Durvalumab Plus Gemcitabine and Cisplatin Versus Gemcitabine and Cisplatin in Biliary Tract Cancer: a Real-World Retrospective, Multicenter Study.

BACKGROUND: The TOPAZ-1 phase III trial reported a survival benefit with the anti-programmed cell death ligand 1 (anti-PD-L1) durvalumab in combination with gemcitabine and cisplatin in patients with advanced biliary tract cancer (BTC). OBJECTIVE: The present study investigated for the first time the impact on survival of adding durvalumab to cisplatin/gemcitabine compared with cisplatin/gemcitabine in a real-world setting. PATIENTS AND METHODS: The analyzed population included patients with unresectable, locally advanced, or metastatic BTC treated with durvalumab in combination with cisplatin/gemcitabine or with cisplatin/gemcitabine alone. The impact of adding durvalumab to chemotherapy in terms of overall survival (OS) and progression free survival (PFS) was investigated with univariate and multivariate analysis. RESULTS: Overall, 563 patients were included in the analysis: 213 received cisplatin/gemcitabine alone, 350 received cisplatin/gemcitabine plus durvalumab. At the univariate analysis, the addition of durvalumab was found to have an impact on survival, with a median OS of 14.8 months versus 11.2 months [hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.50-0.80, p = 0.0002] in patients who received cisplatin/gemcitabine plus durvalumab compared to those who received cisplatin/gemcitabine alone. At the univariate analysis for PFS, the addition of durvalumab to cisplatin/gemcitabine demonstrated a survival impact, with a median PFS of 8.3 months and 6.0 months (HR 0.57, 95% CI 0.47-0.70, p < 0.0001) in patients who received cisplatin/gemcitabine plus durvalumab and cisplatin/gemcitabine alone, respectively. The multivariate analysis confirmed that adding durvalumab to cisplatin/gemcitabine is an independent prognostic factor for OS and PFS, with patients > 70 years old and those affected by locally advanced disease experiencing the highest survival benefit. Finally, an exploratory analysis of prognostic factors was performed in the cohort of patients who received durvalumab: neutrophil-lymphocyte ratio (NLR) and disease stage were to be independent prognostic factors in terms of OS. The interaction test highlighted NLR ≤ 3, Eastern Cooperative Oncology Group Performance Status (ECOG PS) = 0, and locally advanced disease as positive predictive factors for OS on cisplatin/gemcitabine plus durvalumab. CONCLUSION: In line with the results of the TOPAZ-1 trial, adding durvalumab to cisplatin/gemcitabine has been confirmed to confer a survival benefit in terms of OS and PFS in a real-world setting of patients with advanced BTC.

Initial management approach for localized/locally advanced disease is critical to guide metastatic castration-resistant prostate cancer care.

BACKGROUND: Currently, several therapies are available for metastatic castration-resistant prostate cancer (mCRPC) but no specific clinical factors to personalize treatment. We first sought the prognostic value of duration on androgen-deprivation therapy (ADT) for hormone-sensitive prostate cancer (HSPC) in patients receiving androgen-receptor-signaling inhibitors (ARSI) for mCRPC. METHODS: A multicenter cohort of mCRPC patients who started ARSI between July 2011 and October 2021 was identified. Based on their initial disease burden and duration on ADT for HSPC, primary progressive (PP) men were classified into four groups: low/intermediate-risk localized disease (LOC) and high-risk localized/locally advanced disease (LAD) and short-term (ST) < 24 vs. long-term (LT) ADT ≥ 24 months, whereas de novo (DN) mHSPC were subdivided into short-time vs. long-time to CRPC. RESULTS: We included 919 mCRPC patients with a median age of 77 years [interquartile range (IQR) = 71-82)]. Median ADT duration in HSPC was 24 months (IQR = 14-40). Median follow-up was 91 months (IQR = 62-138), median OS and PFS from ARSI start were 20 (IQR 10-32) and 10 months (IQR = 5-19), respectively. In PP developing metastatic disease (n = 655, 71.3%), LOC and LAD with ST ADT had a greater than almost double-risk of death compared to LT ADT (LOC/ST: hazard ratio [HR] = 2.01; 95% CI 1.54-2.64; LAD/ST: HR = 1.73; 95% CI 1.34-2.24; p < 0.001). In the multivariate analysis including age, prognostic cohort, Gleason, ECOG, radical radiotherapy and prostatectomy, groups with ST ADT were associated with worse OS compared to LT ADT (LOC/ST: HR = 1.84; 95% CI 1.38-2.45; p < 0.001; LAD/ST: HR = 1.59; 95% CI 1.21-2.10; p < 0.001), along with ECOG > 2 (HR = 1.55; 95% CI 1.06-2.26; p = 0.03). There were also similar results of PFS. Moreover, long-time to CRPC in patients with history of DN mHSPC (n = 264, 28.7%) resulted in a better OS/PFS (HR = 0.76, 95% CI 0.56-1.02, p = 0.064 and HR = 0.74, 95% CI 0.55-0.99, p = 0.042, respectively). CONCLUSIONS: Our study showed that duration on ADT for mHSPC was significantly associated with survival in mCRPC undergoing ARSI. These findings suggest a possible connection between initial management of prostate tumour and a better prognostication in mCRPC. Prospective trials are warranted.

