Cancer Of Unknown Origin Research Articles

Cholangiocarcinoma Insights: Established Foundations and Cutting-Edge Innovations from Dr. James Cleary’s Pioneering Research

This paper provides insights into the conventional understanding of biliary tract malignancies, with a specific focus on cholangiocarcinoma (CCA). We then delve into the groundbreaking ideas presented by Dr. James Cleary. CCA, originating from biliary tree cells, manifests diverse subtypes contingent upon anatomical localization and differentiation status. These variants exhibit discrete genetic aberrations, yielding disparate clinical phenotypes and therapeutic modalities. Intrahepatic, perihilar, and distal CCAs intricately involve distinct segments of the biliary tree, further categorized as well-differentiated, moderately differentiated, or poorly differentiated adenocarcinomas based on their histological differentiation. Understanding the etiological factors contributing to CCA development assumes paramount importance. Stratifying these factors into two groups, those unrelated to fluke infestations (e.g., viral hepatitis and fatty liver conditions) and those associated with fluke infestations (e.g., chronic liver inflammation), facilitates predictive modeling. The epidemiology of CCA exhibits global variability, with Southeast Asia notably displaying higher incidences attributed primarily to liver fluke infestations. Jaundice resulting from bile duct obstruction constitutes a prevalent clinical manifestation of CCA, alongside symptoms like malaise, weight loss, and abdominal pain. Diagnostic challenges arise due to the symptomatic overlap with other biliary disorders. Employing comprehensive liver function tests and imaging modalities such as computed tomography assumes a pivotal role in ensuring accurate diagnosis and staging. However, the definitive confirmation of CCA necessitates a biopsy. Treatment modalities, predominantly encompassing surgical resection and radiation therapy, hold curative potential, although a considerable subset of patients is deemed unresectable upon exploration. Challenges intensify, particularly in cases classified as cancer of unknown origin, underscoring the imperative for early intervention. Advancements in genomic sequencing have revolutionized precision medicine in CCA. Distinct genomic markers, including fibroblast growth factor receptor 2 (FGFR2) alterations and isocitrate dehydrogenase 1 (IDH1) mutations, have emerged as promising therapeutic targets. FGFR2 alterations, encompassing mutations and rearrangements, play pivotal roles in oncogenesis, with FGFR inhibitors demonstrating promise despite identified resistance mechanisms. Similarly, IDH1 inhibitors face challenges with resistance, despite encouraging early clinical trial results, prompting exploration of novel irreversible inhibitors. Dr. James Cleary’s illuminating discourse underscores the significance of diverse FGFR2 alterations and the potential of IDH1 inhibition in reshaping the treatment landscape for CCA. These findings unveil critical avenues for targeted therapeutic interventions, emphasizing the critical need for ongoing research to optimize outcomes in this challenging cancer subtype, incorporating innovative insights from Dr. Cleary.

Impact of sex on treatment decisions and outcome in patients with neuroendocrine neoplasms.

Sex differences affect the management of several diseases in both male and female patients. However, the influence of sex on neuroendocrine neoplasms (NENs) has been scarcely investigated. Thus, this study aimed to compare tumor characteristics, treatment decisions, and overall survival in patients with NENs, stratified by sex. The retrospective analysis of the SwissNET cohort covered NENs of gastroenteropancreatic, pulmonary, or unknown origin from July 2014 to September 2022. The analysis included 1985 patients (46% female and 54% male). No significant difference in tumor grading was found between male and female patients. However, male patients presented with higher staging at time of diagnosis and with more lymph node and bone metastases. Surgery was performed more often in female compared to male patients (73.4% vs 68.7%, P = 0.023). Male patients received peptide receptor nuclide therapy (PRRT) earlier than female patients (7.8 months vs 13.1 months from time of diagnosis, P = 0.003). The median overall survival was significantly shorter for male compared to female patients (male: 18 years, female: not reached, P < 0.001, hazard ratio (HR) 1.55 (1.19-2.01), P = 0.001). Multivariable analyses revealed advanced age (HR 1.02 (1.01-1.04)), cancer of unknown origin (HR 2.01 (1.09-3.70)), higher grading (G3: HR 6.74 (4.22-10.76)), having metastases at the time of diagnosis (HR 2.11 (1.47-3.02)), and surgical treatment (HR 0.67 (0.48-0.93)) as independent predictors for overall survival. In conclusion, male sex was associated with worse outcome in NEN patients, likely due to more advanced tumor stage at the time of diagnosis. Further investigations are required to understand the underlying mechanisms of these sex differences.

