Tumor Of Unknown Origin Research Articles

Mexican Multicenter Experience of Metastatic Spinal Disease.

Background Spinal metastatic disease is a silent progressive cancer complication with an increasing prevalence worldwide. The spine is the third most common site where solid tumors metastasize. Complications involved in spinal metastasis include root or spinal cord compression, progressing to a declining quality of life as patient autonomy reducesand pain increases. The main objective of this study is to report the incidence of patients and typology of spinal metastases in three reference centers in Mexico. Methodology Retrospective cohorts of patients diagnosed with spinal metastases from January 2010 to February 2017 at the National Cancer Institute, National Rehabilitation Institute, and the Traumatology and Orthopedics Hospital "Lomas Verdes" in Mexico City were analyzed. Results A total of 326 patients (56% males) with spinal metastases were reported. The mean age was 58.06 ± 14.05 years. The main sources of spinal metastases were tumors of unknown origin in 53 (16.25%) cases,breast cancer in 67 (20.5%) cases, prostate cancer in 59 (18%) cases, myeloma in 24 (7.4%) cases, and lung cancer in 23 (7.1%) cases. Conclusions The data obtained in this analysis delivers an updated standpoint on Mexico, providing the opportunity to distinguish the current data from global references. Collecting more epidemiological information for better recording of cancer and its associated complications, as well as further studies on them, is necessary.

Real-world effectiveness and safety of pembrolizumab in mismatch repair-deficient (dMMR) gastrointestinal non-colorectal tumors.

733 Background: The KEYNOTE-158 trial demonstrated durable clinical efficacy with pembrolizumab in long-term follow-up of previously treated unresectable or metastatic MSI-H/dMMR non-colorectal cancer. Our study, the GAIN study, aims to evaluate effectiveness and safety of pembrolizumab in dMMR Gastrointestinal Non-Colorectal Tumors in real-world clinical practice. Methods: We conducted a multicenter, retrospective, observational study on patients with Mismatch Repair-Deficient (dMMR) Gastrointestinal Non-Colorectal Tumors treated with pembrolizumab in real-world practice at six university hospitals affiliated with the Galician Research Group on Digestive Tumors (GiTUD) in Northwest Spain. Results: Between January 2018 and April 2023, 35 patients were enrolled. The median age was 66 years (range 33-88), with 54.3% being male. Tumor locations included 23 (65.7%) gastroesophageal adenocarcinomas, 3 (8.6%) pancreatic adenocarcinomas, 2 (5.7%) duodenal adenocarcinomas, 2 (5.7%) intrahepatic cholangiocarcinoma, 2 (5.7%) jejune adenocarcinomas, 2 (5.7%) esophageal squamous cell carcinomas, and 1 (2.8%) tumor of unknown origin. 54.3% of tumors were poorly differentiated. The most frequent alteration was the loss of MLH1-PMS2 expression (71.4%). By tumor location, 100% of gastroesophageal, jejune, and unknown origin tumors showed MLH1-PMS2 loss; while 100% of duodenal, pancreatic, and biliary tumors exhibited MSH2-MSH6 loss. All patients received pembrolizumab, with 57.1% having no prior metastatic disease treatment, 80% having ECOG PS0-1, and 31.4% having hepatic metastases. Among 33 evaluable patients, the overall response rate (ORR) was 81.8% (including 30.3% complete response) and the disease control rate (DCR) was 90.9%. Specifically, in gastroesophageal adenocarcinomas, the ORR was 81%, and the DCR was 90.5%. In the overall population, the median progression-free survival (PFS) was 34.76 months (95% CI 5.33 – 64.19 months), and the median overall survival (OS) was 39.75 months (95% CI 4.33-75.18 months). Treatment was well-tolerated; only 3 patients discontinued treatment due to nephritis, sarcoidosis-like symptoms, or diarrhea. No treatment-related deaths occurred. Conclusions: Our study underscores the real-world effectiveness of pembrolizumab in patients with dMMR Gastrointestinal Non-Colorectal Tumors. The high ORR, DCR, and favorable safety profile support its use in this challenging patient group, providing valuable real-world evidence for clinical decision-making.

Radioligand Therapy with [177Lu]Lu-DOTA-TATE or [177Lu]Lu-DOTA-TATE and [90Y]Y-DOTA-TATE in Patients with Neuroendocrine Neoplasms of Unknown Locations, or Locations Other Than the Midgut and Pancreas as Primaries in a G1, G2 and G3 Grade.