Tumor treating fields for the treatment of glioblastoma: Current understanding and future perspectives.

Background: This review focuses on the recently published evidence on tumor treating fields (TTFields) administered alone or in combination with locoregional and systemic options for treating glioblastoma (GBM) in the past ten years. The aim is to critically summarize the novelty and results obtained with this innovative tool, which is becoming part of the armamentarium of neurosurgeons and neuro-oncologists. Methods: A comprehensive search and analysis were conducted on pivotal studies published in the past ten years. Furthermore, all completed clinical trials, whose results were published on clinicaltrials.gov, were examined and included in the present review, encompassing both recurrent (r) and newly diagnosed (n) GBM. Finally, an additional examination of the ongoing clinical trials was also conducted. Results: Recent trials have shown promising results both in patients with nGBM and rGBM/progressive (rGBM), leading to Food and Drug Administration approval in selected patients and the Congress of Neurological Surgeons to include TTFields into current guidelines on the management of GBM (P100034/S001-029). Recently, different randomized trials have demonstrated promising results of TTFields in combination with standard treatment of n- and rGBM, especially when considering progression-free and overall survival, maintaining a low rate of mild to moderate adverse events. Conclusion: Optimal outcomes were obtained in nGBM and progressive disease. A possible future refinement of TTFields could significantly impact the treatment of rGBM and the actual standard of care for GBM, given the better safety profile and survival effects.

Multidisciplinary management of HER2-positive breast cancer with brain metastases: An evidence-based pragmatic approach moving from pathophysiology to clinical data.

INTRODUCTION: About 30-50 % of stage IV HER2+ breast cancers (BC) will present brain metastases (BMs). Their management is based on both local treatment and systemic therapy. Despite therapeutic advances, BMs still impact on survival and quality of life and the development of more effective systemic therapies represents an unmet clinical need. MATERIALS AND METHODS: A thorough analysis of the published literature including ongoing clinical trials has been performed, investigating concepts spanning from the pathophysiology of tumor microenvironment to clinical considerations with the aim to summarize the current and future locoregional and systemic strategies. RESULTS: Different trials have investigated monotherapies and combination treatments, highlighting how the blood-brain barrier (BBB) represents a major problem hindering diffusion and consequently efficacy of such options. Trastuzumab has long been the mainstay of systemic therapy and over the last two decades other HER2-targeted agents including lapatinib, pertuzumab, and trastuzumab emtansine, as well as more recently neratinib, tucatinib, and trastuzumab deruxtecan, have been introduced in clinical practice after showing promising results in randomized controlled trials. CONCLUSIONS: We ultimately propose an evidence-based treatment algorithm for clinicians treating HER2 + BCs patients with BMs.

Cytosolic and mitochondrial translation elongation are coordinated through the molecular chaperone TRAP1 for the synthesis and import of mitochondrial proteins.