Epidemiologie und Management neuroendokriner Neoplasien unbekannter Herkunft – ein Überblick

Abstract Background Neuroendocrine neoplasms (NEN) are rare tumors, mainly located in the lungs, pancreas or gastrointestinal tract. In some NENs the origin remains unidentified. They are referred to as cancer of unknown primary (CUP). Since only 9–14% of NENs are CUP, data about prognosis and therapy is scarce. Therefore, this paper aims to summarize the current knowledge on patients with CUP-NENs. Methods This analysis is a literature review, including the following databases, PubMed and Google Scholar, using the keywords neuroendocrine tumor, cancer of unknown origin, unknown primary, CUP, epidemiology, definition, therapy guidelines, survival. In all, 47 articles were selected and included. Results The available literature indicated that the median age of onset was higher in CUP compared to NENs of known origin. CUP had a comparatively higher rate of poorly differentiated neoplasia. The recommended imaging modality was computed tomography (CT), complemented by positron emission tomography (PET)/CT, using 68Gallium-labeled somatostatin analogues (68Ga DOTATOC, DOTANOC or DOTATATE PET/CT). Surgical resection was suggested as first-line therapy. Other treatment options included chemotherapy, somatostatin analogues, molecular therapy and radiotherapy. Compared to NENs of known origin, CUP were associated with a worse prognosis. Conclusion The current data suggest that CUP-NEN are frequently associated with older age and higher grade compared to patients with known-origin NENs. This reflected a worse prognosis for CUP-NENs.

Comparison of immunohistochemistry and next-generation sequencing results in oncogenic PTEN missense mutations

BackgroundPhosphatase and tensin homolog (PTEN) is one of the most frequently mutated tumor suppressor genes in malignant tumors. Oncogenic PTEN mutations have diagnostic, prognostic, and therapeutic implications. Similar to TP53 mutations, oncogenic PTEN mutations can result from nonsynonymous missense mutations. However, there has been no detailed study on the immunostaining pattern of oncogenic PTEN missense mutations. MethodsWe retrospectively selected 18 cancers (13 endometrial cancers, 2 brain tumors, 1 ovarian cancer, 1 lung cancer, and 1 cancer of unknown origin) harboring oncogenic PTEN missense mutations, which were confirmed by targeted next-generation sequencing. PTEN immunohistochemistry was conducted for all cases, and the results were compared with sequencing results. ResultsThe immunostaining results of PTEN missense mutations revealed a diverse pattern depending on the site of mutation and co-occurring mutation. The most frequent oncogenic PTEN mutations were R130G (4/18, 22.2 %) and R130Q (3/18, 16.7 %). Eleven cases harbored PTEN missense mutations only, whereas the remaining seven cases harbored PTEN truncating mutations and PTEN missense mutations. Complete loss of cytoplasmic expression were found in five cases, of which three had missense mutation only. PTEN R130 residue mutation alone did not showed altered PTEN immunostaining pattern in this study. ConclusionsPTEN missense mutation, which comprises a portion of oncogenic PTEN mutation, can manifest as a diverse immunostaining pattern. Complementary testing using both immunostaining and next-generation sequencing should be conducted to accurately evaluate the PTEN status in malignancy.

THU541 Impact Of Gender On Treatment Decisions And Outcome In Patients With Neuroendocrine Neoplasms