Neuroendocrine neoplasms (NENs) are a rare group of tumors with a different clinical course, prognosis and location. Radioligand therapy (RLT) can be used as a first or second line of treatment. It is registered in gastroenteropancreatic NENs (GEP-NENs) as grades G1 and G2. Tumors with an unknown point of origin, diagnosed outside the gastrointestinal tract and pancreas (non-GEP) or at the G3 grade, remain in the "grey area" of treatment. Analysis of 51 patients with NENs who underwent RLT in a single highest reference center from 2018 to 2023 was performed. Treatment was administrated to the patients with neoplasms of unknown origin, non-GEP-NENs, and ones with G3 grade. In total, 35 patients received 177-Lutetium (7.4 GBq), while 16 received 177-Lutetium and 90-Yttrium with equal activities (1.85 + 1.85 GBq). The progression-free survival (PFS) before RLT qualification was 34.39 ± 35.88 months for the whole study group. In subgroups of patients with an unknown tumor location (n = 25), the median PFS was 19 months (IQR = 23), with "other" locations (n = 21) at 31 months (IQR = 28), and with NEN G3 (n = 7) at 18 months (IQR = 40). After RLT, disease stabilization or regression was observed in 42 (87.5% of) patients. RLT did not cause statistical changes in creatinine or GFR values. Hematological parameters (RBC, WBC, PLT, HGB) as well as chromogranin A concentration decreased significantly. There were no statistical differences between both subgroups regarding the type of radioisotope (177-Lutetium vs. 177-Lutetium and 90-Yttrium). After RLT in long-term observation, the median observation time (OT) was 14 months (IQR = 18 months). In patients with progression (n = 8), the median PFS was 20 months (IQR = 16 months), while in patients with confirmed death (n = 9), the median overall survival (OS) was 8 months (IQR = 14 months). Our study showed that 87.5% of NEN patients with unknown origin, non-GEP-NENs, and those with GEP-NEN G3 grade had benefited from the radioligand therapy. There were no significantly negative impacts on renal parameters. The decrease of bone marrow parameters was acceptable in relation to beneficial disease course. The decrease of chromogranin concentration was confirmed as a predictive factor for disease stabilization or regression.

Abstract 4692: Comparison of interassay similarity and cellular deconvolution in spatial transcriptomics data using Visum CytAssist

Abstract Next-generation sequencing (NGS) of bulk cell populations is a useful and ubiquitous tool for the molecular characterization of clinical tumor samples. Bulk NGS reveals transcript abundance within a tumor sample and can further infer cell populations via deconvolution algorithms (PMID:31570899). However, it can’t ascribe the cellular context for a given gene’s expression or elucidate the spatial organization of tumor microenvironments. These additional features are critical to our understanding of tumor biology and are key to the development of immuno-oncology therapeutics. Spatial Transcriptomics (ST) is an emerging technology that characterizes gene expression within the spatial context of tissue. ST data can be generated directly from archival formalin fixed paraffin embedded samples, enabling the study of spatial gene expression in real-world clinical settings. We have studied a dataset comprising 6 samples from non-small cell lung cancer (NSCLC) patients and 1 core needle biopsy from a tumor of unknown origin. We used the 10X Visium CytAssist platform to generate ST data and additionally generated paired bulk RNAseq data. To test the interassay reliability of CytAssist on archival FFPE tissue sections, we compared ST results across 3 sample preparation conditions. We further studied the state of the tumor microenvironment by applying state-of-the-art computational approaches to deconvolve immune cell populations and produce super-resolution ST maps, validated using multiplex immunofluorescence (IF) via CODEX (PMID:30078711). We find key quality control metrics and spatial biomarkers are consistent across all 3 sample preparation conditions. When comparing deconvolution results between bulk and spatially-resolved methods we observe modest correlations for many cell types despite differences in sample preparation, supporting the idea that bulk and spatial samples contain complementary transcriptomic information. However, within samples, we find many of the correlations observed in bulk do not show strong spatial correlation. These comparisons indicate the importance of considering spatial context when studying the tumor immune microenvironment. Finally, we find an agreement between super-resolution ST and multiplex IF across key spatial biomarkers. These results demonstrate clinical archival FFPE samples yield high interassay reliability via the CytAssist platform. Results were consistent through 3 different H&E staining protocols and findings were consistent when superresolution deconvolution was utilized which further strongly correlated with high-resolution multiplex IF. Our findings demonstrate the feasibility and translational utility of ST to discover spatial signatures and the cellular context in retrospective clinical cohorts to empower discovery and translational efforts in precision oncology and therapeutic development. Citation Format: Mario G. Rosasco, Chi-Sing Ho, Tianyou Luo, Michelle M. Stein, Luca Lonini, Martin C. Stumpe, Jagadish Venkataraman, Sonal Khare, Ameen A. Salahudeen. Comparison of interassay similarity and cellular deconvolution in spatial transcriptomics data using Visum CytAssist. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4692.