A complex interplay between mRNA translation and cellular respiration has been recently unveiled, but its regulation in humans is poorly characterized in either health or disease. Cancer cells radically reshape both biosynthetic and bioenergetic pathways to sustain their aberrant growth rates. In this regard, we have shown that the molecular chaperone TRAP1 not only regulates the activity of respiratory complexes, behaving alternatively as an oncogene or a tumor suppressor, but also plays a concomitant moonlighting function in mRNA translation regulation. Herein, we identify the molecular mechanisms involved, showing that TRAP1 (1) binds both mitochondrial and cytosolic ribosomes, as well as translation elongation factors; (2) slows down translation elongation rate; and (3) favors localized translation in the proximity of mitochondria. We also provide evidence that TRAP1 is coexpressed in human tissues with the mitochondrial translational machinery, which is responsible for the synthesis of respiratory complex proteins. Altogether, our results show an unprecedented level of complexity in the regulation of cancer cell metabolism, strongly suggesting the existence of a tight feedback loop between protein synthesis and energy metabolism, based on the demonstration that a single molecular chaperone plays a role in both mitochondrial and cytosolic translation, as well as in mitochondrial respiration.

Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer: An early exploratory analysis of real-world data.

BACKGROUND: The TOPAZ-1 phase III trial reported a survival benefit with the anti-programmed death cell ligand 1 (anti-PD-L1) durvalumab in combination with gemcitabine and cisplatin in patients with advanced biliary tract cancer. The present study investigated the efficacy and safety of this new standard treatment in a real-world setting. METHODS: The analysed population included patients with unresectable, locally advanced or metastatic adenocarcinoma of the biliary tract treated with durvalumab in combination with gemcitabine and cisplatin at 17 Italian centres. The primary endpoint of the study was progression-free survival (PFS), whereas secondary endpoints included overall survival (OS), overall response rate (ORR) and safety. Unadjusted and adjusted hazard ratios (HRs) by baseline characteristics were calculated using the Cox proportional hazards model. RESULTS: From February 2022 to November 2022, 145 patients were enrolled. After a median follow-up of 8.5 months (95% CI: 7.9-13.6), the median PFS was 8.9 months (95% CI: 7.4-11.7). Median OS was 12.9 months (95% CI: 10.9-12.9). The investigator-assessed confirmed ORR was 34.5%, and the disease control rate was 87.6%. Any grade adverse events (AEs) occurred in 137 patients (94.5%). Grades 3-4 AEs occurred in 51 patients (35.2%). The rate of immune-mediated AEs (imAEs) was 22.7%. Grades 3-4 imAEs occurred in 2.1% of the patients. In univariate analysis, non-viral aetiology, ECOG PS >0 and NLR ≥3 correlated with shorter PFS. CONCLUSION: The results reported in this first real-world analysis mostly confirmed the results achieved in the TOPAZ-1 trial in terms of PFS, ORR and safety.

Pancreatic Enzyme Replacement and Nutritional Support With nab-Paclitaxel-based First-Line Chemotherapy Regimens in Metastatic Pancreatic Cancer.

BACKGROUND: At diagnosis, more than 80% of patients with pancreatic cancer (PC) suffer from significant weight loss due to malnutrition which is a major concern for patient management, and this may negatively impact treatment outcomes and patient prognosis. PATIENTS AND METHODS: We performed an observational, retrospective study on patients with metastatic PC (mPC) undergoing first-line chemotherapy with nab-Paclitaxel containing schedules and receiving or not receiving nutritional support (NS) and pancreatic enzyme replacement therapy (PERT) to investigate their relevance in this setting. RESULTS: We observed that PERT and ancillary dietary interventions are related to longer overall survival (OS; median: 16.5 vs. 7.5 months, P < .001) and have a significant, independent, prognostic impact for better outcomes (P = .013), independently from the therapeutic regimen. Furthermore, PERT and NS prevented weight loss during chemotherapy and obtained an improvement of nutritional parameters such as phase angle and free-fat mass index, after 3 months of anticancer treatment. Consistently, the positive impact on OS correlated also with the prevention of Karnofsky performance status deterioration and a lower incidence of maldigestion-related symptoms. CONCLUSIONS: Our data suggest that an early and well-conducted NS in patients with mPC may impact on survival and preserve performance status, thus improving quality of life.