Abstract Disclosure: J. Beck: None. A. Siebenhüner: None. D. Wild: None. E.R. Christ: None. J. Refardt: None. Introduction/Background: Gender differences affect the treatment of several diseases in both male and female patients. However, the influence of gender on treatment decisions and outcome in neuroendocrine neoplasms (NENs) has scarcely been investigated. Aims: Comparison of tumor characteristics, treatment decisions and outcome of patients with NENs, stratified by gender. Material and Methods: Retrospective analysis of the SwissNET cohort involving NENs of gastroenteropancreatic, pulmonal or unknown origin from 07/14 – 09/21. Site of origin, tumor grading, time to first treatment, choice of treatment and overall survival was assessed. Results: 2329 patients were included in the analysis with 54% being male and 46% female patients. No significant difference in site of origin, tumor grading and staging was found between male and female patients. There was also no difference in time of symptoms onset until diagnosis and first treatment intervention. Surgery was performed in 66.3% of male and 71% of the female patients, p=0.016. Meanwhile, male patients received more often PRRT (22% vs 19.3%, p=0.007) and chemotherapy (15.9% vs 12.7%, p=0.032). Despite the similar tumor characteristics, the median overall survival of male patients was significantly lower compared to female patients (Male: 124.8 months, Female: 158.5 months, p&amp;lt;0.001). Interestingly, this difference was most pronounced in patients with lung NENs (Male: 142 months, Female: not reached) and cancer of unknown origin (Male: 18.5 months, Female: 35 months). Conclusions: Male gender seems to be a risk factor for worse outcome, specifically for lung NENs and NENs of unknown origin. The underlying mechanisms of these findings remain to be established. Presentation: Thursday, June 15, 2023

Retroperitoneal mass revealed to be metastatic lymph node of unknown primary origin – Cancer of unknown origin

Cancer of unknown primary origin is a rare form of metastatic solid tumour representing less than 2% of malignancies. These patients tend to have an unfavourable prognosis, with long-term survivors scarcely reported in the literature. Here we present a rare case of a 56- year-old female with eight year survival, after surgical resection of a metastatic retroperitoneal lymph node, despite relapse of her tumour and no adjuvant treatment. We hope that this case report will aid in increasing awareness and understanding of this often overlooked entity.

Cancer of unknown origin in gynaecologic oncology

Tumour of unknown primary (primum ignotum) is a metastatic disease that generally shows a poor response to treatment and prognosis. Although it exhibits a trend of decreasing incidence, the diagnostic processes are complicated. The available literature shows that 5–30% of metastases involve the ovary, but it remains unclear how often ovarian infiltration is found in tumours of unknown primary. The most common metastatic disease that affects the ovaries are malignant tumours of the gastrointestinal tract, breast, pancreas, and haematological malignancies. Usually, the first step to distinguish between a primary and a secondary tumour of the ovary is an ultrasound examination, where the ovarian metastases have some characteristic features. Here we report our experience with primum ignotum in a patient with simultaneous ovarian and bone marrow involvement.

Updated Incidence, Treatment and Survival of a Nationwide Cohort of Patients with Peritoneal Metastases of Unknown Origin

The aim of this study was to investigate the incidence, treatment and survival of patients with peritoneal metastases (PM) of unknown origin. All Dutch patients diagnosed in 2017 and 2018 with PM of unknown origin (PM-CUP) were evaluated. Data were extracted from the Netherlands Cancer Registry (NCR). Patients with PM-CUP were categorized into the following histological subtypes: 1) adenocarcinoma, 2) mucinous adenocarcinoma, 3) carcinoid, 4) unspecified carcinoma and 5) other. Treatments were compared between the different histological subtypes in patients with PM-CUP. Overall survival (OS) was calculated using the Kaplan–Meier method for all patients with cancer of unknown origin and between histological subtypes in patients with PM-CUP. Significant differences in OS were assessed by using the log-rank test. In total, 3026 patients were diagnosed with cancer of unknown origin, 513 (17%) among them were diagnosed with PM-CUP. Most PM-CUP patients received best supportive care only (76%), whereas 22% received systemic treatment and 4% underwent metastasectomy. Median OS was 1.1 months for all patients with PM-CUP but varied from 0.6 months to 30.5 months depending on the underlying histology. In this study, PM-CUP were diagnosed in 17% of all patients with cancer of unknown primary and the reported survival in this cohort was extremely poor. Since survival differed among histological subtypes and recently more treatment options became available for a selected group of patients with peritoneal malignancies, it is of great importance to identify the histology of the metastases and whenever possible the primary tumor.