Here is the metastasis - find the primary carcinoma for it: a large biopsy study

Objectives: According to estimates, cancer of unknown primary origin (CUP) accounts for approximately 3 to 5% of new cancer cases annually in the United States. With early diagnosis, many CUP patients can achieve long-term remission. The aim of this study was to document the organ tropism for metastasis for tumors with a definite primary cancer. In addition, we sought to contribute to understanding organ tropism in tumors of unknown origin. Methods: Retrospectively, biopsies of 492 metastatic cancers were evaluated. The required immunohistochemical panel was applied to determine the tumors’ origins. Results: A total of 492 patients with metastases were included in the study. The most common origins of metastasizing tumors were lung (25.4%), colon (18.9%), breast (15.4%) and stomach cancers (10.6%). The least metastatic tumors were the salivary gland, neuroendocrine, adrenal, tubal, nasopharynx, rectum and esophagus cancers (0.22% for all). The most common cancers that metastasized to the liver were colon cancer (29.0%), stomach cancer (18.6%) and pancreatic cancer (18.6%). The most common cancers that metastasized to the bone were lung cancer (58.0%), breast cancer (29.0%), and prostate cancer (13.9%). The most common types of tumors that metastasized to the lungs, the kidney (35.1%), colon (29.7%), and breast cancers (16.2%), were the most common. The most common tumors that metastasized to the brain were the lung (61.1%), the breast (16.7%), and kidney cancers (8.7%). The most common tumors metastasizing to the skin were lung (31.0%), breast (27.6%), and colon (13.8%) cancers. Conclusions: Primary cancers have different metastatic patterns, which may help determine their causes. By involving distant anatomical structures and disrupting their function, tumor metastases increase the morbidity and mortality associated with the disease; thus, they affect staging, prognosis, and treatment. Metastases (or cancers from unknown primary sites) usually require extensive investigation to determine their primary source. Whether the cancer is tracked prospectively or retrospectively, a detailed observational template highlighting expected metastatic patterns would greatly assist in diagnosis and treatment.

Novel ATXN1/ATXN1L::NUTM2A fusions identified in aggressive infant sarcomas with gene expression and methylation patterns similar to CIC-rearranged sarcoma

CIC-rearranged sarcomas are newly defined undifferentiated soft tissue tumors with CIC-associated fusions, and dismal prognosis. CIC fusions activate PEA3 family genes, ETV1/4/5, leading to tumorigenesis and progression. We report two high-grade CNS sarcomas of unclear histological diagnosis and one disseminated tumor of unknown origin with novel fusions and similar gene-expression/methylation patterns without CIC rearrangement. All three patients were infants with aggressive diseases, and two experienced rapid disease deterioration and death. Whole-transcriptome sequencing identified an ATXN1-NUTM2A fusion in the two CNS tumors and an ATXN1L-NUTM2A fusion in case 3. ETV1/4/5 and WT1 overexpression were observed in all three cases. Methylation analyses predicted CIC-rearranged sarcoma for all cases. Retrospective IHC staining on case 2 demonstrated ETV4 and WT1 overexpression. ATXN1 and ATXN1L interact with CIC forming a transcription repressor complex. We propose that ATXN1/ATXN1L-associated fusions disrupt their interaction with CIC and decrease the transcription repressor complex, leading to downstream PEA3 family gene overexpression. These three cases with novel ATXN1/ATXN1L-associated fusions and features of CIC-rearranged sarcomas may further expand the scope of “CIC-rearranged” sarcomas to include non-CIC rearrangements. Additional cases are needed to demonstrate if ATXN1/ATXN1L-NUTM2A fusions are associated with younger age and more aggressive diseases.

Landscape of KRASG12C, Associated Genomic Alterations, and Interrelation With Immuno-Oncology Biomarkers in KRAS-Mutated Cancers.

PURPOSEPromising single-agent activity from sotorasib and adagrasib in KRASG12C-mutant tumors has provided clinical evidence of effective KRAS signaling inhibition. However, comprehensive analysis of KRAS-variant prevalence, genomic alterations, and the relationship between KRAS and immuno-oncology biomarkers is lacking.MATERIALS AND METHODSRetrospective analysis of deidentified records from 79,004 patients with various cancers who underwent next-generation sequencing was performed. Fisher's exact test evaluated the association between cancer subtypes and KRAS variants. Logistic regression assessed KRASG12C comutations with other oncogenes and the association between KRAS variants and immuno-oncology biomarkers.RESULTSOf the 79,004 samples assessed, 13,758 (17.4%) harbored KRAS mutations, with 1,632 (11.9%) harboring KRASG12C and 12,126 (88.1%) harboring other KRAS variants (KRASnon-G12C). Compared with KRASnon-G12C across all tumor subtypes, KRASG12C was more prevalent in females (56% v 51%, false discovery rate-adjusted P value [FDR-P] = .0006), current or prior smokers (85% v 56%, FDR-P < .0001), and patients age > 60 years (73% v 63%, FDR-P ≤ .0001). The most frequent KRAS variants across all subtypes were G12D (29.5%), G12V (23.0%), G12C (11.9%), G13D (6.5%), and G12R (6.2%). KRASG12C was most prevalent in patients with non–small-cell lung cancer (9%), appendiceal (3.9%), colorectal (3.2%), tumor of unknown origin (1.6%), small bowel (1.43%), and pancreatic (1.3%) cancers. Compared with KRASnon-G12C-mutated, KRASG12C-mutated tumors were significantly associated with tumor mutational burden-high status (17.9% v 8.4%, odds ratio [OR] = 2.38; FDR-P < .0001). KRASG12C-mutated tumors exhibited a distinct comutation profile from KRASnon-G12C-mutated tumors, including higher comutations of STK11 (20.59% v 5.95%, OR = 4.10; FDR-P < .01) and KEAP1 (15.38% v 4.61%, OR = 3.76; FDR-P < .01).CONCLUSIONThis study presents the first large-scale, pan-cancer genomic characterization of KRASG12C. The KRASG12C mutation was more prevalent in females and older patients and appeared to be associated with smoking status. KRASG12C tumors exhibited a distinct comutation profile and were associated with tumor mutational burden-high status.

