Tumor-associated and immunochemotherapy-dependent long-term alterations of the peripheral blood NK cell compartment in DLBCL patients

Natural Killer (NK) cells are a key component of tumor immunosurveillance and thus play an important role in rituximab-dependent killing of lymphoma cells via an antibody-dependent cellular cytotoxicity (ADCC) mechanism. We evaluated the phenotypic and functional assets of peripheral blood NK cell subsets in 32 newly-diagnosed diffuse large B-cell lymphoma (DLBCL) patients and in 27 healthy controls. We further monitored long-term modifications of patient NK cells for up to 12 months after rituximab-based immunochemotherapy. At diagnosis, patients showed a higher percentage of CD56dim and CD16C NK cells, and a higher frequency of GrzBC cells in CD56dim, CD56bright, and CD16C NK cell subsets than healthy controls. Conversely, DLBCL NK cell killing and interferon g (IFNg) production capability were comparable to those derived from healthy subjects. Notably, NK cells from refractory/relapsed patients exhibited a lower “natural” cytotoxicity. A marked and prolonged therapy-induced reduction of both “natural” and CD16- dependent NK cytotoxic activities was accompanied by the down-modulation of CD16 and NKG2D activating receptors, particularly in the CD56dim subset. However, reduced NK cell killing was not associated with defective lytic granule content or IFNg production capability. This study firstly describes tumor-associated and therapy-induced alterations of the systemic NK cell compartment in DLBCL patients. As these alterations may negatively impact rituximab-based therapy efficacy, our work may provide useful information for improving immunochemotherapeutic strategies

Correlation of Serum Cystatin C with Glomerular Filtration Rate in Patients Receiving Platinum-Based Chemotherapy

Objectives. Serum cystatin C seems to be an accurate marker of glomerular filtration rate (GFR) compared to serum creatinine. The aim of this work was to explore the possibility of using serum cystatin C instead of serum creatinine to early predict renal failure in cancer patients who received platinum based chemotherapy. Design and Methods. Serum creatinine, serum cystatin C concentrations, and GFR were determined simultaneously in 52 cancer patients received carboplatin-based or cisplatin-based chemotherapy. Serum creatinine was assayed on Cobas C6000-Roche, serum cystatin C assay was performed on AIA 360-Tosoh, and GFR was determined in all patients, before the first cycle of chemotherapy and before the subsequent administrations. Results. In the overall series, for the prediction of a fall of GFR < 80 mL/min/1.73 m2, the AUC of the ROC curve for cystatin C was 0,667 and the best threshold was 1.135 mg/L (sensitivity 90.5%, specificity 61.1%). For a GFR fall < 60 mL/min/1.73 m2, the AUC of ROC curve for cystatin C was 74.3% and the best threshold was 1.415 mg/L (sensitivity 66.7%, specificity 73.2%). Conclusions. Baseline cystatin C values were not able to predict renal failure during subsequent treatment. In conclusion, serum cystatin C is not a reliable early marker to efficiently predict renal failure in patients receiving chemotherapy

Very Early PSA Response to Abiraterone in mCRPC Patients: A Novel Prognostic Factor Predicting Overall Survival

BACKGROUND Abiraterone Acetate (AA) is approved for the treatment of mCRPC after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated and for treatment of mCRPC progressed during or after docetaxel-based chemotherapy regimen. The aim of this study is to evaluate the role of early PSA decline for detection of therapy success or failure in mCRPC patients treated with AA in post chemotherapy setting.PATIENTS AND METHODS We retrospectively evaluated 87 patients with mCRPC treated with AA. Serum PSA levels were evaluated after 15, 90 days and then monthly. The PSA flare phenomenon was evaluated, according to a confirmation value at least one week apart. The primary endpoint was to demonstrate that an early PSA decline correlates with a longer progression free survival (PFS) and overall survival (OS). The secondary endpoind was to demonstrate a correlation between better outcome and demographic and clinical patient characteristics.RESULTS We have collected data of 87 patients between Sep 2011 and Sep 2014. Early PSA response (≥ 50% from baseline at 15 days) was found in 56% evaluated patients and confirmed in 29 patients after 90 days. The median progression free survival (PFS) was 5,5 months (4,6-6,5) and the median overall survival (OS) was 17,1 months (8,8-25,2). In early responders patients (PSA RR ≥ 50% at 15 days), we found a significant statistical advantage in terms of PFS at 1 year, HR 0.28, 95%CI 0.12-0.65, p=0.003, and OS, HR 0.21 95% CI 0.06-0.72, p=0.01. The results in PFS at 1 years and OS reached statistical significance also in the evaluation at 90 days.CONCLUSION A significant proportion (78.6%) of patients achieved a rapid response in terms of PSA decline. Early PSA RR (≥ 50% at 15 days after start of AA) can provide clinically meaningful information and can be considered a surrogate of longer PFS and OS