Extensive intrathoracic and intraperitoneal splenosis mimicking mesothelioma: a case report

BackgroundSplenosis is the heterotopic autotransplantation of splenic tissue after severe splenic trauma and/or splenectomy. The epidemiology is elusive, but splenosis is frequently misdiagnosed as malignant tumors of gastrointestinal, gynecological, or hematological origin before the correct diagnosis is ultimately found. We herein report a rare case of combined, extensive intraabdominal and intrathoracic splenosis initially presenting as pleural mesothelioma.Case presentationA 63-year-old Caucasian male presented with dyspnea and recurring thoracic pain. Initial X-ray and computed tomography scans showed disseminated intrathoracic and intraabdominal lesions. Consequently, thoracoabdominal mesothelioma or a polytopically metastasized cancer of unknown origin was suspected. A thorough examination of the patient’s medical history and contrast-enhanced ultrasound by a skilled examiner revealed the diagnosis of extensive abdominal and thoracic splenosis as a consequence of an abdominal gunshot wound with a ruptured diaphragm several decades earlier. Timely diagnosis by noninvasive measures prevented the patient from potential complications of harmful diagnostic procedures, including nuclear imaging and biopsies. The patient is currently treated for hepatitis C and chronic obstructive lung disease, whereas no specific treatment for splenosis is required.ConclusionsWe present a case of rare intrathoracic and intraperitoneal splenosis mimicking mesothelioma. Contrast-enhanced ultrasound and thorough patient history were used for diagnosis and prevented this patient from having to undergo potentially harmful diagnostics. Splenosis can occur after splenic trauma and, consequently, needs to be considered as a rare differential diagnosis to malignant tumors of various origins when a matching patient history is obtained.

Using a Recently Approved Tumor Mutational Burden Biomarker to Stratify Patients for Immunotherapy May Introduce a Sex Bias.

Abstract The U.S. Food and Drug Administration (FDA) recently approved the treatment with pembrolizumab, an immune checkpoint inhibitor (ICI) targeting PD1 (anti-PD1), for patients with advanced solid tumors with a high tumor mutational burden (TMB) (defined as TMB ≥10 mutations/Mb). However, following recent studies suggest that TMB levels and response to ICI treatment may differ between male and female melanoma patients, we investigated whether using this high-TMB threshold for selecting patients for anti-PD1 treatment may induce a sex-dependent bias. We analyzed a large ICI cohort of 1,286 patients across nine cancer types treated with anti-PD1/PDL1. We find that using this threshold would indeed result in an unwarranted sex bias in melanoma, successfully stratifying female but not male patients. While this threshold is currently not a regulatory prerequisite for ICI treatment in melanoma, it is important to raise awareness to this bias. Notably, no sex-dependent significant differences were observed in the response of melanoma patients to anti-CTLA4 therapies, different chemotherapies or combination therapies. Beyond melanoma, the high-TMB threshold additionally introduces a sex bias of considerable magnitude in glioblastoma and in patients with cancers of unknown origin, however, these results are not statistically significant. A power analysis shows that these biases may become significant with larger sample size, warranting further careful testing in larger cohorts.

Abstract 29: The recently approved high-TMB criteria may introduce a sex bias in response to PD1 inhibitors