Landscape of KRASG12C, associated genomic alterations, and interrelation with immuno-oncology (IO) biomarkers.

3127 Background: Sotorasib has shown promising activity in cancer patients (pts) specifically harboring the KRASG12C mutation. Response rates vary significantly by tumor type, suggesting KRASG12C pathogenesis may be cancer-type-dependent. Methods: We retrospectively analyzed de-identified records of 79,004 pts with various cancer types that underwent Tempus xT and xF next generation sequencing assays. Fisher’s exact test was used to analyze the association between cancer subtypes and KRAS variants. Logistic regression was used to study co-mutations between KRASG12C and other oncogenes, as well as the association between KRAS variants and IO biomarkers. False discovery rate-adjusted P-value (FDR P) was used for multiple testing. Results: In total, 13,578 (17.4%) tumors harbored KRAS mutations, of which 1,632 were G12C; 750 KRAS wild-type (WT) tumors gained KRAS mutation on follow-up testing, with 79 harboring G12C. The most frequent KRAS variants across all cancers were G12D, G12V, G12C, and G13D (see Table). The distribution of KRAS variants significantly varied by cancer type, with G12C and G12D being the most prevalent in non-small cell lung (NSCLC) and colorectal (CRC) cancers, respectively. G12C was most prevalent in NSCLC (9%), appendiceal cancer (3.9%), CRC (3.2%), tumors of unknown origin (1.6%), and pancreatic cancer (1.3%). Compared to non-G12C, G12C was more frequently identified in females (56% vs. 51%, FDR P = 0.0005), smokers/prior smokers (85% vs. 56%, FDR P &lt; 0.0001), and pts &gt; 60 years of age (73% vs. 63%, FDR P = 0.0006). While no G12C tumors exhibited BRAFV600E co-mutations, BRAFnon-V600E co-mutations were seen in 3.1% of pts. Significant differences were observed in genomic alterations co-occurring with G12C compared to non-G12C (e.g., STK11 (20.6% vs 6%), KEAP1 (15.4% vs 4.6%), SMAD4 (7.2% vs 19%), and PDGFRA (5.8% vs 3%); FDR P &lt; 0.0001). However, G12C and oncogene co-mutations were not significantly different between NSCLC and CRC, except for KEAP1 (FDR_ P = 0.04). Compared to non-G12C and WT, G12C tumors were associated with TMB-High and PD-L1 over expression but were less likely to have MSI-H status (FDR P &lt; 0.0001; Table). Conclusions: Our data suggest that KRAS variants significantly differ by cancer type. Tumors harboring KRASG12C were significantly associated with high TMB and PD-L1 overexpression. KRASG12C mutation appeared to be associated with smoking status. These results may guide future therapeutic strategies.[Table: see text]