Cytosolic and mitochondrial translation elongation are coordinated through the molecular chaperone TRAP1 for the synthesis and import of mitochondrial proteins.

A complex interplay between mRNA translation and cellular respiration has been recently unveiled, but its regulation in humans is poorly characterized in either health or disease. Cancer cells radically reshape both biosynthetic and bioenergetic pathways to sustain their aberrant growth rates. In this regard, we have shown that the molecular chaperone TRAP1 not only regulates the activity of respiratory complexes, behaving alternatively as an oncogene or a tumor suppressor, but also plays a concomitant moonlighting function in mRNA translation regulation. Herein we identify the molecular mechanisms involved, demonstrating that TRAP1: i) binds both mitochondrial and cytosolic ribosomes as well as translation elongation factors, ii) slows down translation elongation rate, and iii) favors localized translation in the proximity of mitochondria. We also provide evidence that TRAP1 is coexpressed in human tissues with the mitochondrial translational machinery, which is responsible for the synthesis of respiratory complex proteins. Altogether, our results show an unprecedented level of complexity in the regulation of cancer cell metabolism, strongly suggesting the existence of a tight feedback loop between protein synthesis and energy metabolism, based on the demonstration that a single molecular chaperone plays a role in both mitochondrial and cytosolic translation, as well as in mitochondrial respiration.

Circulating myeloid-derived suppressor cells and survival in prostate cancer patients: systematic review and meta-analysis.

BACKGROUND: Immunotherapy has not achieved improvement of survival in prostate cancer patients. Myeloid-derived suppressor cells (MDSCs) in tumor microenvironment can hamper its efficacy. Some preclinical studies explored the role of MDSCs in prostate cancer development. We aimed to verify the availability of studies exploring the prognostic effect of circulating MDSCs in prostate cancer patients. METHODS: We systematically selected studies for a meta-analysis, which compares survival between prostate cancer patients with high vs low circulating MDSC levels. We extracted or calculated hazard ratios (HRs) and relative 95% confidence intervals (CIs) in terms of overall survival (OS) from selected studies. We calculated the pooled HR and relative 95% CIs and estimated publication bias. RESULTS: Among 133 studies retrieved from search on Pubmed, 5 eligible studies (236 prostate cancer patients) met inclusion criteria. High circulating MDSC levels are associated with a worse OS (HR = 2.19; 95%CI = 1.51-3.17). Heterogeneity was not significant (I2 = 0%; p = 0.64). Publication bias was also not significant (Egger's test, p = 0.09). CONCLUSIONS: High levels of circulating MDSCs induce a worse OS in prostate cancer patients than in those with low levels. This finding supports the importance of MDSC detection and targeting also in prostate cancer patients.

Regulation of mitochondrial complex III activity and assembly by TRAP1 in cancer cells.

BACKGROUND: Metabolic reprogramming is an important issue in tumor biology. A recently-identified actor in this regard is the molecular chaperone TRAP1, that is considered an oncogene in several cancers for its high expression but an oncosuppressor in others with predominant oxidative metabolism. TRAP1 is mainly localized in mitochondria, where it interacts with respiratory complexes, although alternative localizations have been described, particularly on the endoplasmic reticulum, where it interacts with the translational machinery with relevant roles in protein synthesis regulation. RESULTS: Herein we show that, inside mitochondria, TRAP1 binds the complex III core component UQCRC2 and regulates complex III activity. This decreases respiration rate during basal conditions but allows sustained oxidative phosphorylation when glucose is limiting, a condition in which the direct TRAP1-UQCRC2 binding is disrupted, but not TRAP1-complex III binding. Interestingly, several complex III components and assembly factors show an inverse correlation with survival and response to platinum-based therapy in high grade serous ovarian cancers, where TRAP1 inversely correlates with stage and grade and directly correlates with survival. Accordingly, drug-resistant ovarian cancer cells show high levels of complex III components and high sensitivity to complex III inhibitory drug antimycin A. CONCLUSIONS: These results shed new light on the molecular mechanisms involved in TRAP1-dependent regulation of cancer cell metabolism and point out a potential novel target for metabolic therapy in ovarian cancer.

