Sarcomatoid Component Research Articles

Hepatic adenosquamous carcinoma with sarcomatous transformation: a case report and review of the literature.

Adenosquamous carcinoma (ASC) with the presence of a sarcomatous component is exceptionally uncommon in intrahepatic cholangiocarcinoma (iCCA). We report a case of hepatic ASC with rhabdoid transformation, one variation of sarcomatous change. A 72-year-old man was admitted to our hospital after being diagnosed with a 45mm-diameter neoplastic lesion in the right hepatic duct on abdominal computed tomography. Laboratory findings showed increases in AST, ALT, ALP, gamma-GT, CA19-9 and DUPAN-II. The patient then underwent an extended right hepatectomy. Histopathologically, the tumor was composed of an ASC component within an abundant fibrous stroma and a sarcomatoid carcinoma component. By immunohistochemistry, keratin 7 and keratin 19 were expressed by all tumor cells. Expression of keratin 5/6, p40 and p63 was restricted to the squamous component. The sarcomatoid component was immunoreactive for vimentin with no loss of INI1 expression. This component also showed a loss of membranous E-cadherin expression and a reduction of membranous β-catenin expression. Staining for desmin, myoglobin and HepPar1 was negative in any tumor cells. The patient died of liver failure 3months after surgery. This report aims to provide a better understanding of the clinicopathological characteristics and disease progression of the rare variants of iCCA to aid diagnosis and treatment.

Comparison of the efficacy of sunitinib and pazopanib in patients with advanced non-clear renal cell carcinoma

Non-clear cell renal cell carcinoma (non-ccRCC) is a highly heterogeneous disease group, accounting for approximately 25% of all RCC cases. Due to its rarity and especially heterogeneity, phase III trial data is limited and treatment options generally follow those of clear cell RCC. In the literature, there exists a number of studies with sunitinib, cabozantinib, and everolimus, but data on the efficacy of pazopanib are limited. Our aim in this study was to compare the efficacy of pazopanib and sunitinib, in a multicenter retrospective cohort of non-ccRCC patients. Our study included patients diagnosed with non-ccRCC who received pazopanib or sunitinib treatment as first-line therapy from 22 tertiary hospitals. We compared the progression-free survival (PFS), overall survival (OS), and response rates of pazopanib and sunitinib treatments. Additionally, we investigated prognostic factors in non-ccRCC. PFS and response rates of sunitinib and pazopanib were found to be similar, while a numerical difference was observed in OS. Being 65 years and older, being in the intermediate or poor risk group according to the International Metastatic Renal Cell Carcinoma Database Consortium, having liver metastases, presence of a sarcomatoid component, and having de novo metastatic disease were found to be significantly associated with shorter PFS. Pazopanib treatment appears to have similar efficacy in the treatment of non-ccRCC compared to sunitinib. Though randomized controlled trials are lacking and will probably be never be available, we suggest that pazopanib could be a preferred agent like sunitinib and cabozantinib.

1700P Impact of sarcomatoid (S) and rhabdoid (R) components (comp.) on the efficacy of nivolumab (N) +/- ipilimumab (I) in the first-line (L1) treatment of metastatic clear cell renal cell carcinoma (mRCC) in the randomized phase II BIONIKK trial

1700P Impact of sarcomatoid (S) and rhabdoid (R) components (comp.) on the efficacy of nivolumab (N) +/- ipilimumab (I) in the first-line (L1) treatment of metastatic clear cell renal cell carcinoma (mRCC) in the randomized phase II BIONIKK trial

Clinical outcome predictors for metastatic renal cell carcinoma: a retrospective multicenter real-life case series

