Tumor Of Unknown Primary Origin Research Articles

Combining germline, tissue and liquid biopsy analysis by comprehensive genomic profiling to improve the yield of actionable variants in a real-world cancer cohort

BackgroundComprehensive next-generation sequencing is widely used for precision oncology and precision prevention approaches. We aimed to determine the yield of actionable gene variants, the capacity to uncover hereditary predisposition and liquid biopsy appropriateness instead of, or in addition to, tumor tissue analysis, in a real-world cohort of cancer patients, who may benefit the most from comprehensive genomic profiling.MethodsSeventy-eight matched germline/tumor tissue/liquid biopsy DNA and RNA samples were profiled using the Hereditary Cancer Panel (germline) and the TruSight Oncology 500 panel (tumor tissue/cfDNA) from 23 patients consecutively enrolled at our center according to at least one of the following criteria: no available therapeutic options; long responding patients potentially fit for other therapies; rare tumor; suspected hereditary cancer; primary cancer with high metastatic potential; tumor of unknown primary origin. Variants were annotated for OncoKB and AMP/ASCO/CAP classification.ResultsThe overall yield of actionable somatic and germline variants was 57% (13/23 patients), and 43.5%, excluding variants previously identified by somatic or germline routine testing. The accuracy of tumor/cfDNA germline-focused analysis was demonstrated by overlapping results of germline testing. Five germline variants in BRCA1, VHL, CHEK1, ATM genes would have been missed without extended genomic profiling. A previously undetected BRAF p.V600E mutation was emblematic of the clinical utility of this approach in a patient with a liver undifferentiated embryonal sarcoma responsive to BRAF/MEK inhibition.ConclusionsOur study confirms the clinical relevance of performing extended parallel tumor DNA and cfDNA testing to broaden therapeutic options, to longitudinally monitor cfDNA during patient treatment, and to uncover possible hereditary predisposition following tumor sequencing in patient care.

Non-Hematological Primary Source of Bone Marrow Metastasis in Adults: A Systematic Review

Introduction: In recent years, scientific interest in bone marrow invasion or infiltration by non-hematological malignant cells has increased due to growing evidence suggesting a prognostic impact in certain specific types of solid tumors. However, the available data on the primary source of metastasis are scarce. Objective: synthesize the reported data on non-hematological tumors infiltrating the bone marrow in studies based on histopathological confirmation of metastases. Methodology: PubMed/Medline and Google Scholar were used for the systematic review; the filters used were human studies, adult age (>14 years old), and the period between 1990-2021. The main inclusion criteria was the histopathological confirmation of bone marrow invasion. The exclusion criteria were small case reports, specific neoplasm criteria, and grou-ped case series in secondary literature to minimize bias. Three different researchers evaluated all the titles and abstracts available. Two researchers independently extracted and recorded data; this process was cross-checked again. Finally, data were summarized and presented in tables using descriptive statistics. Results: 31 articles from 12 countries were included; four were multicenter, and all but 2 were retrospective. One thousand four hundred fifty-one adult patients with Bone Marrow Metastasis due to solid tumors were found. All included studies presented the distribution of the primary source of metastases: 82 % were epithelial neoplasms, 14 % were tumors of unknown primary origin, and 10 % were low-frequency specific neoplasms grouped as ‘others’. Conclusion: The results can be considered with caution due to the methodological heterogeneity of the studies and the risk of bias.

THU014 Post-surgical Remission After Resection Of Solitary Mediastinal Lymph Node In A Metastatic Occult Ectopic ACTH Syndrome Patient

