 10.6 ± 1.6 daytime anal gas evacuations and, by the third day, non‐gaseous colonic content was 479 ± 36 mL. The high‐residue diet increased the three parameters to 16.5 ± 2.9 anal gas evacuations, 223 ± 19 mL fecal output, and 616 ± 55 mL non‐gaseous colonic content (P<.05 vs low‐residue diet for all). On the low‐residue diet, non‐gaseous content in the right colon had increased by 41 ± 11 mL, 4 hours after the test meal, whereas no significant change was observed after 4‐hour fast (−15 ± 8 mL; P=.006 vs fed). Defecation significantly reduced the non‐gaseous content in distal colonic segments.
Conclusion & Inferences
Colonic content exhibits physiologic variations with an approximate 1/3 daily turnover produced by meals and defecation, superimposed over diet‐related day‐to‐day variations.
Ingestion of unabsorbable residues and defecation produce profound changes in colonic content. The rapid turnover of colonic biomass (about 1/3 daily) indicates a high adaptation potential of microbiota to the intraluminal environment.
Summary
Background
Patients with multiple relapsed/refractory germ cell tumours (GCTs) have an extremely poor prognosis. PARP (poly-ADP-ribose polymerase) is overexpressed in GCTs compared to normal ...testes, and PARP overexpression is an early event in GCT development. This study aimed to determine the efficacy and toxicity of gemcitabine, carboplatin and the PARP inhibitor veliparib in patients with multiple relapsed/refractory GCTs.
Methods
Fifteen patients with multiple relapsed/refractory GCTs were enrolled in this phase II study from October 2016 to October 2020. Gemcitabine was administered at a dose of 800 mg/m2 on days 1 and 8 every 3 weeks; carboplatin at a target AUC of 4 on day 1 every 3 weeks; and veliparib at a dose of 250 mg b.i.d. throughout. The primary end point was 12-month progression-free survival (PFS).
Results
The median number of treatment cycles was 4 (range 2–8). Twelve-month PFS was achieved in 1 (6.7 %) patient. The median PFS was 3.1 months (95 % CI 2.2–3.9), and the median overall survival was 10.5 months (95 % CI 8.9–11.1). Partial remission was achieved in 4 (26.7 %) patients, and disease stabilization was observed in 5 (33.3 %) patients. A favourable response was achieved in 3 (20.0 %) patients. Treatment was well tolerated; however, 11 (73.3 %) patients experienced grade 3/4 neutropenia, 10 (66.7 %) experienced thrombocytopenia, 5 (33.3 %) anaemia and 2 (13.3 %) febrile neutropenia.
Conclusions
This study failed to achieve its primary endpoint, and our data suggest limited efficacy of gemcitabine, carboplatin and veliparib for multiple relapsed/refractory GCTs. ClinicalTrials.gov Identifier: NCT02860819, registered August 9, 2016.
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