Solitary fibrous tumor/hemangiopericytoma of the cervical spine: A systematic review of the literature with an illustrative case.

Background: In the WHO 2016 classification of central nervous system tumors, solitary fibrous tumors (SFT) and hemangiopericytomas (HPC) were considered part of the same category given a shared mutation. Nevertheless, since the new 2021 WHO classification, the term "hemangiopericytoma" has been retired, and SFT is considered an independent pathological entity. Methods: We reviewed the literature following preferred reporting items for systematic reviews and meta-analyses guidelines focusing on the treatment options and prognosis of patients with cervical SFT. We also present a 68-year-old female with spinal intradural extramedullary SFT complicated by diffuse extension into paravertebral tissues and muscles. Results: We found 38 cervical SFT in the literature. Patients averaged 47.3 years of age and 47.4% were female. Typically, these lesions spanned two spinal levels resulting in cord compression and most frequently exhibited benign features (i.e., diagnosed as Grade I SFTs). Interestingly, two patients exhibited distant metastases and had initial pathology consistent with grade II SFT. Conclusion: SFT of the cervical spine is rare and its management varies according to the histological grade and the clinical behavior, generally warranting surgical excision and adjuvant radiation therapy and/or systemic chemotherapy.

Recurrent Glioblastoma Treatment: State of the Art and Future Perspectives in the Precision Medicine Era.

Current treatment guidelines for the management of recurrent glioblastoma (rGBM) are far from definitive, and the prognosis remains dismal. Despite recent advancements in the pharmacological and surgical fields, numerous doubts persist concerning the optimal strategy that clinicians should adopt for patients who fail the first lines of treatment and present signs of progressive disease. With most recurrences being located within the margins of the previously resected lesion, a comprehensive molecular and genetic profiling of rGBM revealed substantial differences compared with newly diagnosed disease. In the present comprehensive review, we sought to examine the current treatment guidelines and the new perspectives that polarize the field of neuro-oncology, strictly focusing on progressive disease. For this purpose, updated PRISMA guidelines were followed to search for pivotal studies and clinical trials published in the last five years. A total of 125 articles discussing locoregional management, radiotherapy, chemotherapy, and immunotherapy strategies were included in our analysis, and salient findings were critically summarized. In addition, an in-depth description of the molecular profile of rGBM and its distinctive characteristics is provided. Finally, we integrate the above-mentioned evidence with the current guidelines published by international societies, including AANS/CNS, EANO, AIOM, and NCCN.

Lymphocyte antigen 6G6D-mediated modulation through p38α MAPK and DNA methylation in colorectal cancer.

In addition to being novel biomarkers for poor cancer prognosis, members of Lymphocyte antigen-6 (Ly6) gene family also play a crucial role in avoiding immune responses to tumors. However, it has not been possible to identify the underlying mechanism of how Ly6 gene regulation operates in human cancers. Transcriptome, epigenome and proteomic data from independent cancer databases were analyzed in silico and validated independently in 334 colorectal cancer tissues (CRC). RNA mediated gene silencing of regulatory genes, and treatment with MEK and p38 MAPK inhibitors were also tested in vitro. We report here that the Lymphocyte antigen 6G6D is universally downregulated in mucinous CRC, while its activation progresses through the classical adenoma-carcinoma sequence. The DNA methylation changes in LY6G6D promoter are intimately related to its transcript regulation, epigenomic and histological subtypes. Depletion of DNA methyltransferase 1 (DNMT1), which maintains DNA methylation, results in the derepression of LY6G6D expression. RNA-mediated gene silencing of p38α MAPK or its selective chemical inhibition, however, reduces LY6G6D expression, reducing trametinib's anti-inflammatory effects. Patients treated with FOLFOX-based first-line therapy experienced decreased survival due to hypermethylation of the LY6G6D promoter and decreased p38α MAPK signaling. We found that cancer-specific immunodominant epitopes are controlled by p38α MAPKs signaling and suppressed by DNA methylation in histological variants with Mucinous differentiation. This work provides a promising prospective for clinical application in diagnosis and personalized therapeutic strategies of colorectal cancer.