Abstract Disclosure: I.P. de Magalhães: None. C.P. Oliveira: None. L.P. Lins: None. N.X. Andrade: None. M.S. Lima: None. S.A. Siqueira: None. J.S. Fonini: None. E.C. Assis Filho: None. A.W. Mariani: None. M.C. Machado: None. BACKGROUND: The prevalence of occult cases has been increasing in the most recent series of Ectopic ACTH syndrome (EAS) maybe due to the small size of pulmonary neuroendocrine tumors. We present an atypical and very rare case of EAS with initial presentation of a single metastatic mediastinal lymph node that evolved with remission after your resection with no defined primary tumor. CASE REPORT: A 15-year-old female patient presented a clinical feature of Cushing’s syndrome (CS) with a 1-year evolution. Hormonal evaluation confirmed ACTH-dependent CS: urinary free cortisol of 819 µg/24h (3-43), late night salivary cortisol of 409 ng/dL (<274) and ACTH of 105 pg/mL (<63.3). Noninvasive methods for differential diagnosis of ACTH-dependent CS did not clarify the etiology (conflicting results): pituitary MRI negative, suppression of 59.6% of cortisol after high dose dexamethasone suppression test, positive response of ACTH and cortisol at desmopressin test, suppression of 81% of ACTH at acute octreotide SC test, negative serum tumor markers (gastrin, calcitonin, CEA, CA125, alpha-fetoprotein, CA19.9 and bhCG), negative cervical and pelvic ultrasound, negative computed tomography of thorax and negative abdominal MRI. Bilateral and simultaneous petrosal inferior sinus sampling with desmopressin confirmed EAS due to negative central to peripheral ACTH gradient, even after normalized PRL/ACTH gradients. Finally, PET/CT with Ga68-DOTATATE revealed a single infracarinal nodule of 1.5x0.6 cm with high capture of radioligand, SUVmax of 23.2, suggestive of affected mediastinal lymph node. The patient was submitted to thoracic surgery and the infracarinal lymph node was dissected and removed. Anatomopathological and immunohistochemical analyses disclosed a lymph node metastatic of a well-differentiated grade neuroendocrine tumor ACTH positive, Ki-67 2%. After surgery, the patient exhibited CS improvement and impressive drop of hormones at 5th postsurgical day (serum cortisol <1.0 µg/dL and ACTH of 2.2 pg/mL) confirming remission of CS. CONCLUSION: To our knowledge, approximately 36 cases of EAS due to neuroendocrine tumor of unknown primary origin were reported. However, previous cases commonly exhibited no remission after only removal of metastasis. Our case presented initial remission even with no primary tumor identified (occult primary tumor non-functioning?). Follow up with clinical, hormonal and imaging methods are necessary due to recurrence risk. Presentation: Thursday, June 15, 2023

Intra-Arterial Chemotherapy in Patients with Liver Metastases from Gastrointestinal Stromal Tumors

Purpose: To evaluate clinical effectiveness of arterial therapy in patients with gastrointestinal stromal tumors (GIST) metastases to the liver. Material and methods: Between 2005 and 2021, intra-arterial chemotherapy was performed in 11 patients: 6 men and 5 women aged 40–78 (mean 59) years with immunohistochemically verified liver metastases of GIST. Resection of gastric (n = 4), jejunal (n = 3), sigmoid (n = 1), and pancreatic tumor (n = 1) was performed in 9 patients; tumor of unknown primary origin was in 2 patients. Before intra-arterial treatment, all patients received specific treatment of liver metastases in outside hospitals (liver resection, radiofrequency ablation, tyrosine kinase inhibitors or systemic chemotherapy), but progressed. We performed 56 treatment cycles: oily chemoembolization (n = 37) or its combination with chemoinfusion (n = 19). Results: According to mRECIST, 1 patient showed complete and 3 partial responses. Stable disease in 4 and progression in 3 patients was seen. Liver resection was carried out in 3 responders. At present, 8 patients died in 28,4 mo (median 32 mo). Three patients are alive for 5–7 years. Conclusion: Intra-arterial chemotherapy seems to be safe and promising treatment of GIST liver metastases, including patients showing refractory to tyrosine kinase inhibitors.

Histopathological Analysis of Central Nervous System Metastases: Six Years of Data From a Tertiary Center.

Introduction: The most common cause of neurological symptoms in patients with systemic malignant tumors is central nervous system (CNS) metastases, and CNS metastases are one of the important causes of morbidity and mortality in these patients. The most common metastatic tumors to the CNS are lung, breast, malignant melanoma, genitourinary, and gastrointestinal tumors. We aimed to analyze our data on patients with CNS metastases in our department, which belongs to a large archive in the field of neuropathology.Methods: The data of patients who had CNS metastases between January 2015 and August 2021 in our department were reviewed retrospectively. The patients were grouped in terms of demographic data, location, histopathological diagnosis, and primary origin characteristics, and their frequency and immunohistochemical staining characteristics were investigated.Results: There were 256 patients with CNS metastases in our study. The mean age was found to be 56.12. Of the patients, 30.5% were female and 69.5% were male. Astrocytic and oligodendral tumors (25.3%), followed by meningiomas (24.1%), and then CNS metastases (21.3%) were the most common CNS tumors. Among the CNS metastases, the most common primary sites were the lung (58%), breast (16%), tumors of unknown primary origin (TUP) (5%), colon (4%), and gynecologic tract (3.1%). Localization was found as cerebral (69.5%), cerebellar (28.1%), and spinal (2.3%).Conclusion: In CNS system metastases, an accurate histological diagnosis should be made by histomorphological evaluation supported by compatible immunohistochemical results in the presence of clinical history and radiological findings. Despite performing a larger immunohistochemical panel, it should be kept in mind that a primary site of origin cannot be found in a significant number of cases.