Over the last decades, the therapeutic armamentarium of metastatic renal cell carcinoma (mRCC) has been revolutionized by the advent of tyrosin-kinase inhibitors (TKI), immune-checkpoint inhibitors (ICI), and immune-combinations. RCC is heterogeneous, and even the most used validated prognostic systems, fail to describe its evolution in real-life scenarios. Our aim is to identify potential easily-accessible clinical factors and design a disease course prediction system. Medical records of 453 patients with mRCC receiving sequential systemic therapy in two high-volume oncological centres were reviewed. The Kaplan-Meier method and Cox proportional hazard model were used to estimate and compare survival between groups. As first-line treatment 366 patients received TKI monotherapy and 64 patients received ICI, alone or in combination. The mean number of therapy lines was 2.5. A high Systemic Inflammation Index, a BMI under 25 Kg/m2, the presence of bone metastases before systemic therapy start, age over 65 years at the first diagnosis, non-clear-cell histology and sarcomatoid component were correlated with a worse OS. No significant OS difference was observed between patients receiving combination therapies and those receiving exclusively monotherapies in the treatment sequence. Our relapse prediction system based on pathological stage and histological grade was effective in predicting the time between nephrectomy and systemic treatment. Our multicentric retrospective analysis reveals additional potential prognostic factors for mRCC, not included in current validated prognostic systems, suggests a model for disease course prediction and describes the outcomes of the most common therapeutic strategies currently available.

Cabozantinib and nivolumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial

Supplementation with CBM588, a bifidogenic live bacterial product, has been associated with improved clinical outcomes in persons with metastatic renal cell carcinoma (mRCC) receiving nivolumab and ipilimumab. However, its effect on those receiving tyrosine kinase inhibitor-based combinations is unknown. In this open-label, randomized, investigator-initiated, phase 1 study, 30 participants with locally advanced or mRCC with histological confirmation of clear cell, papillary or sarcomatoid component were randomized in a 2:1 fashion to receive cabozantinib (an inhibitor of vascular endothelial growth factor receptor, MET and AXL) and nivolumab (anti-programmed cell death protein 1) with or without CBM588 as first-line treatment. Metagenomic sequencing was performed on stool samples to characterize their gut microbiome at baseline and 13 weeks into treatment. The primary endpoint was a change in the relative abundance of Bifidobacterium spp.; secondary endpoints included objective response rate (ORR), progression-free survival (PFS) and toxicity profile. The primary endpoint of the study was not met and the addition of CBM588 to cabozantinib and nivolumab did not result in a difference in the relative abundance of Bifidobacterium spp. or alpha diversity (as measured by the Shannon index). However, ORR was significantly higher in participants treated with CBM588 compared to those in the control arm (14 of 19, 74% versus 2 of 10, 20%; P = 0.01). PFS at 6 months was 84% (16 of 19) and 60% (6 of 10) in the experimental and control arms, respectively. No significant difference in toxicity profile was seen between the study arms. Our results provide a preliminary signal of improved clinical activity with CBM588 in treatment-naive participants with mRCC receiving cabozantinib and nivolumab. Further investigation is needed to confirm these findings and better characterize the underlying mechanism driving this effect.ClinicalTrials.gov identifier: NCT05122546

Salivary duct carcinoma with squamous differentiation: histomorphological and immunophenotypical analysis of six cases.

Salivary duct carcinoma (SDC) is an aggressive salivary malignancy with multiple morphological subtypes. Primary salivary squamous cell carcinoma (SCC) requires exclusion of high-grade salivary malignancies and metastatic disease and is considered exceptionally rare. We report six cases of SDC with resemblance to SCC on account of variable, but often extensive, squamous differentiation. A retrospective review (2009-2023) at two institutions of SDC with histological and immunophenotypical evidence of squamous differentiation identified six cases. Medical charts and available glass slides were reviewed. There were five males and one female with a median age of 63 years, with tumours involving the parotid (five of six) and submandibular (one of six) glands. All six tumours showed a conventional SDC component comprising < 5-90% of viable tumour. Squamous differentiation comprised 10-95%+ (> 75% in three of six cases) of total viable tumour, and demonstrated CK5/6, p63 and/or p40 immunoexpression in all cases. A sarcomatoid component, comprising 10-60% of viable tumour, was present in three of six (50%) cases. All tumours were androgen receptor (AR)-positive, but only two of six (33.3%) retained AR immunoreactivity in the squamous component. Metastatic SDC to regional lymph nodes exhibited exclusive squamous differentiation in two of six (33.3%) cases. Squamous differentiation, histologically and immunophenotypically, can be extensive in SDC. AR expression may be lost in the squamous component and metastases may demonstrate only squamous differentiation. These findings cast further doubt on the existence of primary salivary SCC. SDC should be considered whenever encountering a carcinoma with squamous differentiation in major salivary glands or within cervical lymph nodes in the setting of a salivary mass.

