Immunotherapy with immune checkpoint inhibitors and predictive biomarkers in malignant mesothelioma: Work still in progress

Malignant mesothelioma (MM) is a rare and aggressive neoplasm, usually associated with a poor prognosis (5 years survival rate <10%). For unresectable disease, platinum and pemetrexed chemotherapy has been the only standard of care in first line for more than two decades, while no standard treatments have been approved in subsequent lines. Recently, immunotherapy has revolutionized the therapeutic landscape of MM. In fact, the combination of ipilimumab plus nivolumab has been approved in first line setting. Moreover, immune checkpoint inhibitors (ICIs) showed promising results also in second-third line setting after platinum-based chemotherapy. Unfortunately, approximately 20% of patients are primary refractory to ICIs and there is an urgent need for reliable biomarkers to improve patient’s selection. Several biological and molecular features have been studied for this goal. In particular, histological subtype (recognized as prognostic factor for MM and predictive factor for chemotherapy response), programmed death ligand 1 (PD-L1) expression, and tumor mutational burden (widely hypothesized as predictive biomarkers for ICIs in several solid tumors) have been evaluated, but with unconclusive results. On the other hand, the deep analysis of tumor infiltrating microenvironment and the improvement in genomic profiling techniques has led to a better knowledge of several mechanisms underlying the MM biology and a greater or poorer immune activation. Consequentially, several potential biomarkers predictive of response to immunotherapy in patients with MM have been identified, also if all these elements need to be further investigated and prospectively validated.In this paper, the main evidences about clinical efficacy of ICIs in MM and the literature data about the most promising predictive biomarkers to immunotherapy are reviewed

U-CHANGE Project: a multidimensional consensus on how clinicians, patients and caregivers may approach together the new urothelial cancer scenario

IntroductionAdvanced urothelial carcinoma remains aggressive and very hard to cure, while new treatments will pose a challenge for clinicians and healthcare funding policymakers alike. The U-CHANGE Project aimed to redesign the current model of care for advanced urothelial carcinoma patients to identify limitations (“as is” scenario) and recommend future actions (“to be” scenario).MethodsTwenty-three subject-matter experts, divided into three groups, analyzed the two scenarios as part of a multidimensional consensus process, developing statements for specific domains of the disease, and a simplified Delphi methodology was used to establish consensus among the experts.ResultsRecommended actions included increasing awareness of the disease, increased training of healthcare professionals, improvement of screening strategies and care pathways, increased support for patients and caregivers and relevant recommendations from molecular tumor boards when comprehensive genomic profiling has to be provided for appropriate patient selection to ad hoc targeted therapies.DiscussionWhile the innovative new targeted agents have the potential to significantly alter the clinical approach to this highly aggressive disease, the U-CHANGE Project experience shows that the use of these new agents will require a radical shift in the entire model of care, implementing sustainable changes which anticipate the benefits of future treatments, capable of targeting the right patient with the right agent at different stages of the disease

Bladder metastases of appendiceal mucinous adenocarcinoma: a case presentation

<p>Abstract</p> <p>Background</p> <p>Appendiceal adenocarcinoma is rare with a frequency of 0.08% of all surgically removed appendices. Few cases of appendiceal carcinoma infiltrating the bladder wall for spatial contiguity have been documented.</p> <p>Case Presentation</p> <p>A case is reported of a 45-years old woman with mucinous cystadenocarcinoma of the appendix with bladder metastasis. Although ultrasonography and voided urinary cytology were negative, abdomen computed tomography (CT) scan and cystoscopy and subsequent pathological examination revealed a mass exclusively located in the anterior wall of the bladder. Histopathology of the transurethral bladder resection revealed a bladder adenocarcinoma [6 cm (at the maximum diameter) × 2,5 cm; approximate weight: 10 gr] with focal mucinous aspects penetrating the muscle and perivisceral fat. Laparotomy evidenced the presence of a solid mass of the appendix (2,5 cm × 3 cm × 2 cm) extending to the loco-regional lymph nodes. Appendectomy and right hemicolectomy, linfoadenectomy and partial cystectomy were performed. The subsequent pathological examination revealed a mucinous cystadenocarcinoma of the appendix with metastatic cells colonising the anterior bladder wall and several colic lymph nodes.</p> <p>Conclusions</p> <p>The rarity of the appendiceal carcinoma invading the urinary bladder and its usual involvement of nearest organs and the posterior bladder wall, led us to describe this case which demonstrates the ability of the appendiceal cancer to metastasize different regions of urinary bladder.</p

The prognostic value of peripheral blood inflammatory indices early variation in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with nivolumab (Δ-Meet-URO analysis)