Effective examination methods for identifying the primary origins of metastatic bone tumors of unknown primary origin during the initial visit: A retrospective chart review study

Objective:To provide appropriate treatment for patients, early diagnosis of the primary origin of skeletal metastases of unknown primary origin is important. This study aimed to assess the examination strategy effective for identifying the primary origin of skeletal metastases of unknown primary origin.Methods:Sixty-one patients with skeletal metastases of unknown primary origin were reviewed. The primary origin was examined via physical examination, blood test including tumor markers, chest radiography, thoracoabdominal computed tomography scan, positron emission tomography–computed tomography scan, metastatic lesion biopsy, and other assessments. Examination methods considered effective for the diagnosis of the primary origin in a specific type of cancer were investigated.Results:The lung was the most common primary origin site, followed by the lymph nodes, prostate, and breast. Meanwhile, biopsy was the most effective examination, followed by positron emission tomography–computed tomography scan and thoracoabdominal computed tomography scan. Blood tests are useful for detecting hematological malignancies and prostate cancer. Computed tomography scans can be used to identify cancers in the lung, breast, and kidney, which are the common primary origins. Forty-one (67.2%) of the 61 patients with skeletal metastases of unknown primary origin were diagnosed via the first four steps, that is, physical examination, blood test, chest radiography, and thoracoabdominal computed tomography scan. Finally, two patients were diagnosed with skeletal metastases of unknown primary origin.Conclusion:The examination steps used in this study, including physical examination, blood test including tumor markers, chest radiography, thoracoabdominal computed tomography scan, positron emission tomography–computed tomography scan, biopsy, and other assessments were effective in determining the primary origin of skeletal metastases of unknown primary origin during the initial visit.

Metastatic Epithelioid Angiosarcoma of the Spine, Hip, and Femur

Epithelioid Angiosarcoma (EA) is an extremely rare and highly aggressive malignant tumor. It comprises <1 % of all soft tissue sarcomas and is associated with a poor prognosis. In this case report, we are reporting an 85-years-old male who presented with lower back and left hip pain. A computerized tomography (CT) of the lumbar spine and left hip showed a significant fracture of lumbar spine L3 and osteolytic lesions involving the left hip and femur. The patient underwent L1-L5 fusion with cement augmentation and biopsy of L3. Surgical pathology showed a metastatic undifferentiated tumor of unknown primary origin. Histologic analysis of the specimen and immunohistochemistry confirmed EA. Given extensive diffuse bone involvement, our patient was not a candidate for definitive surgical treatment.

A Case of Left Supraclavicular Neuroendocrine Tumor of Unknown Primary Origin Overlapped with Right Breast Cancer

A Case of Left Supraclavicular Neuroendocrine Tumor of Unknown Primary Origin Overlapped with Right Breast Cancer

Liječenje tumora nepoznatog primarnog sijela

Cancer of an unknown primary site is most commonly an aggressive metastatic tumor with a median patient survival of 6 to 9 months. Histologically, it is predominantly adenocarcinoma, and if the primary site is subsequently diagnosed, it is usually the pancreas or lung. Biopsy should be performed whenever possible to classify a tumor of unknown primary origin into one of the following entities: adenocarcinoma, poorly differentiated carcinoma with characteristics similar to adenocarcinoma, squamous cell carcinoma, neuroendocrine carcinoma, poorly differentiated neoplasm. After determining the primary tumor type, the subtype is determined by immunohistochemical staining. In oligometastatic disease, there is a possibility of surgical treatment. Radiotherapy is used as a part of combined modality treatment. Most patients with cancer of unknown primary have an unfavorable prognosis despite multiple chemotherapy agents, and no protocol can be recommended as standard therapy.

Clinical value of 68Ga-DOTA-SSTR PET/CT in the diagnosis and detection of neuroendocrine tumors of unknown primary origin: a systematic review and meta-analysis.