Circulating kidney injury molecule-1 (KIM-1) biomarker analysis in IMmotion010: A randomized phase 3 study of adjuvant (adj) atezolizumab (atezo) vs placebo (pbo) in patients (pts) with renal cell carcinoma (RCC) at increased risk of recurrence after resection.

4506 Background: In IMmotion010, adj atezo did not prolong investigator-assessed disease-free survival (DFS; primary endpoint) vs pbo after resection in pts with RCC (HR: 0.93, 95% CI: 0.75, 1.15; P=0.50; Pal Lancet 2023). This exploratory analysis of circulating protein biomarkers was performed to identify high-risk pts with minimal residual disease (MRD) who may show differential benefit from treatment (tx) with atezo. Methods: Pts with RCC with clear-cell or sarcomatoid component and increased recurrence risk post nephrectomy were randomized 1:1 to atezo 1200 mg or pbo IV q3w for 16 cycles or 1 year. A retrospective proteomics analysis was done with an affinity-based proximity extension assay (PEA) panel of ≈3000 analytes to identify circulating proteins with differential abundance patterns in matched serum samples (baseline vs at recurrence). A high sensitivity electrochemiluminescence (ECL) assay was then used to evaluate levels of KIM-1, a membrane glycoprotein overexpressed in clear-cell and papillary RCC, in all available baseline and post-tx serum samples. Outcomes in pts with KIM-1 high (≥86 pg/mL) vs low status at baseline were analyzed. Results: In pts with matched PEA samples (n=73), circulating KIM-1 was identified as the most significantly enriched protein at recurrence vs baseline. Of 778 pts enrolled in IMmotion010, 752 (97%) had baseline KIM-1 data (high: 300 [40%]; low: 452 [60%]). KIM-1–high status was associated with reduced DFS, and pts with KIM-1 high had better DFS with atezo vs pbo (Table). Longitudinal analysis of matched samples showed that in KIM-1–high pts, 9% (12/138) and 26% (36/141) of pts had a ≥30% increase from baseline in KIM-1 levels at Cycle 4 Day 1 with atezo vs pbo, compared with 16% (34/213) and 12% (25/207) in KIM-1-low pts, respectively. A ≥30% KIM-1 increase was associated with worse DFS in both KIM-1–high (atezo HR: 1.68, 95% CI: 0.77, 3.69; pbo HR: 3.53, 95% CI: 2.24, 5.58) and KIM-1–low (atezo HR: 3.56, 95% CI 2.21, 5.75; pbo HR: 3.22, 95% CI: 1.81, 5.70) subgroups. In pts with matched ECL samples (n=103), median KIM-1 levels were higher ( P&lt;0.001) at recurrence (172 pg/mL) than at baseline (79 pg/mL). Conclusions: In IMmotion010, high baseline serum KIM-1 levels were associated with poorer prognosis but improved clinical outcomes with atezo vs pbo. Increased post-tx KIM-1 was associated with worse DFS. These data suggest that circulating KIM-1 may be a non-invasive marker of MRD and disease recurrence and be associated with benefit from atezo in adj RCC. Further investigation of KIM-1 in adj RCC is warranted. Clinical trial information: NCT03024996 . [Table: see text]

Sarcomatoid and Rhabdoid Renal Cell Carcinoma: Clinical, Pathologic, and Molecular Genetic Features.