Lactobacillus spp. act in synergy to attenuate splenomegaly and lymphadenopathy in lupus-prone MRL/lpr mice

Commensal bacteria and the immune system have a close and strong relationship that maintains a balance to control inflammation. Alterations of the microbiota, known as dysbiosis, can direct reactivity to self-antigens not only in the intestinal mucosa but also at the systemic level. Our laboratory previously reported gut dysbiosis, particularly lower abundance of bacteria in the family Lactobacillaceae, in lupus-prone MRL/lpr mice, a model of systemic autoimmunity. Restoring the microbiota with a mix of 5 different Lactobacillus species (spp.), L. reuteri, L. oris, L. johnsonii, L. gasseri and L. rhamnosus, attenuated lupus-liked clinical signs, including splenomegaly and lymphadenopathy. However, our understanding of the mechanism was limited. In this study, we first investigated the effects of individual species. Surprisingly, none of the species individually recapitulated the benefits of the mix. Instead, Lactobacillus spp. acted synergistically to attenuate splenomegaly and renal lymphadenopathy through secreted factors and a CX3CR1-dependent mechanism. Interestingly, oral administration of MRS broth exerted the same benefits likely through increasing the relative abundance of endogenous Lactobacillus spp. Mechanistically, we found increased percentages of FOXP3-negative type 1 regulatory T cells with administration of the mix in both spleen and mesenteric lymph nodes. In addition, oral gavage of Lactobacillus spp. decreased the percentage of central memory T cells while increasing that of effector memory T cells in the lymphoid organs. Furthermore, a decreased percentage of double negative T cells was observed in the spleen with the mix. These results suggest that Lactobacillus spp. might act on T cells to attenuate splenomegaly and lymphadenopathy. Together, this study advances our understanding of how Lactobacillus spp. attenuate lupus in MRL/lpr mice. The synergistic action of these bacteria suggests that multiple probiotic bacteria in combination may dampen systemic autoimmunity and benefit lupus patients

CA-125 early dynamics to predict overall survival in women with newly diagnosed advanced ovarian cancer based on meta-analysis data

(1) Background: Cancer antigen 125 (CA-125) is a protein produced by ovarian cancer cells that is used for patients’ monitoring. However, the best ways to analyze its decline and prognostic role are poorly quantified. (2) Methods: We leveraged individual patient data from the Gynecologic Cancer Intergroup (GCIG) meta-analysis (N = 5573) to compare different approaches summarizing the early trajectory of CA-125 before the prediction time (called the landmark time) at 3 or 6 months after treatment initiation in order to predict overall survival. These summaries included observed and estimated measures obtained by a linear mixed model (LMM). Their performances were evaluated by 10-fold cross-validation with the Brier score and the area under the ROC (AUC). (3) Results: The estimated value and the last observed value at 3 months were the best measures used to predict overall survival, with an AUC of 0.75 CI 95% [0.70; 0.80] at 24 and 36 months and 0.74 [0.69; 0.80] and 0.75 [0.69; 0.80] at 48 months, respectively, considering that CA-125 over 6 months did not improve the AUC, with 0.74 [0.68; 0.78] at 24 months and 0.71 [0.65; 0.76] at 36 and 48 months. (4) Conclusions: A 3-month surveillance provided reliable individual information on overall survival until 48 months for patients receiving first-line chemotherapy

Safety of PARP inhibitors as maintenance therapy in ovarian cancer

IntroductionAntiangiogenic agents and poly(ADP-ribose) polymerase inhibitors (PARP-Is) have improved the outcome of patients suffering from ovarian cancer. However, as they are associated with many adverse events (AEs), it is important to be aware of their safety and toxicity profiles.Areas coveredWe reviewed PARP-I therapeutical indications, mechanism of action, metabolism, and interactions. We reported on all major and minor AEs that have emerged from clinical trials (SOLO1, PRIMA, PAOLA1, ATHENA, SOLO2, NOVA, ARIEL3, NORA), their follow-ups, meta-analyses, and real-world studies, particularly hematologic toxicities and their management, and secondary malignancies (myelodysplastic syndrome and acute myeloid leukemia). We also addressed gastrointestinal, neurological, respiratory, hepatic, and renal toxicity and the use of PARP-Is in older, pregnant, and lactating patients. No specific research strategy in terms of keywords, inclusive dates and databases was used.Expert opinionPARP-Is benefits largely outweigh the risks associated with potential AEs. Randomized controlled trials produced strong good, quality data, but they enrolled a selected population and failed to capture rare events. More pharmacovigilance data and real-life studies on a larger and more heterogeneous sample are needed to understand PARP-Is differences and to clarify the incidence of late AEs to balance the risk/benefit ratio

Mirvetuximab soravtansine in folate receptor alpha (FRα)–high platinum-resistant ovarian cancer: final overall survival and post hoc sequence of therapy subgroup results from the SORAYA trial