Abstract Motivation and research question: The U.S. Food and Drug Administration recently approved treatment with pembrolizumab, an immune checkpoint inhibitor (ICI) targeting PD1 (anti-PD1), for all advanced solid tumors with high tumor mutational burden (TMB), defined as ≥10 mutations/Megabase (mut/Mb). Recent studies have suggested that strength of immune selection, biomarkers of outcome, TMB levels and response to ICI treatment may differ between male and female cancer patients in some tumor types. This motivated us to examine what are the sex-specific implications, if any, of the ≥10 mut/Mb threshold on selecting patients for ICI treatment. Data &amp; Methods: We analyzed the largest ICI cohort publicly available to date (Samstein et al. 2019), including 1,070 patients treated with anti-PD1/PD-L1 monotherapy, 99 treated with anti-CTLA4 and 255 treated with an ICI combination. We focused on the nine solid tumor types with TMB and clinical response data (median follow-up of 19 months) for at least 50 patients. Results: 1.We observed a significant difference in the median TMB across sex among melanoma patients (n=130, female vs male median TMB=8.36 vs 11.81, P&amp;lt;0.02), in concordance with previous observations.2.Notably, we found that the FDA-approved threshold of ≥10 mut/Mb to select patients would result in an unwarranted sex bias in melanoma patients. This threshold successfully identifies female melanoma patients with better overall survival (hazard ratio (HR) =0.19, P&amp;lt;0.03) but fails to do so in male patients (HR=0.94, P&amp;lt;0.85), resulting in a five times higher HR in males vs females at that threshold level (interaction between sex and TMB P&amp;lt;0.03). This bias in effect size by sex is confirmed in two additional melanoma cohorts treated with anti-PD1 (Hugo et al. 2016, N=38, P&amp;lt;0.024; Liu et al. 2016, N=114, P&amp;lt;0.03; and P&amp;lt;0.01 for all three melanoma datasets combined, N=312). We do not observe this differential effect for anti-CTLA4 treatment (P&amp;lt;0.14, N=174) or for anti-PD1 + anti-CTLA4 combination (P&amp;lt;0.8, N=115) or for non-ICI treatments (P&amp;lt;0.4, N=322).3.Analysis of additional eight cancer types whose data are available in (Samstein et al 2019) points to glioblastoma (female vs male HR=0.87 vs 0.5) and cancer of unknown origin (female vs male HR= 1.03 vs 0.15), which show marked differences in the HR between male and female patients when applying the FDA threshold for TMB. However, despite these large effects, they do not achieve statistical significance, probably due to the small size of these datasets. Conclusions: The FDA-approved criteria of 10 mutations/Mb could serve as an informative biomarker for stratifying female melanoma patients but is inadequate for stratifying male patients for anti-PD1 treatment. Our results indicate that its usage is likely to introduce a sex bias in additional cancer types, which will be highly important to carefully test further in larger datasets. Citation Format: Neelam Sinha, Sanju Sinha, Kuoyuan Cheng, Sanna Madan, Alejandro Schaffer, Kenneth Aldape, Ayelet Erez, Brid M. Ryan, Eytan Ruppin. The recently approved high-TMB criteria may introduce a sex bias in response to PD1 inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 29.

Incidence of venous thromboembolism in patients with solid cancers in Japan: retrospective study of 2735 patients.

The incidence of cancer-associated venous thromboembolism (CA-VTE) in Japan has not been fully investigated. Clinicopathological information from patients with solid malignancies who first visited our department between November 2011 and March 2018 were retrospectively reviewed from medical records. The primary outcome was incidence of CA-VTE, defined as deep-vein thrombosis (DVT) and/or pulmonary embolism (PE). On median follow-up of 187days, 91 of 2735 patients (3.3%) developed CA-VTE during their clinical course, giving an incidence rate of 40.7 per 1000 person-years. Of the 91 patients, 75 (82%) were diagnosed with DVT alone, 6 (7%) with PE alone, and 10 (11%) with both DVT and PE. CA-VTE was most frequent in non-small cell lung cancer (10.8%), followed by cancer of unknown origin (5.8%). Forty-four patients (48%) had one or more symptoms at the initial diagnosis of VTE. Five patients (6%) had a normal D-dimer level (≤ 1.0µg/mL); of these, 2 were asymptomatic. In this retrospective study, the incidence of CA-VTE in Japanese patients with cancer was equivalent to that in Western populations. Approximately half of CA-VTE patients were asymptomatic and 6% had normal D-dimer levels, indicating the need for closer attention to occult CA-VTE.

Exploring the diagnostic journey and life impact of patients with cholangiocarcinoma (CCA): Results from a large patient survey in the United States.