Renal cell carcinoma (RCC) with sarcomatoid and rhabdoid morphologies has an aggressive biological behavior and a typically poor prognosis. The current 2022 WHO classification of renal tumors does not include them as distinct histologic entities but rather as transformational changes that may arise in a background of various distinct histologic types of RCC. The sarcomatoid component shows malignant spindle cells that may grow as intersecting fascicles, which is reminiscent of pleomorphic undifferentiated sarcoma. The rhabdoid cells are epithelioid cells with eccentrically located vesicular nuclei with prominent nucleoli and large intracytoplasmic eosinophilic inclusions. Studies have shown that RCCs with sarcomatoid and rhabdoid differentiation have distinctive molecular features. Sarcomatoid RCC harbors shared genomic alterations in carcinomatous and rhabdoid components, but also enrichment of specific genomic alterations in the sarcomatoid element, suggesting molecular pathways for development of sarcomatoid growth from a common clonal ancestor. Rhabdoid differentiation also arises through clonal evolution although less is known of specific genomic alterations in rhabdoid cells. Historically, treatment has lacked efficacy, although recently immunotherapy with PD-1/PD-L1/CTLA-4 inhibitors has produced significant clinical responses. Reporting of sarcomatoid and rhabdoid features in renal cell carcinoma is required by the College of American Pathologists and the International Collaboration on Cancer Reporting. This manuscript reviews the clinical, pathologic, and molecular features of sarcomatoid RCC and rhabdoid RCC with emphasis on the morphologic features of these tumors, significance of diagnostic recognition, the molecular mechanisms of tumorigenesis and differentiation along sarcomatoid and rhabdoid lines, and advances in treatment, particularly immunotherapy.

Advances in immunotherapy for pulmonary sarcomatoid carcinoma

Pulmonary sarcomatoid carcinoma (PSC) is a rare, poorly differentiated non-small cell lung cancer (NSCLC) that contains sarcomatoid components or sarcomatoid differentiation, and accounts for less than 1% of all lung tumors. Compared to other types of NSCLC, PSC has more invasive biological behavior, is prone to metastasis, and has a higher recurrence rate after early surgery. Its greater resistance to traditional treatments leads to a poorer prognosis compared to other NSCLCs. Immunotherapy offers the possibility of long-term survival for PSC patients.

Tracing Tumor Heterogeneity of Pleomorphic Carcinoma of the Lung

IntroductionPulmonary pleomorphic carcinoma (PPC) is an aggressive and highly heterogeneous NSCLC whose underlying biology is still poorly understood. MethodsA total of 42 tumor areas from 20 patients with PPC were microdissected, including 39 primary tumors and three metastases, and the histologically distinct components were subjected to whole exome sequencing separately. We further performed in silico analysis of microdissected bulk RNA sequencing and methylation data of 28 samples from 14 patients with PPC. We validated our findings using immunohistochemistry. ResultsThe epithelial and the sarcomatoid components of PPCs shared a large number of genomic alterations. Most mutations in cancer driver genes were clonal and truncal between the two components of PPCs suggesting a common ancestor. The high number of alterations in the RTK-RAS pathway suggests that it plays an important role in the evolution of PPC. The metastases morphologically and genetically resembled the epithelial or the sarcomatoid components of the tumor.The transcriptomic and epigenetic profiles of the sarcomatoid components of PPCs with matched squamous-like or adenocarcinoma-like components differed from each other, and they shared more similarities to their matched epithelial components. NCAM1/CD56 was preferentially expressed in the sarcomatoid component of squamous-like PPCs, whereas CDH1/E-Cadherin expression was down-regulated in the sarcomatoid component of most PPCs. ConclusionLung adenocarcinoma-like PPCs are mainly driven by RTK-RAS signaling, whereas epithelial-mesenchymal transition programs as highlighted by increased NCAM1 and decreased CDH1 expression govern the epithelial-sarcomatoid transition between the clonally related tumor components. Several alterations in PPCs pinpoint therapeutic opportunities.