Background: Immunotherapy has improved the treatment landscape of mRCC pts and identifying biomarkers for patients’ selection is clinically needed. Inflammatory indices from peripheral blood showed a prognostic value in different tumors and therapies, including immunotherapy. These biomarkers are inexpensive and readily available in clinical practice. We aimed to assess the prognostic role of the dynamic evaluation of these indices in immunotherapy-naïve pretreated mRCC pts. Methods: The Meet-URO 15 multicentric retrospective study enrolled 571 pretreated mRCC pts receiving nivolumab. The Δ-Meet-URO was a secondary analysis on the early variation through the first four cycles of therapy compared with baseline (difference, delta - Δ) of white blood cells, platelets and inflammatory indices, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII, platelets x NLR), their comparison with baseline values and correlation with treatment response, overall (OS) and progression-free survival (PFS). The baseline and Δ cut-offs were identified by ROC curves for OS. Results: The analysis was performed on 422 mRCC pts (74% of the entire cohort). Patients with ΔNeutrophils &lt; 730 at 2nd, 3rd and 4th cycles were more responders (p &lt; 0.001, p = 0.003 and p &lt; 0.001) with longer mPFS (11 vs 6.1 months, p = 0.033) and mOS (46.9 vs 20.8 months, p = 0.046) compared to ΔNeutrophils ≥ 730. There was a significant interaction between baseline and ΔNeutrophils on PFS (p = 0.047). Pts with baseline neutrophils ≥ 4330/mm3 had longer mPFS when ΔNeutrophils &lt; 730 (p = 0.002), whilst no difference was observed in those pts with baseline neutrophils &lt; 4330/mm3 according to ΔNeutrophils (p = 0.46). Similar non-significant trends were observed in mOS. Patients with ΔNLR &lt; 0.5 at 3rd and 4th cycles were more responders (p = 0.004 and p = 0.001, respectively) with doubled mPFS (12.1 vs 6.4 months, p = 0.007) and mOS (46.9 vs 21.7 months, p = 0.062) compared to ΔNLR ≥ 0.5. No significant interaction between baseline NLR and ΔNLR was observed in PFS and OS, suggesting a similar association between ΔNLR and PFS or OS, regardless of the baseline NLR cut-off of 3.2. The multivariable analyses confirmed all these results. Conclusions: The early assessment of NLR and neutrophils variations during immunotherapy for mRCC pts is a promising, affordable and non-invasive prognostic tool. Prospective and external validation analyses are warranted

Management of Germ Cell Tumors During the Outbreak of the Novel Coronavirus Disease-19 Pandemic:A Survey of International Expertise Centers

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has become a public health emergency affecting frail populations, including patients with cancer. This poses the question of whether cancer treatments can be postponed or modified without compromising their efficacy, especially for highly curable cancers such as germ cell tumors (GCTs). MATERIALS AND METHODS: To depict the state-of-the-art management of GCTs during the COVID-19 pandemic, a survey including 26 questions was circulated by e-mail among the physicians belonging to three cooperative groups: (a) Italian Germ Cell Cancer Group; (b) European Reference Network-Rare Adult Solid Cancers, Domain G3 (rare male genitourinary cancers); and (c) Genitourinary Medical Oncologists of Canada. Percentages of agreement between Italian respondents (I) versus Canadian respondents (C), I versus European respondents (E), and E versus C were compared by using Fisher's exact tests for dichotomous answers and chi square test for trends for the questions with three or more options. RESULTS: Fifty-three GCT experts responded to the survey: 20 Italian, 6 in other European countries, and 27 from Canada. Telemedicine was broadly used; there was high consensus to interrupt chemotherapy in COVID-19-positive patients (I = 75%, C = 55%, and E = 83.3%) and for use of granulocyte colony-stimulating factor primary prophylaxis for neutropenia (I = 65%, C = 62.9%, and E = 50%). The main differences emerged regarding the management of stage I and stage IIA disease, likely because of cultural and geographical differences. CONCLUSION: Our study highlights the common efforts of GCT experts in Europe and Canada to maintain high standards of treatment for patients with GCT with few changes in their management during the COVID-19 pandemic. IMPLICATIONS FOR PRACTICE: Despite the chaos, disruptions, and fears fomented by the COVID-19 illness, oncology care teams in Italy, other European countries, and Canada are delivering the enormous promise of curative management strategies for patients with testicular cancer and other germ cell tumors. At the same time, these teams are applying safe and innovative solutions and sharing best practices to minimize frequency and intensity of patient contacts with thinly stretched health care capacity

The prognostic value of the previous nephrectomy in pretreated metastatic renal cell carcinoma receiving immunotherapy: a sub-analysis of the Meet-URO 15 study

Nephrectomy is considered the backbone of managing patients with localized and selected metastatic renal cell carcinoma (mRCC). The prognostic role of nephrectomy has been widely investigated with cytokines and targeted therapy, but it is still unclear in the immunotherapy era

A specific inhibitor of lactate dehydrogenase overcame the resistance toward gemcitabine in hypoxic mesothelioma cells, and modulated the expression of the human equilibrative transporter-1

Malignant pleural mesothelioma (MPM) is a very hypoxic malignancy, and hypoxia has been associated with resistance towards gemcitabine. The muscle-isoform of lactate dehydrogenase (LDH-A) constitutes a major checkpoint for the switch to anaerobic glycolysis. Therefore we investigated the combination of a new LDH-A inhibitor (NHI-1) with gemcitabine in MPM cell lines. Under hypoxia (O2 tension of 1%) the cell growth inhibitory effects of gemcitabine, were reduced, as demonstrated by a 5- to 10-fold increase in IC50s. However, the simultaneous addition of NHI-1 was synergistic (combination index < 1). Flow cytometry demonstrated that hypoxia caused a G1 arrest, whereas the combination of NHI-1 significantly increased gemcitabine-induced cell death. Finally, the mRNA expression levels of the human equilibrative transporter-1 (hENT1) were significantly down-regulated under hypoxia, but treatment with NHI-1 was associated with a recovery of hENT1 expression. In conclusion, our data show that hypoxia increased MPM resistance to gemcitabine. However, cell death induction and modulation of the key transporter in gemcitabine uptake may contribute to the synergistic interaction of gemcitabine with the LDH-A inhibitor NHI-1 and support further studies for the rational development of this combination