Primary versus secondary antiemetic prophylaxis with NK1 receptor antagonists in patients affected by gastrointestinal malignancies and treated with a doublet or triplet combination regimen including oxaliplatin and/or irinotecan plus fluoropyrimidines: A propensity score matched analysis.

Aim: The aim of the current study is to investigate the impact of primary compared to secondary chemotherapy-induced nausea and vomiting (CINV) prophylaxis with NK1 receptor antagonists (NK1-RA) in patients affected by gastrointestinal malignancies and treated with oxaliplatin- and/or irinotecan-based doublet or triplet regimens. Study design and methods: Clinical data of patients affected by gastrointestinal malignancies, treated with an oxaliplatin and/or irinotecan-based doublet or triplet regimen as neo/adjuvant or advanced-line treatment, and who received NK1-RA as primary (from the first cycle of treatment) or secondary (after the onset of CINV with a previous regimen with 5HT3-RA and dexamethasone) prophylaxis for CINV, were retrospectively collected in an observational study involving 16 Italian centers. A propensity score matching was performed by taking into account the following stratification factors: sex (male vs. female), age (< vs. ≥70 years old), overweight (body mass index, BMI < vs. ≥25), underweight (BMI < vs. ≥19), disease spread (early vs. advanced/metastatic), tumor type (esophagogastric cancer vs. the rest, hepatobiliary tumor vs. the rest, colorectal cancer vs. the rest), type of NK1-RA used as primary/secondary prophylaxis (netupitant-palonosetron vs. fosaprepitant/aprepitant), concomitant use of opioids (yes vs. no), concomitant use of antidepressant/antipsychotic drugs (yes vs. no), Eastern Cooperative Oncology Group (ECOG) performance status at the start of NK1-RA treatment (0 vs. 1-2), and intensity of chemotherapy regimen (doublet vs. triplet). Results: Among 409 patients included from January 2015 to January 2022 and eligible for analysis, 284 (69%) and 125 (31%) were treated with NK1-RA as primary and secondary antiemetic prophylaxis, respectively. After matching, primary NK1-RA use was not associated with higher rates of protection from emesis regardless the emesis phase (acute phase, p = 0.34; delayed phase, p = 0.14; overall phase, p = 0.80). On the other hand, a lower rate of relevant nausea (p = 0.02) and need for rescue antiemetic therapy (p = 0.000007) in the overall phase was found in primary NK1-RA users. Furthermore, a higher rate of both complete antiemetic response (p = 0.00001) and complete antiemetic protection (p = 0.00007) in the overall phase was more frequently observed in primary NK1-RA users. Finally, chemotherapy delays (p = 0.000009) and chemotherapy dose reductions (p = 0.0000006) were less frequently observed in primary NK1-RA users. Conclusion: In patients affected by gastrointestinal malignancies, a primary CINV prophylaxis with NK1-RA, 5HT3-RA, and dexamethasone might be appropriate, particularly in those situations at higher risk of emesis and in which it is important to avoid dose delays and/or dose reductions, keeping a proper dose intensity of chemotherapy drugs.

Are We Ready to Implement Molecular Subtyping of Bladder Cancer in Clinical Practice? Part 2: Subtypes and Divergent Differentiation.

Following several attempts to achieve a molecular stratification of bladder cancer (BC) over the last decade, a "consensus" classification has been recently developed to provide a common base for the molecular classification of bladder cancer (BC), encompassing a six-cluster scheme with distinct prognostic and predictive characteristics. In order to implement molecular subtyping (MS) as a risk stratification tool in routine practice, immunohistochemistry (IHC) has been explored as a readily accessible, relatively inexpensive, standardized surrogate method, achieving promising results in different clinical settings. The second part of this review deals with the pathological and clinical features of the molecular clusters, both in conventional and divergent urothelial carcinoma, with a focus on the role of IHC-based subtyping.

Solitary metastasis from renal cell carcinoma to the choroid plexus: A case illustration and review of the literature.