BAP1 Loss, Nuclear Grading, and Nonepithelioid Features in the Diagnosis of Mesothelioma in Italy: Nevermore without the Pathology Report.

The pathologic diagnosis of pleural mesothelioma is generally based on international guidelines, but no compulsory points based on different drugs approvals in different European countries are required to be reported. According to the last (2021) edition of the World Health Organization classification of pleural tumors, the nuclear grade of epithelioid-type mesothelioma should be always inserted in the pathologic report, while the presence of BRCA-associated protein-1 (BAP1) (clone C4) loss and a statement on the presence of the sarcomatoid/nonepithelioid component are fundamental for both a screening of patients with suspected BAP1 tumor predisposition syndrome and the eligibility to perform first-line immunotherapy at least in some countries. Several Italian experts on pleural mesothelioma who are deeply involved in national scientific societies or dedicated working groups supported by patient associations agreed that the pathology report of mesothelioma of the pleura should always include the nuclear grade in the epithelioid histology, which is an overt statement on the presence of sarcomatoid components (at least 1%, in agreement with the last classification of pleural mesothelioma) and the presence of BAP1 loss (BAP1-deficient mesothelioma) or not (BAP1-retained mesothelioma) in order to screen patients possibly harboring BAP1 tumor predisposition syndrome. This review aims to summarize the most recent data on these three important elements to provide evidence regarding the possible precision needs for mesothelioma.

Prostatic Carcinosarcoma: Report of a Case with Immunohistochemical Characterization

Carcinosarcoma of the prostate is a rare neoplasm characterized by a sarcomatoid component coexisting with an adenocarcinoma. This tumor has a poor outcome and presents usually with distant metastasis. Immunohistochemically, the epithelial and mesenchymal components are different, and on a molecular basis, the presence of mutations of TP53 and phosphate and tensin homolog (PTEN) supports the role of epithelial-mesenchymal transition in the pathogenesis of this entity. We report the case of a 63-year-old man presented with advanced prostate carcinosarcoma showing a negative reaction for PTEN and a positive staining for P53 in both components by immunohistochemical study.

Abstract 4922: Unraveling sarcomatoid features in clear cell renal cell carcinoma with RNA-seq

Abstract Introduction: Sarcomatoid сlear cell renal cell carcinoma (ccRCC) represents a challenging and aggressive subset of kidney cancers with poor prognosis and resistance to conventional treatments. Recent studies have shown the benefit of checkpoint inhibitors (CPIs) for patients with sarcomatoid components; therefore, precise and objective evaluation of sarcomatoid differentiation is essential for CPI selection. Here, we developed a predictive model to identify sarcomatoid features in ccRCC. Methods: The machine learning-based transcriptomic sccRCC model was developed on 512 samples from publicly available datasets: TCGA-KIRC and CPTAC-ccRCC. Samples were excluded with the following criteria: inconsistent with ccRCC, less than 10% sarcomatoid component, or &amp;lt;20% tumor neoplastic cellularity. Sarcomatoid features for each case were assessed by 3 pathologists. The meta-cohort was divided into training (n = 348) and validation (n = 164) cohorts.The model was tested on a publicly available cohort of ccRCC patients from Sato et al. (n = 100). Clinical validation was performed using an additional prospective cohort that received BostonGene’s Tumor PortraitTM test (n = 32) with RNA-seq and whole exome sequencing (WES). The JAVELIN Renal 101 cohort was used to uncover differences in progression-free survival (PFS) associated with a predicted sarcomatoid component in advanced or metastatic ccRCCs treated with a combination of CPIs and tyrosine kinase inhibitors (TKIs). Results: H&amp;E analysis of the TCGA, CPTAC, and BostonGene cohorts identified zones with sarcomatoid features in 129 out of 556 (23.2%) samples. The sarcomatoid predictive model demonstrated robust performance, with weighted F1-scores of 0.85 when applied to the test cohort (Sato et al.) and 0.70 for the prospective clinical cohort. The model accurately classified 9 out of 10 total sarcomatoid samples in the prospective clinical cohort, highlighting its potential for real-world clinical applications. When applied to TCGA validation samples, sarcomatoid patients identified by the transcriptomic model exhibited median overall survival (mOS) of 55 months, whereas sarcomatoid patients based on H&amp;E assessment had a mOS of 67 months, indicative of the model’s superior performance when detecting sarcomatoid features for OS prediction. Moreover, the sarcomatoid ccRCCs predicted by transcriptomic model that were treated with a combination of CPIs and TKIs had statistically (p=0.0001) improved PFS compared to the TKI-treated group. Conclusion: The developed transcriptomic model effectively differentiated sarcomatoid from non-sarcomatoid ccRCC samples with robust performance metrics. With additional investigation, the predictive value of the sarcomatoid ccRCC transcriptomic model can be leveraged to guide CPI and TKI selection. Citation Format: Kirill Kryukov, Suren Davitavyan, Danil Stupichev, Anna Sharun, Anna Love, Mikhail Kleimenov, Stepan Kuznetsov, Arina Tkachuk, Vladimir Kushnarev. Unraveling sarcomatoid features in clear cell renal cell carcinoma with RNA-seq [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4922.