277 Background: Patients (pts) with CCA typically present with advanced disease and face a poor prognosis and impaired quality of life (QoL). Despite improvements in therapies, the impact of CCA on pts’ daily lives has been rarely studied. This pt-focused survey explored the diagnostic journey, life impact including work status, QoL and psychosocial impacts of CCA. Methods: Pts with CCA were recruited in partnership with the Cholangiocarcinoma Foundation from Aug 23 through Sept 20, 2019, and were categorized by AJCC stage. Pts participated in a 30-min online survey to assess disease staging, symptoms, demographics, diagnosis journey, daily life impact, mental health, and sexual function. The survey included the validated disease specific European Organization for Research and Treatment of Cancer (EORTC) QLQ-BIL21, the Patient Health Questionnaire-9 (PHQ-9), and the Work Productivity and Activity Impairment (WPAI) questionnaire. Results: Of 1,286 pts invited, 707 (55%) completed the survey (male, 77%; age ≥55 y, 13%; currently employed, 78%; perihilar CCA, 47%; intrahepatic CCA, 41%; distal CCA, 12%; stage 1–2, 22%, stage 3a, 51%, stage 3b–4, 20%, in remission, 4%, unknown stage, 2%). Median duration from symptom onset to CCA diagnosis was 19 months (range, 1–241), and median duration from diagnosis to completing survey was 24 months (0–744). Initial misdiagnosis occurred in 35% of pts (n=247); among whom the most common misdiagnosis was gall bladder cancer (52% [n=129]); misdiagnosis of cancer of unknown origin occurred in 9% of pts (n=21). CCA was most frequently first suspected and diagnosed by oncologists (38% [n=269] and 70% [n=492]); among non-specialty physicians, more first suspected than diagnosed CCA (eg, primary care physicians, 22% [n=156] vs 3% [n=22]). Pts’ primary considerations in treatment decisions were physician judgment (38% [n=272]), QoL (16% [n=111]), time spent in hospital (11% [n=75]), laboratory results (11% [n=79]), other pt experiences (6% [n=42]). On the EORTC QLQ-BIL21, pts reported negative life impact from anxiety (mean [SD], 52.9 [19.2]), tiredness (52.3 [19.3]), and treatment (51.3 [28.8]). On the WPAI, 61% of pts (n=429) reported some, and 28% (n=200) reported considerable impact on work status. On the PHQ-9, 58% (n=408) of pts reported significant impact of depression on daily life, with 72% (n=506) and 25% (n=177) reporting that depression makes daily life somewhat, or very difficult, respectively. Pts also reported considerable or some impact on sexual desire (51% [n=362]; 36% [n=255]) and intimacy (47% [n=332]; 39% [n=273]). Conclusions: Pts with CCA who participated in this survey were mostly &lt;55 y of age and had experienced CCA symptoms for an extended time (2 y) before diagnosis, at which time CCA was often initially misdiagnosed. The burden of CCA symptoms on daily lives, work productivity, and mental health is immense.

A meta-analysis of reversion mutations in BRCA genes identifies signatures of DNA end-joining repair mechanisms driving therapy resistance

Germline mutations in the BRCA1 or BRCA2 (BRCA) genes predispose to hereditary breast and ovarian cancer and, mostly in the case of BRCA2, are also prevalent in cases of pancreatic and prostate malignancies. Tumours from these patients tend to lose both copies of the wild-type BRCA gene, which makes them exquisitely sensitive to platinum drugs and poly(ADP-ribose) polymerase inhibitors (PARPi), treatments of choice in these disease settings. Reversion secondary mutations with the capacity of restoring BRCA protein expression have been documented in the literature as bona fide mechanisms of resistance to these treatments. We analysed published sequencing data of BRCA genes (from tumour or circulating tumour DNA) in 327 patients with tumours harbouring mutations in BRCA1 or BRCA2 (234 patients with ovarian cancer, 27 with breast cancer, 13 with pancreatic cancer, 11 with prostate cancer and 42 with a cancer of unknown origin) that progressed on platinum or PARPi treatment. We describe 269 cases of reversion mutations in 86 patients in this cohort (26.0%). Detailed analyses of the reversion events highlight that most amino acid sequences encoded by exon 11 in BRCA1 and BRCA2 are dispensable to generate resistance to platinum or PARPi, whereas other regions are more refractory to sizeable amino acid losses. They also underline the key role of mutagenic end-joining DNA repair pathways in generating reversions, especially in those affecting BRCA2, as indicated by the significant accumulation of DNA sequence microhomologies surrounding deletions leading to reversion events. Our analyses suggest that pharmacological inhibition of DNA end-joining repair pathways could improve durability of drug treatments by preventing the acquisition of reversion mutations in BRCA genes. They also highlight potential new therapeutic opportunities when reversions result in expression of hypomorphic versions of BRCA proteins, especially with agents targeting the response to DNA replication stress.