Abstract IA024: Tumor exosome and exomere biomarkers for early cancer detection

Abstract In 1889, Stephen Paget first proposed that organ distribution of metastases is a non-random event, yet metastatic organotropism remains one of the greatest mysteries in cancer biology. A growing number of studies demonstrate that tumor-derived microvesicles, referred to as exosomes, may alter the tumor microenvironment at future sites of metastasis promoting pre-metastatic niche formation, and thus creating a favorable “soil” for incoming metastatic “seeds.” However, by what mechanism, and whether their role is significant in tumor progression remains unknown. We have recently demonstrated that exosomes released by lung-, liver- and brain-tropic tumor cells preferentially fuse with resident cells at their future metastatic sites, such as fibroblasts and epithelial cells in the lung, Kupffer cells in the liver, and endothelial cells in the brain. We found that tumor-derived exosome homing to organ-specific cell types prepares the pre-metastatic niche. Moreover, treatment with exosomes derived from lung-tropic models can redirect to the lung the metastatic distribution of cells that normally lack the capacity to form lung metastasis. Proteomic profiling of exosomes revealed distinct integrin expression patterns associated with each organ-specific metastatic site. Whereas exosomal α6β4 integrins were associated with lung metastasis, exosomal integrin αvβ5 was linked to liver metastasis and αvβ3 to brain metastasis. Targeting α6β4 and αvβ5 integrins decreased exosome uptake and metastasis in the lung and liver, respectively. Moreover, our clinical data indicate that integrin expression profiles in circulating plasma exosomes from cancer patients could be used to predict organ-specific metastasis. To gain a more comprehensive understanding of the relationship between exosomal protein cargo and tumor progression, we have built one of the largest exosome proteomics databases, including human and murine normal, pre-cancer and cancer exosomes from a variety sources, from cell lines to plasma and other bodily fluids. This dataset has allowed us to extend the list of markers that can be used to identify and isolate exosomes from human samples. When comparing the protein cargo of blood plasma exosomes isolated from normal subjects versus cancer patients with early stage pancreatic, colorectal, breast and lung cancer, we were able to define a cancer-specific proteomic signature that distinguishes cancer exosomes. Using paired samples from tumor tissue and plasma of the same cancer patients with breast, lung or pancreatic cancer, we were able to derive cancer type-specific exosomal signatures, which can be used as biomarkers to identify and classify tumors of unknown origin. Therefore, proteomic profiling of exosomes has great clinical potential as a non-invasive, rapid liquid biopsy that could aid in tumor detection classification. Citation Format: Ayuko Hoshino, Han Sang Kim, Linda Bojmar, Kofi Ennu Gyan, Haiying Zhang, Irina Matei, David Lyden. Tumor exosome and exomere biomarkers for early cancer detection [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr IA024.

Evaluation of Human Kidney Injury Molecule 1 (hKIM-1) Expression in Tumors From Various Organs by Messenger RNA In Situ Hybridization.

Human kidney injury molecule 1 (hKIM-1) is a sensitive and specific marker for detection of clear cell renal cell carcinoma (CRCC), papillary renal cell carcinoma (PRCC), and ovarian clear cell carcinoma (OCCC). Its use was limited to a few surgical pathology laboratories because this specific antibody to hKIM-1 was not commercially available. We investigated the diagnostic utility of RNA in situ hybridization/RNAscope in the detection of hKIM-1 in tumors from various organs. RNAscope for hKIM-1 was performed on 1,252 cases on tissue microarray sections, including CRCC (n = 185), PRCC (n = 59), chromophobe renal cell carcinoma (n = 18), oncocytoma (n = 12), OCCC (n = 27), and metastatic CRCC (n = 46). Fifty-nine (100%) of 59 PRCCs, 94 (95%) of 99 low-grade CRCCs, 83 (96%) of 86 high-grade CRCCs, and 24 (89%) of 27 OCCCs, and 44 (96%) of 46 metastatic CRCCs were positive for hKIM-1. In contrast, hKIM-1 expression was not seen in normal renal tubules or in most nonrenal tumors. Low-level expression could be seen in a small percentage of urothelial, hepatocellular, and colon carcinomas. hKIM-1 is a sensitive and relatively specific marker (1) for diagnosing PRCC, CRCC, and OCCC when working on a tumor of unknown origin and (2) for differentiating CRCC from chromophobe renal cell carcinoma and oncocytoma.

Complete remission of Cdx-2 positive primary testicular carcinoid tumor: 10-years follow-up and literature review

BackgroundThe neuroendocrine cells can cause a variety of malignancies throughout the human body known as the neuroendocrine tumors (NETs) or carcinoid tumors. The primary testicular carcinoid tumor (PTCT) accounts for less than 1% of the testicular neoplasms and for only 0.2% of all carcinoid tumors representing already a very rare neoplastic entity. Here, we present a patient with a history of an exceptionally rare primary testicular carcinoid tumor, staining positive for Cdx-2 along with a literature review.Case presentationA 44-year old patient without significant past medical history was diagnosed in September 2009 with primary testicular carcinoid tumor, which was surprisingly staining positively for Cdx-2, too. At the time of the initial diagnosis the tumor was already showing histopathological infiltration of veins. DOTA-TATE-PET/CT imaging and endoscopy studies did not show any signs of distant metastases and in particular no gastrointestinal manifestation following no further medical indication for systemic chemotherapy. The continuous and close follow-up of the patient has reached a total of over 10 years at the time of publication remaining in complete remission.ConclusionThe diagnosis of primary testicular carcinoid is based on histopathology. The detailed histopathologic assessment of biomarkers based on immunohistochemistry is very important for the classification and the prognosis of the primary testicular carcinoid tumor. Primary testicular carcinoid tumor with Cdx-2 positive stain outlines an exceptionally rare neoplastic entity without a consensus about general follow-up guidelines, requiring close clinical and imaging aftercare and consideration in Cdx-2 positive metastatic tumor of unknown origin.