Biological characteristics and clinical treatment of pulmonary sarcomatoid carcinoma: a narrative review.

Pulmonary sarcomatoid carcinoma (PSC) is a subset of non-small cell lung cancer (NSCLC) with highly malignant, aggressive, and heterogeneous features. Patients with this disease account for approximately 0.1-0.4% of lung cancer cases. The absence of comprehensive summaries on the basic biology and clinical treatments for PSC means there is limited systematic awareness and understanding of this rare disease. This paper provides an overview of the biological characteristics of PSC and systematically summarizes various treatment strategies available for patients with this disease. For this narrative review, we have searched literature related to the basic biology and clinical treatment approaches of PSC by searching the PubMed database for articles published from July 16, 1990 to August 29, 2023. The following keywords were used: "pulmonary sarcomatoid carcinoma", "genetic mutations", "immune microenvironment", "hypoxia", "angiogenesis", "overall survival", "surgery", "radiotherapy", "chemotherapy", and "immune checkpoint inhibitors". Classical PSC comprises epithelial and sarcomatoid components, with most studies suggesting a common origin. PSC exhibits a higher tumor mutational burden (TMB) and mutation frequency than other types of NSCLC. The tumor microenvironment (TME) of PSC is characterized by hypoxia, hypermetabolism, elevated programmed cell death protein 1/programmed cell death-ligand 1 expression, and high immune cell infiltration. Treatment strategies for advanced PSC are mainly based on traditional NSCLC treatments, but PSC exhibits resistance to chemotherapy and radiotherapy. The advancement of genome sequencing has introduced targeted therapies as an option for mutation-positive PSC cases. Moreover, due to the characteristics of the immune microenvironment of PSC, many patients positively respond to immunotherapy, demonstrating its potential for the management of PSC. Although several studies have examined and assessed the TME of PSC, these are limited in quantity and quality, presenting challenges for research into the clinical treatment strategies for PSC. With the emergence of new technologies and the advancement of clinical research, for example, savolitinib's clinical study for MET exon 14 skipping mutations positive PSC patients have shown promising outcomes, more in-depth studies on PSC are eagerly anticipated.

Combination nivolumab and ipilimumab with and without camu camu in first-line treatment of metastatic renal cell carcinoma (mRCC).