Ovarian CancerCáncer de ovarioCàncer d'ovariObjective The single-arm, phase II SORAYA trial (NCT04296890) of mirvetuximab soravtansine-gynx in folate receptor alpha (FRα)–high platinum-resistant ovarian cancer (n=105 (efficacy-evaluable)) met its primary endpoint with an objective response rate of 32.4% (95% CI, 23.6 to 42.2). Here we report final SORAYA trial results for overall survival and post hoc objective response rates in subgroups by sequence and number of prior therapies. Methods Eligible patients had high-grade serous platinum-resistant ovarian cancer with high FRα expression and one to three prior therapies (prior bevacizumab required). Enrolled participants received 6 mg/kg mirvetuximab soravtansine-gynx adjusted ideal body weight intravenously once every 3 weeks until progressive disease, unacceptable toxicity, withdrawal of consent, or death. Final overall survival and post hoc objective response rates were assessed in efficacy-evaluable participants. The safety population included all patients who received ≥1 dose of mirvetuximab soravtansine-gynx. Results At data cut-off (December 22, 2022; n=105), final median overall survival was 15.0 months (95% CI, 11.5 to 18.7). Median overall survival in participants with one to two prior therapy lines was 18.7 months (95% CI, 13.8 to not estimable (NE)) and 11.6 months (95% CI, 7.1 to 16.7) with three prior therapy lines. Median overall survival was 15.0 months (95% CI, 11.5 to NE) in participants with prior poly (ADP-ribose) polymerase inhibitor (PARPi) treatment versus 14.0 months (95% CI, 7.1 to NE) in those without. Objective response rate (data cut-off: November 17, 2021) differed among participants who received mirvetuximab soravtansine-gynx as their first treatment in the platinum-resistant setting (34.8%; 95% CI, 23.5 to 47.6) versus a different first treatment (28.2%; 95% CI, 15.0 to 44.9) or had received prior bevacizumab in a platinum-sensitive (34.0%; 95% CI, 24.6 to 44.5) versus platinum-resistant setting (17.6%; 95% CI, 3.8 to 43.4). No new safety signals were observed. Conclusion These results support the clinically meaningful efficacy of mirvetuximab soravtansine-gynx in FRα-expressing platinum-resistant ovarian cancer, irrespective of prior treatment or sequence.This study was funded by ImmunoGen, Inc

Olaparib as maintenance treatment in relapsed platinum-sensitive BRCA mutated ovarian cancer: real world experience in two Italian cancer Centers

Background: In 2014, after FDA approval, the therapeutic armamentarium of relapsed platinum-sensitive (RPS) ovarian cancer has been enriched by the introduction of a new drug, belonging to the class of poly (ADP-ribose) polymerase inhibitors (PARPi), olaparib. This oral PARPi demonstrated to significantly prolong progression-free survival (PFS) compared to placebo as maintenance in patients with platinum-sensitive recurrent (PSR) BRCA mutated serous ovarian cancer in the pivotal phase II trial. Olaparib is actually used in daily practice, but very few data are available about its safety and activity out of clinical trials. The aim of this paper is to describe the early data on this agent according to its approval in two clinical cancer care Institutions in Italy. Materials and Methods: This is an observational, retrospective study, carried out in two Italian Hospitals (National Cancer Institute of Naples and National Cancer Institute of Milan). Archival medical records of all the BRCA mutated relapsed ovarian cancer patients treated with olaparib in two Italian centers from September 1st, 2015 to March 14th, 2017 were analyzed. The primary endpoint is to describe the percentage of patients that received olaparib for ≥6 months and ≥12 months. Secondary endpoints include: the description of objective response rate (ORR), disease control rate (DCR), PFS and safety profile of olaparib treatment. Olaparib 400 mg twice daily capsules was given orally according to indication. Results: From September 1st, 2015 to March 14th, 2017 twenty-two patients with RPS ovarian cancer were considered eligible for the analysis. At the time of data cut off point, about 55% of patients were receiving olaparib for at least 6 months, and 27.2% for 12 or more months. Actually, most of the patients (77.3%) is still on treatment with the PARPi. Only 3 progressions of disease (PD) were registered, therefore the median PFS has not been reached. The ORR was 33.4% and the DCR was 75%. Olaparib was globally manageable and well tolerated. Safety data were consistent with previously reported findings in literature. Most common adverse events were: fatigue (63.3%); nausea (77.3%); anemia (54.5%); thrombocytopenia (18.1%); leucopenia (36.4%). All the events were mainly of grade 1 and were transient and managed with supportive care. Conclusions: Our preliminary analysis suggests a good benefit/toxicity ratio of olaparib also in unselected population out of clinical trials. The need to evaluate the reproducibility of literature findings in heterogeneous patients require further studies