Abstract 5432: Cancer of unknown primary site-of-origin: An enigma ready to be miR-solved

Abstract Background Cancer of Unknown Primary is a rare syndrome of metastatic cancers for which the primary site cannot be recognized after detailed physical examinations, blood analyses, imaging and immunohistochemical (IHC) testing. CUPs make up 3-5% of newly diagnosed cancers worldwide and represent an important diagnostic and clinical problem. Treatment failure to empirical chemotherapy is common, resulting in progressive disease and poor prognosis. We and others proposed that a molecular inference of the tissue of origin could be feasible for most CUP tumors (Ferracin et al. J Pathol, 2011), thus giving access to more effective therapeutic agents and potentially extending CUP patient life-expectancy. Methods We optimized a cancer-type classifier based on microRNA (miRNA) expression for the prediction of CUP primary tumor site (Laprovitera et al., Front Oncol. 2018). Specifically, we designed a molecular assay to quantify the absolute copy number of 89 miRNAs in formalin-fixed paraffin-embedded (FFPE) samples using EvaGreen-based Droplet Digital PCR (BioRad). We tested 153 samples from three groups: primary tumors (N=95), metastases of known origin (N=10) and cancers of unknown origin (N=48). CUP diagnosis was obtained after a detailed histo-pathological investigation as per CUP diagnostic guidelines (NCCN occult primary v.2-2019 and ESMO guidelines). The study was approved by the local ethical committee. Results We investigated a pre-determined set of 89 miRNAs to infer the site-of origin of metastatic cancers of unknown or uncertain primary. Primary tumors from 16 different sites (lung, pancreas, liver, bile duct, kidney, bowel, testis, ovary, endometrium, stomach, bladder, breast, prostate, melanoma, gastrointestinal neuroendocrine, head and neck) were tested for absolute miRNA expression and used to train our classifier (Tibshirani et al. PNAS, 2002). We used the metastases of known origin as a test-set for our molecular prediction. We applied the shrunken centroids approach as predictive algorithm to obtain the most probable CUP site(s)-of- origin. Our results were judged against the hypothesized primary site suggested by standard diagnostic workup and pathological assessment. The molecular test was successfully applied to all CUP samples and provided a site-of-origin identification (with a probability &amp;gt; 50%) for all samples, potentially within a one-week time frame from sample inclusion. Conclusions Our study demonstrated that miRNA expression profiling in CUP samples have the potential to be employed in a clinical setting. Our molecular analysis can be performed on-request, concomitantly with the standard diagnostic workup and in association with genetic profiling, to offer valuable indication about the possible primary site thereby supporting treatment decisions. This work was supported by grants from the Italian Association for Cancer Research (AIRC) to MF (IG 18464). Citation Format: Noemi Laprovitera, Elisa Porcellini, Mattia Riefolo, Elisabetta Broseghini, Ingrid Garajova, Silvia Sabbioni, Martin Pichler, Andrea Ardizzoni, Antonia D'Errico, Manuela Ferracin. Cancer of unknown primary site-of-origin: An enigma ready to be miR-solved [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5432.

First-in-human study of the cancer peptide vaccine, TAS0313, in patients with advanced solid tumors: Phase I dose-finding part results.