TPS491 Background: Combination immune checkpoint inhibition (ICI) with ipilimumab and nivolumab (ipi/nivo) is an established first-line treatment for patients (pts) with intermediate and poor-risk mRCC. CheckMate214 demonstrated a survival advantage with ipi/nivo over sunitinib; unfortunately, 20% of cases developed primary progression to immunotherapy. Recent data suggest that the gut microbiome is key in modulating clinical responses and immune-related toxicities. Therefore, modulating the gut microbiome is a novel adjunct strategy to dual ICI in mRCC. Our group has previously proven that the addition of a live bacterial product (CBM588) enhances clinical responses in pts with mRCC treated with ICI, and the combination of ICI (Dizman et al., 2022) or with a tyrosine kinase inhibitor (Ebrahimi et al., 2023). Camu camu ( Myrciaria dubia) is a comestible berry characterized by a polyphenol-rich nutritional profile. In extract form, it is rich in castalagin, which appears to have probiotic properties. In mouse tumor models, camu camu increased the abundance of fecal Ruminococcus spp. when combined with ICI (Messaoudene et al., 2022). This shift in the gut microbiome composition was associated with stronger CD8+ T-cell and CD4+ Th1-dependent antitumor responses. Camu camu and ICI reestablished the efficacy of anti-PD1 therapy, reducing tumor size compared to ICI alone. This pilot study aims to identify the biological effect of camu camu with ipi/nivo in pts with mRCC. Methods: This is an investigator-initiated, randomized, open-label, single-center trial comparing camu camu with ipi/nivo versus ipi/nivo alone in pts with treatment-naïve mRCC. Eligibility criteria include pts ≥ 18 year old, PS 0-1, histological confirmation of clear-cell RCC with or without a sarcomatoid component, intermediate or poor risk per IMDC, no prior systemic treatment and measurable disease,. 30 pts will be enrolled and randomized in a 2:1 fashion, favoring the study arm. Pts will be treated with camu camu at 1500 mg PO daily, in with ipi/nivo at standard dosing. Pts will be followed monthly. Treatment will be continued until progression (RECIST v1.1) or toxicity. The primary endpoint is change in the abundance of Ruminococcus spp. in the stool from baseline to week 12 of therapy. We have 80% power to detect a 1 SD difference between the mean change detected in the two groups using a two-group T-test with a one-sided type I error of 0.05. Secondary endpoints include overall response rate, progression-free survival, safety, effect on gut microbiome diversity and function, comparison of the proportion of circulating cytokines and chemokines from baseline to week 12, and changes in the abundance of metabolic pathways and fungal microbiome profile. Response will be assessed by CT after the first 12 weeks of therapy and every 12 weeks, thereafter. The study is currently open to enrollment. Clinical trial information: NCT06049576 .

Genetic Profiling Uncovers Genome-Wide Loss of Heterozygosity and Provides Insight into Mechanisms of Sarcomatoid Transformation in Chromophobe Renal Cell Carcinoma

Sarcomatoid transformation occurs in ∼8% of chromophobe renal cell carcinoma (chRCC) and is associated with aggressive clinical behavior. In recent years, several studies have identified genomic, transcriptomic, and epigenomic correlates of aggressive behavior in chRCC; however, the molecular mechanisms associated with sarcomatoid transformation remain incompletely understood. In this study, we analyzed paired conventional and sarcomatoid histologic components of individual chRCC to elucidate the genomic alterations that underlie sarcomatoid transformation in this tumor type. Massively parallel sequencing was performed on paired (conventional and sarcomatoid) components from 8 chRCCs. All cases harbored TP53 variants (87.5% showing TP53 variants in both components and 12.5% only in the sarcomatoid component). Intratumor comparisons revealed that TP53 variants were concordant in 71% and discordant in 29% of cases. Additional recurrent single-nucleotide variants were found in RB1 (37.5% of cases) and PTEN (25% of cases), with the remaining single-nucleotide variants detected in these tumors (PBRM1, NF1, and ASXL1) being nonrecurrent. Copy number variant analysis showed the characteristic pattern of chromosomal losses associated with chRCC (1, 2, 6, 10, 13, 17, and 21) in the conventional histologic components only. Interestingly, the sarcomatoid components of these tumors demonstrated widespread loss of heterozygosity but lacked the above chromosomal losses, likely as a consequence of whole-genome duplication/imbalanced chromosomal duplication events. Overall, the findings suggest that TP53 variants followed by whole-genome duplication/imbalanced chromosomal duplication events underlie sarcomatoid transformation in chRCC.