Risk Factors for Laryngectomy for Dysfunctional Larynx After Organ Preservation Protocols: A Case-Control Analysis.

(1) To identify factors associated with severe dysfunctional larynx leading to total laryngectomy after curative treatment of head and neck squamous cell carcinoma and (2) to describe swallowing and voice outcomes. Retrospective single-institution case-control study. Tertiary care referral center. A 10-year chart review was performed for patients who had previously undergone radiation or chemoradiation for head and neck mucosal squamous cell carcinoma and planned to undergo total laryngectomy for dysfunctional larynx, as well as a control group of matched patients. Controls were patients who had undergone radiation or chemoradiation for mucosal squamous cell carcinoma but did not have severe dysfunction warranting laryngectomy; these were matched to cases by tumor subsite, T stage, and time from last treatment to video swallow study. Main outcomes assessed were postoperative diet, alaryngeal voice, pharyngeal dilations, and complications. Twenty-six patients were scheduled for laryngectomy for dysfunctional larynx, of which 23 underwent surgery. Originally treated tumor subsites included the larynx, oropharynx, hypopharynx, oral cavity, and a tumor of unknown origin. The median time from end of cancer treatment to laryngectomy was 11.5 years. All cases were feeding tube or tracheostomy dependent or both prior to laryngectomy. As compared with matched controls, cases were significantly less likely to have undergone IMRT (intensity-modified radiotherapy) and more likely to have pulmonary comorbidities. Eighty-nine percent of cases with follow-up achieved functional alaryngeal voice, and all were able to have oral intake. Non-IMRT approaches and pulmonary comorbidities are associated with laryngectomy for dysfunction after radiation or chemoradiation.

Undifferentiated pleomorphic sarcoma in the anterior mediastinum with a rapidly progressive course: A case report.

A 77-year-old woman with heart failure was admitted to our hospital. Computed tomography (CT) of the chest revealed an anterior mediastinal tumor. CT-guided biopsy revealed a malignant nonepithelial tumor of unknown origin. She was not treated with chemotherapy or radiotherapy because of her poor clinical condition. She died 33 days after admission. Following autopsy, we confirmed that the mediastinal tumor had infiltrated the large blood vessels. After final histological examination, undifferentiated pleomorphic sarcoma was diagnosed. Primary mediastinal sarcomas are very rare; clinicians should be aware of their possibility because some cases may progress rapidly as evidenced in this case.

Metastases of soft tissue sarcoma to the liver: A Historical Cohort Study from a Hospital-based Cancer Registry.

BackgroundHepatic metastasis of soft tissue sarcoma is rare compared to lung metastasis, and the literature is scarce. We examined the risk of hepatic metastasis according to the site of occurrence and histological type.MethodsFrom a Hospital‐based Cancer Registry, 658 patients registered between 2007 and 2017 with soft tissue sarcomas were evaluated. The exclusion criteria were gastrointestinal stromal tumors, tumors of unknown origin, and follow‐up periods of less than 1 month. SPSS 25 was used for statistical analysis.ResultsThe risk of hepatic metastasis was significantly higher in the retroperitoneum (HR, 5.981; 95% CI, 2.793‐12.808) and leiomyosarcoma (HR, 4.303; 95% CI, 1.782‐10.390). Multivariate analysis showed that the risk of hepatic metastasis as first distant metastasis was high in leiomyosarcoma (HR, 4.546; 95% CI, 2.275‐9.086) and retroperitoneal onset (HR, 4.588; 95% CI, 2.280‐9.231). The 2‐year survival rate after hepatic metastasis was 21.7%.ConclusionsThe onset of hepatic metastasis indicates a poor prognosis. However, hepatic metastasis from retroperitoneal sarcoma and leiomyosarcoma may be the first distant metastasis in some cases. For retroperitoneal sarcoma and leiomyosarcoma, additional screening for hepatic metastasis such as contrast CT should be considered during staging and follow‐up after treatment.

GIANT GASTROINTESTINAL STROMAL TUMOR OF THE SIGMOID COLON (case report)

The paper presents a clinical case of a rare stromal colon tumor in a patient previously operated for breast cancer. The patient with a rapidly growing abdominal tumor of unknown origin underwent tests in the department of coloproctology. According to ultrasound and CT examina-tion, the lumpy formation with large size and low mobility, compressing the surrounding organs and probably coming from the colon, has been revealed. The removal of the tumor coming from the sigmoid colon with segmental resection anastomosis was performed. The postoperative period was uncomplicated, patient discharged from the clinic 7 days after surgery. Immunohistochemical examination of the tumor showed Gastrointestinal Autonomous Neurogenic Tumor (GANT) – a variant of GIST. Surgery for rare mesenchymal tumors is better in the coloproctologi-cal units with sufficient skills of surgeons. The multidisciplinary approach is necessary in such cases.