73 Background: TAS0313 is a cancer vaccine cocktail containing three long peptides, with a total of 12 cytotoxic T lymphocyte (CTL) epitope peptides. These peptides were derived from eight cancer-associated antigens that are highly expressed in various cancers. We report the results of a phase I part examining the tolerability, safety, potential efficacy, and immunological responses of 9 and 27 mg TAS0313 in patients (pts) with advanced solid tumors. Methods: The enrolled pts had at least one of the following HLA types: HLA-A*02:01, -A*02:06, -A*02:07, -A*11:01, -A*24:02, -A*31:01, or -A*33:03. TAS0313 was subcutaneously administered on Days 1, 8, and 15 of Cycles 1 and 2 and on Day 1 of Cycle 3 or later in 21-day cycles until disease progression, or unacceptable toxicity. Tolerability was assessed in at least six pts during the first cycle. Tumor response was evaluated using RECIST v1.1. The antigen specific CTL and IgG were analyzed post treatment by blood samples. Optional serial tumor biopsies were performed for tumor infiltrating leukocyte (TIL) analysis. CTL, IgG, and TIL were measured by ELISPOT assay, Luminex assay, and IHC (CD8 positive), respectively. Results: Seventeen pts were enrolled in 9mg (n = 10) and 27mg (n = 7) groups. There was no serious adverse drug reaction (ADR) in any patient. All ADRs were of grade 1 or 2, with the most frequent being dermatological injection site reaction, in 7/10 (70%) and 6/7 (86%) pts and pyrexia, in 1/10 (10%) and 2/7 (29%) for the 9 and 27mg groups, respectively. The best overall response was stable disease, in 2/10 (20%) and 2/7 (28%) pts. One patient with cancer of unknown origin received prolonged administration (over 10 months) of the 9mg dose. Increment of CTL and IgG by treatment were detected in 9 and 27mg groups. TIL counts were increased in 2/3(67%) and 3/4(75%) in 9 and 27mg groups compared with pre-treatment samples, respectively. Conclusions: TAS0313 demonstrated safety, tolerability, and immunological responses in pts with advanced solid tumors in the 9 and 27mg groups. A phase II part, evaluating the efficacy of combination therapy with pembrolizumab in pts with urothelial carcinoma and monotherapy in glioblastoma pts, is currently underway. Clinical trial information: JapicCTI-183824.

Abstract 1280: Chromosome-scale haplotyping enables comprehensive discovery of cancer rearrangements and germline-related susceptibility mutations

Abstract To understand the complexity of cancer genomes, one needs to define both the structure and order of genomic variants relative to their respective parental chromosome. This process is commonly referred to as phasing and generates haplotypes with group of variants that originated from one parental chromosome or the other. Importantly, genetic variants such as rearrangements are difficult to detect and phase with conventional next-generation sequencing; short reads do not contain long-range genomic information for phasing. Recently, we demonstrated a new technology called linked-read sequencing, which uses droplet barcoding to tag high-molecular-weight (HMW) DNA in order to reconstruct genomic haplotypes and SVs in the range of megabases. Using single nanograms of DNA, we determined the structure of normal and cancer genomes at single-molecule resolution. In this study, we developed a method to generate haplotypes spanning entire chromosome arms and even across centromeric regions. The method is based on leveraging identity-by-descent (IBD) principles in haplotype-resolved sequence data. Taking advantage of shared haplotypes between an individual and a single parent, we exploited the fact that any single chromosomal homologue consists of a contiguous segment from one parent regardless of any recombination events that occurred during meiosis. By determining which of the two homologous segments in a haplotyped segment belongs to a parent, we can then stitch together the haplotypes that are physically contiguous in the child. Using phased haplotypes generated from linked-read sequencing, we improve on the experimentally generated haplotypes by at least an order of magnitude. As a control, we performed this type of analysis on a series of control genomes with comprehensive haplotype information. We achieved near-perfect concordance in the comprehensive phasing of these control samples regardless of which parental genome was used. We performed this analysis on linked-read whole-genome sequence data derived from familial cohorts with an inherited predisposition to cancer of unknown origin. For example, in one family predisposed to cholangiocarcinoma, we resolved the haplotype structure of entire chromosomes and segregated entire segments belonging to affected and unaffected individuals. A similar process was applied to the cancer samples originating from affected family members. The joint information was used to identify potential candidate driver genes for this cancer type. Overall, we demonstrated the utility of linked-read analysis and whole-chromosome haplotypes in discovering cancer genes. Citation Format: Stephanie U. Greer, Billy T. Lau, Lincoln D. Nadauld, Hanlee P. Ji. Chromosome-scale haplotyping enables comprehensive discovery of cancer rearrangements and germline-related susceptibility mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1280.

AB021. 176. Cancer of unknown origin: incidence and clinical course

AB021. 176. Cancer of unknown origin: incidence and clinical course

原発不明癌のpulmonary tumor thrombotic microangiopathyにより死亡した1例

原発不明癌のpulmonary tumor thrombotic microangiopathyにより死亡した1例

Oral Manifestations of Multiple Myeloma Case Report

Sudanese female 68 years old with a history of a back cancer of unknown origin. She complained of painful swelling in the posterior border of the mandible, confirmed diagnosis by incisional biopsy was multiple myeloma. After chemotherapy impressive improvement was observed. The present case was diagnosed with multiple myeloma based on the oral findings.