Background: Metastatic renal cell carcinoma (RCC) of the choroid plexus is an exceedingly rare condition, with only 35 reported cases to date. Surgical resection of these tumors poses a unique challenge to neurosurgeons since evidence-based treatment guidelines are yet to be designed. Case Description: The authors describe the case of a 58-year-old woman presenting with progressive neurological deterioration 5 years after a right nephrectomy for a WHO 2016 Stage I RCC. A head, contrast-enhanced, and magnetic resonance revealed signs of obstructive hydrocephalus and a homogeneously contrast-enhancing 5 cm mass located in the trigone of the right lateral ventricle. Furthermore, a search of the literature was performed in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. After screening for duplicates, 35 publications met the eligibility criteria. Finally, 17 manuscripts were included for analysis. Moreover, a detailed description of an illustrative case is provided. The median age at diagnosis for intraventricular metastasis from RCC was 62.9 years, showing a slight female prevalence. The lateral ventricles were reported as the most frequent location with only one patient presenting with obstructive hydrocephalus caused by the obliteration of Monro foramen. Management options included either open craniotomy or radiosurgery. Conclusion: The management of choroid plexus metastasis from RCC is still controversial with various authors proposing different treatment strategies. In this article, in addition to an in-depth case description, a qualitative review of the literature on metastatic RCCs of the choroid plexus using the PRISMA is provided.

Differential and divergent activity of insulin-like growth factor binding protein 6 in platinum-sensitive versus platinum-resistant high-grade serous ovarian carcinoma cell lines.

Insulin-like growth factor binding protein 6 (IGFBP6) is a secreted protein with a controversial role in human malignancies, being downregulated in most types of human cancer, but upregulated in selected tumors. Ovarian cancer (OC) is a human malignancy characterized by IGFBP6 downregulation; however, the significance of its low expression during ovarian carcinogenesis is still poorly understood. In the present study, IGFBP6 expression and activation of its associated signaling pathway were evaluated in two matched OC cell lines derived from a high-grade serous OC before and after platinum resistance (PEA1 and PEA2 cells, respectively). A whole genome gene expression analysis was comparatively performed in both cell lines upon IGFBP6 stimulation using Illumina technology. IGFBP6 gene expression data from human OC cases were obtained from public datasets. Gene expression data from public datasets confirmed the downregulation of IGFBP6 in primary and metastatic OC tissues compared with in normal ovarian tissues. The comparative analysis of platinum-sensitive (PEA1) and platinum-resistant (PEA2) cell lines showed quantitative and qualitative differences in the activation of IGFBP6 signaling. Notably, IGFBP6 enhanced ERK1/2 phosphorylation only in PEA1 cells, and induced more evident and significant gene expression reprogramming in PEA1 cells compared with in PEA2 cells. Furthermore, the analysis of selected genes modulated by IGFBP6 (i.e., FOS, JUN, TNF, IL6, IL8 and EGR1) exhibited an inverse regulation in PEA1 versus PEA2 cells. In addition, selected hallmarks (TNFA_signaling_via_NFKB, TGF_beta_signaling, P53_pathway) and IL-6 signaling were positively regulated in PEA1 cells, whereas they were inhibited in PEA2 cells in response to IGFBP6. These data suggested that dysregulation of IGFBP6 signaling may serve a role in the progression of OC, and is likely associated with the development of platinum resistance.

TRAP1 regulates the response of colorectal cancer cells to hypoxia and inhibits ribosome biogenesis under conditions of oxygen deprivation.