Intracranial synovial sarcoma: A clinical, radiological and pathological study of 16 cases

IntroductionSynovial sarcoma (SS) is a tumor of unknown origin and is extremely rare in the central nervous system. Most studies on intracranial SS included only one or two cases. To better understand the disease, we review a series of primary intracranial SS. Method and materials16 primary intracranial SS in Tiantan Hospital during 2008–2017 were included. The clinical characteristics, including radiological and histological examination, operative records, and prognoses were reviewed. ResultThe case series included nine male and seven female patients with an average age of 23.8 years. Radiological results showed that the supratentorial region (81.25%) was the most common site of the brain involved. All patients were misdiagnosed as non-SS tumors. Gross total resection (GTR) was achieved in 12 cases (75.0%), and subtotal resection (STR) was achieved in 4 cases. All cases showed the characteristic SYT-SSX fusion gene, as detected by RT-PCR. The mean progression-free survival time (PFS) was 10.0 months and the mean overall survival time (OS) was 15.5 months. Multivariate analysis revealed that GTR and postoperative adjuvant radiotherapy were independent factors for PFS (HR = 6.143, 95% CI = 1.491–25.312; P = 0.012, HR = 6.143, 95% CI = 1.491–25.312; P = 0.012 respectively) and OS (HR = 9.000, 95% CI = 1.627–49.773; P = 0.012, HR = 0.017, 95% CI = 0.001–0.213; P = 0.002 respectively). ConclusionIntracranial SS were more frequently observed in the supratentorial region and in young patients without sex predilection. We recommend adjuvant radiation regardless of the extent of resection. More patients and longer follow-up periods were needed to further elucidate the biological features of intracranial SS.

Prevalence of Neuroendocrine Tumors in the Gastrointestinal and Hepatobiliary Systems

Background: Carcinoid tumors are the most common neuroendocrine tumors. In recent years, these tumors have had an increasein incidence, which is probably due to a higher number of them being incidentally found as a result of the rise of preventivemedicine.Objectives: This study aimed to analyze a series of digestive carcinoid tumors detected by conventional endoscopy and/or echoendoscopyto evaluate the prevalence of those located in the colon and rectum, and subsequently make a comparison with data availablein the literature.Methods: In this retrospective, multicenter study (two centers), the clinical records of 100 white patients with more than 100 digestivecarcinoid tumors (some multiple) diagnosed from 1994 to 2018 were reviewed.Results: The mean age of presentation was 52 years and 57% of the patients were men. The mean tumor size was 10 mm. The localizationof the tumors was: stomach 43% (n = 43); duodenum 5% (n = 5); intestine 8% (n = 8); appendix 14% (n = 14); colon 4% (n = 4);rectum 19% (n = 19); pancreas 3% (n = 3); liver 2% (n = 2); gallbladder 1% (n = 1); primary tumor of unknown origin 1% (n = 1). Mostmultifocal tumors were in the stomach (20%; n = 20), followed by the duodenum (1%; n = 1) and intestine (1%; n = 1). Metastases andcarcinoid syndrome were observed in 6% and 5% of the cases, respectively. General survival at the closure of the study was 80%.Conclusions: Age and sex were similar to those described in the literature, while the colon and rectum represented 23% of all carcinoidtumors. There was a predominance of gastroduodenal and rectal carcinoid tumors, probably because the series analyzedwas essentially endoscopic. In comparison with the literature, less cases of metastases or carcinoid syndrome were recorded andsurvival was greater, perhaps due to earlier diagnosis and treatment.

Transcriptome-based cancer type prediction for tumors of unknown origin.

3081 Background: Tumors of unknown origin occur in approximately 5% of newly diagnosed cancers and are difficult to treat without establishing the tissue type from which they derive. Establishing tumor origin guides standard of care treatment for several NCCN targeted therapy guidelines. Leveraging tissue specificity in gene expression profiles, classification models based on RNA expression offer a promising approach to identify the likely primary cancer site in tumors of unknown origin. Methods: In this study, we developed a transcriptome-based cancer type classifier trained on over 10,000 tissue samples annotated by pathologists and sequenced for RNA expression to identify conserved patterns of expression characteristic of 30 tumor types across primary and metastatic tissue sites. The classifier probabilistically ranks cancer of origin. Results: Overall, the accuracy of the most probable cancer prediction was 85%, 88% within primary tumors and 77% within metastatic tumors. The top three cancers types with the highest accuracy were colorectal (accuracy in metastatic: 93%, accuracy in primary tumors: 99%), breast (95%, 96%) and lung (87%, 94%). Classifier performance was lower in low-purity metastatic tumors where the surrounding normal tissue obscures the tumor transcriptional profile, though the classifier still achieves 71% accuracy on metastatic tumors with less than 50% purity. Conclusions: We present a novel method to probabilistically predict tumor type for cancers of unknown origin using RNA-Seq. Our method achieves robust classification that is applicable to primary and metastatic tumors and demonstrates the value of utilizing RNA-Seq to aid cancer diagnosis and treatment decisions.