MesoGraph: Automatic profiling of mesothelioma subtypes from histological images

Mesothelioma is classified into three histological subtypes, epithelioid, sarcomatoid, and biphasic, according to the relative proportions of epithelioid and sarcomatoid tumor cells present. Current guidelines recommend that the sarcomatoid component of each mesothelioma is quantified, as a higher percentage of sarcomatoid pattern in biphasic mesothelioma shows poorer prognosis. In this work, we develop a dual-task graph neural network (GNN) architecture with ranking loss to learn a model capable of scoring regions of tissue down to cellular resolution. This allows quantitative profiling of a tumor sample according to the aggregate sarcomatoid association score. Tissue is represented by a cell graph with both cell-level morphological and regional features. We use an external multicentric test set from Mesobank, on which we demonstrate the predictive performance of our model. We additionally validate our model predictions through an analysis of the typical morphological features of cells according to their predicted score.

A rare case of sarcomatoid carcinoma of the pancreas

Sarcomatoid carcinoma of the pancreas is a rare malignancy characterised by a predominant sarcomatoid component associated with a well-differentiated adenocarcinomatous component. We report the case of an 84-year-old patient with a history of cardiac arrhythmia who was admitted to hospital with jaundice of one month's duration. Ultrasound and abdominal computed tomography revealed a solid and locally advanced pancreatic head mass. The patient underwent endoscopic ultrasound with biopsy of the mass and placement of a biliary stent. Pathological examination of the biopsy revealed a sarcomatoid carcinoma of the pancreas. In view of the patient's bedridden condition and comorbidities, it was decided at a multidisciplinary consultation meeting to withhold treatment. The patient died 1 month later.

SLUG and SNAIL as Potential Immunohistochemical Biomarkers for Renal Cancer Staging and Survival.

Renal cell carcinoma (RCC) is the deadliest urological neoplasm. Up to date, no validated biomarkers are included in clinical guidelines for the screening and follow up of patients suffering from RCC. Slug (Snail2) and Snail (Snail1) belong to the Snail superfamily of zinc finger transcriptional factors that take part in the epithelial-mesenchymal transition, a process important during embryogenesis but also involved in tumor progression. We examined Slug and Snail immunohistochemical expression in patients with different stages of renal cell carcinomas with the aim to investigate their potential role as staging and prognostic factors. A total of 166 samples of malignant renal cell neoplasms were analyzed using tissue microarray and immunohistochemistry. Slug and Snail expressions were evaluated qualitatively (presence or absence), in nuclear and cytoplasmic cell compartments and compared in relation to clinical parameters. The Kaplan-Meier survival analysis showed the impact of the sarcomatoid component and Slug expression on the survival longevity. Cox regression analysis separated Slug as the only independent prognostic factor (p = 0.046). The expression of Snail was associated with higher stages of the disease (p = 0.004), especially observing nuclear Snail expression (p < 0.001). All of the tumors that had metastasized showed nuclear immunoreactivity (p < 0.001). In clear cell RCC, we showed a significant relationship between a high nuclear grade and nuclear Snail expression (p = 0.039). Our results suggest that Slug and Snail could be useful immunohistochemical markers for staging and prognosis in patients suffering from various RCCs, representing potential targets for further therapy strategies of renal cancer.

On a case of prostatic Sarcomatoid carcinoma

Sarcomatoid carcinoma of the prostate is a very rare variant of prostate cancer; it generally consists of malignant glandular elements and spindle cells, while the sarcomatoid component ranges from 5 to 99 percent. It can affect both young and old, with the onset of symptoms ranging from difficulty urinating to incomplete emptying. In addition, this form of neoplasm tends to metastasize frequently to bones, lungs, and liver.