Metabolic rewiring fuels rapid cancer cell proliferation by promoting adjustments in energetic resources, and increasing glucose uptake and its conversion into lactate, even in the presence of oxygen. Furthermore, solid tumors often contain hypoxic areas and can rapidly adapt to low oxygen conditions by activating hypoxia inducible factor (HIF)­1α and several downstream pathways, thus sustaining cell survival and metabolic reprogramming. Since TNF receptor­associated protein 1 (TRAP1) is a HSP90 molecular chaperone upregulated in several human malignancies and is involved in cancer cell adaptation to unfavorable environments and metabolic reprogramming, in the present study, its role was investigated in the adaptive response to hypoxia in human colorectal cancer (CRC) cells and organoids. In the present study, glucose uptake, lactate production and the expression of key metabolic genes were evaluated in TRAP1­silenced CRC cell models under conditions of hypoxia/normoxia. Whole genome gene expression profiling was performed in TRAP1­silenced HCT116 cells exposed to hypoxia to establish the role of TRAP1 in adaptive responses to oxygen deprivation. The results revealed that TRAP1 was involved in regulating hypoxia­induced HIF­1α stabilization and glycolytic metabolism and that glucose transporter 1 expression, glucose uptake and lactate production were partially impaired in TRAP1­silenced CRC cells under hypoxic conditions. At the transcriptional level, the gene expression reprogramming of cancer cells driven by HIF­1α was partially inhibited in TRAP1­silenced CRC cells and organoids exposed to hypoxia. Moreover, Gene Set Enrichment Analysis of TRAP1­silenced HCT116 cells exposed to hypoxia demonstrated that TRAP1 was involved in the regulation of ribosome biogenesis and this occurred with the inhibition of the mTOR pathway. Therefore, as demonstrated herein, TRAP1 is a key factor in maintaining HIF­1α­induced genetic/metabolic program under hypoxic conditions and may represent a promising target for novel metabolic therapies.

The classification of neuroendocrine neoplasms of the lung and digestive system according to WHO, 5th edition: similarities, differences, challenges, and unmet needs.

Neuroendocrine neoplasms (NENs) are a group of disease entities sharing common morphological, ultrastructural and immunophenotypical features, yet with distinct biological behavior and clinical outcome, ranging from benign to frankly malignant. Accordingly, a spectrum of therapeutic options for each single entity is available, including somatostatin analogues (SSA), mTOR-inhibitors, peptide receptor radionuclide therapy (PRRT), non-platinum and platinum chemotherapy. In the last few decades, several attempts have been made to better stratify these lesions refining the pathological classifications, so as to obtain an optimal correspondence between the scientific terminology and, the predictive and prognostic features of each disease subtype, and achieve a global Classification encompassing NENs arising at different anatomical sites. The aim of this review was to analyze, compare and discuss the main features and issues of the latest WHO Classifications of NENs of the lung and the digestive system, in order to point out the strengths and limitations of our current understanding of these complex diseases.

What Do We Have to Know about PD-L1 Expression in Prostate Cancer? A Systematic Literature Review (Part 6): Correlation of PD-L1 Expression with the Status of Mismatch Repair System, BRCA, PTEN, and Other Genes.

Pembrolizumab (anti-PD-1) is allowed in selected metastatic castration-resistant prostate cancer (PC) patients showing microsatellite instability/mismatch repair system deficiency (MSI-H/dMMR). BRCA1/2 loss-of-function is linked to hereditary PCs and homologous recombination DNA-repair system deficiency: poly-ADP-ribose-polymerase inhibitors can be administered to BRCA-mutated PC patients. Recently, docetaxel-refractory metastatic castration-resistant PC patients with BRCA1/2 or ATM somatic mutations had higher response rates to pembrolizumab. PTEN regulates cell cycle/proliferation/apoptosis through pathways including the AKT/mTOR, which upregulates PD-L1 expression in PC. Our systematic literature review (PRISMA guidelines) investigated the potential correlations between PD-L1 and MMR/MSI/BRCA/PTEN statuses in PC, discussing few other relevant genes. Excluding selection biases, 74/677 (11%) PCs showed dMMR/MSI; 8/67 (12%) of dMMR/MSI cases were PD-L1+. dMMR-PCs included ductal (3%) and acinar (14%) PCs (all cases tested for MSI were acinar-PCs). In total, 15/39 (39%) PCs harbored BRCA1/2 aberrations: limited data are available for PD-L1 expression in these patients. 13/137 (10%) PTEN- PCs were PD-L1+; 10/29 (35%) PD-L1+ PCs showed PTEN negativity. SPOP mutations may increase PD-L1 levels, while the potential correlation between PD-L1 and ERG expression in PC should be clarified. Further research should verify how the efficacy of PD-1 inhibitors in metastatic castration-resistant PCs is related to dMMR/MSI, DNA-damage repair genes defects, or PD-L1 expression.