Metastatic bone lesions of men in combination with an increase in serum PSA from the point of view of diagnosing carcinomas of unknown primary localization

In cases of “malignant neoplasm of unknown origin” of men with bone metastases, it is the serum PSA level that can be crucial for further treatment. The literature describes carcinomas with bone metastases and an increase in the prostate-specific antigen, which were twice refuted by a prostate biopsy but had a positive dynamic during anti-androgen therapy (bicalutamide) in combination with chemotherapy (zoledronic acid). The aim of the work is to improve diagnostic algorithms, to investigate a complex of morphological, morphometric and immunohistochemical characteristics of metastatic foci in the bones, which are represented by adenocarcinomas of unknown primary localization in men with increased serological marker PSA, compared with primary carcinomas of the prostate gland. Materials and methods. A retrospective analysis of clinical data, histological and immunohistochemical characteristics of 21 observations of biopsy material from patients with primary carcinoma of the prostate gland (group 1, men aged 56 to 82 years, average 66.00 ± 7.76; median 65) and 10 patients with bone carcinoma metastases without primary localization and increased serum marker PSA (group 2, men aged 43 to 57 years, mean 50.00 ± 9.89; median 46.5) on the basis of the morphological department of diagnostic center “Pharmacy of Medical Academy” for the period 2015–2017. Results. Morphological, morphometric and immunohistochemical changes of carcinomas of unknown primary site in men with metastatic bone lesions and increased serum marker PSA associated with the acquisition of more aggressive properties were identified in comparison with the primary carcinomas of the prostate gland, which tend to local distribution. There were prevalence of poorly differentiated histological forms of metastatic adenocarcinomas, an objective reduction in the area and perimeter of nuclei (P = 0.00002, P < 0.0001, respectively), possible loss of immunohistochemical markers AMACR (p504s) and AR (androgen receptors) specific for acinar prostate carcinomas (P = 0.008). Conclusion. The use of minimal primary immunohistochemical panel from cytokeratin, Pan AE1/AE3 (+) / Vimentin(-) / CD45(-) / S100(-) and secondary – cytokeratin 8(+) / PSA(+) / AMACR (p504s)(+) panels / AR(+/-) will allow to prove the conformity of the carcinoma phenotype with unknown primary site in men with metastatic bone lesions and an increase in the PSA serological marker to the form of disseminated prostate carcinoma with justification for the use of appropriate therapy in cases of non-informative prostate biopsy.

A case of autonomous cortisol secretion in a patient with subclinical Cushing\u2019s syndrome, GNAS mutation, and paradoxical cortisol response to dexamethasone

BackgroundIncreased urinary free cortisol in response to the oral administration of dexamethasone is a paradoxical reaction mainly reported in patients with primary pigmented nodular adrenocortical disease. Here, we describe the first case of subclinical Cushing’s syndrome represented by autonomous cortisol secretion and paradoxical response to oral dexamethasone administration, harboring an activating mutation in the α subunit of the stimulatory G protein (GNAS).Case presentationA 65-year-old woman was diagnosed with subclinical Cushing’s syndrome during an evaluation for bilateral adrenal masses. Tumors of unknown origin were found in the heart, brain, thyroid gland, colon, pancreas, and both adrenal glands. Adenocarcinoma of the sigmoid colon and systemic brown-patchy skin pigmentation were also present. Her urinary cortisol levels increased in response to oral dexamethasone, while serum dehydroepiandrosterone-sulfate was not suppressed. After right adrenalectomy, genetic analysis of the resected tumor revealed the somatic GNAS activating mutation, p.R201H. Paradoxical urinary cortisol response persisted even after unilateral adrenal resection, although serum and urinary cortisol levels were attenuated.ConclusionsThis patient harbored a GNAS activating mutation, and presented with a mild cortisol- and androgen-producing adrenal adenoma. Administration of oral dexamethasone paradoxically increased cortisol levels, possibly via the stimulation of the cyclic adenosine monophosphate-dependent protein kinase A signaling pathway, which is seen in patients with pigmented nodular adrenocortical disease or Carney complex. GNAS mutations may provide clues to the mechanisms of hyper-function and tumorigenesis in the adrenal cortex, especially in bilateral adrenal masses accompanied by multiple systemic tumors. Examining GNAS mutations could help physicians detect extra-adrenal malignancies, which may contribute to an improved prognosis for patients with this type of Cushing’s syndrome.