The ability of 68Ga-DOTA-SSTR to detect the primary sites of neuroendocrine tumors (NETs) remains undetermined, and the clinical benefit of this imaging agent is not clear. To evaluate the diagnostic accuracy of 68Ga-DOTA-SSTR for carcinoma unknown primary (CUP) neuroendocrine tumors and to further analyze the detection rate of 68Ga-DOTA-SSTR for primary and metastatic sites. A comprehensive literature search of PubMed/MEDLINE and ScienceDirect was performed in October 2019 in accordance with the Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) guidelines. We critically reviewed all studies based on the PICOS criteria. QUADAS-2 was used to evaluate the quality of the methodology of the included studies. A total of 10 studies (484 patients, mean age = 56.6 ± 4.3 years) were included in the study. The pooled sensitivity and specificity of 68Ga-DOTA-SSTR in identifying CUP-NETs were 82% and 55%, respectively. The area under the receiver operating characteristic curve was 69%. Regarding metastasis sites, 68Ga-DOTA-SSTR found the most metastases in the liver (57.9%), followed by the lymph nodes (22.8%), bones (12.8%), lung (2.8%), and others (1.7%). The pooled detection rate of 68Ga-DOTA-SSTR for CUP-NETs was 61%. The present study demonstrated the high diagnostic sensitivity of 68Ga-DOTA-SSTR for CUP-NETs. 68Ga-DOTA-SSTR PET/CT was highly effective in locating the primary and metastatic sites of CUP-NETs.

The Diagnostic Value of Cadherin 17 and CDX2 Expression as Immunohistochemical Markers in Colorectal Adenocarcinoma.

Colorectal cancer is a major cause of morbidity and mortality throughout the world. Although the diagnosis of colorectal cancer is straightforward in primary site, yet it may represent a diagnostic problem in metastatic tumor of unknown primary origin. Hence, immunohistochemical analysis in combination with morphologic assessment and correlation with clinical data becomes crucial, because it is important to specify the primary site of metastasis since some specific tumor types may respond well to targeted molecular therapies. Therefore, establishment of reliable diagnostic markers that confirm or rule out colorectal origin is mandatory. To study the expression of cadherin 17 and CDX2 in colorectal carcinoma and to evaluate their diagnostic roles in identifying metastatic colonic from non-colonic adenocarcinomas in cancer of unknown primary site. This retrospective study included 65 cases of adenocarcinomas: 35 cases of colorectal adenocarcinoma (primary or metastatic) and 30 cases of non-colorectal adenocarcinoma. They were retrieved from the archives of Pathology Department of Ain Shams University and Ain Shams University Specialized Hospitals during the period from 2010 to 2015. Immunohistochemical study was performed using cadherin 17 and CDX2 antibodies. The sensitivity and specificity of CDX2 and cadherin 17 are 97.1% and 53.3% and 100% and 50% in detecting colonic adenocarcinoma respectively. The PPV, NPV, and overall accuracy of CDX2 versus cadherin 17 were 70.8%, 94.1%, and 76.9% versus 70%, 100%, and 76.9% respectively. Cadherin 17 is a more sensitive marker than CDX2 in diagnosis of carcinoma of unknown primary site especially when colorectal carcinoma is suspected.

Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers

There is an unmet clinical need for improved tissue and liquid biopsy tools for cancer detection. We investigated the proteomic profile of extracellular vesicles and particles (EVPs) in 426 human samples from tissue explants (TEs), plasma, and other bodily fluids. Among traditional exosome markers, CD9, HSPA8, ALIX, and HSP90AB1 represent pan-EVP markers, while ACTB, MSN, and RAP1B are novel pan-EVP markers. To confirm that EVPs are ideal diagnostic tools, we analyzed proteomes of TE- (n= 151) and plasma-derived (n= 120) EVPs. Comparison of TE EVPs identified proteins (e.g., VCAN, TNC, and THBS2) that distinguish tumors from normal tissues with 90% sensitivity/94% specificity. Machine-learning classification of plasma-derived EVP cargo, including immunoglobulins, revealed 95% sensitivity/90% specificity in detecting cancer. Finally, we defined a panel of tumor-type-specific EVP proteins in TEs and plasma, which can classify tumors of unknown primary origin. Thus, EVP proteins can serve as reliable biomarkers for cancer detection and determining cancer type.

Digital carcinoma of a sweat gland metastasizing to the lacrimal gland: report of a rare case

AbstractPurposeTo report a rare case of a digital carcinoma of the sweat gland with lacrimal gland metastasis.MethodsObservational case reportResultsA 62‐year‐old woman presented with right proptosis and diplopia. General examination showed unilateral lymphedema of the left upper limb, initially restricted to the forearm and progressively involving the upperarm with an axillary lymphadenopathy. Work‐up included a whole‐body 18F‐FDG‐PET/CT showing high uptake in the right lacrimal gland, the cervical and axillary glands. Screening for breast carcinoma was negative. A biopsy of the axillary lymph nodes was performed. Immunohistochemical analysis was positive for CK7 and negative for GATA3, ER, PR, TTF1 and SOX10. The diagnosis of a metastatic process of a CK7 positive undifferentiated tumor of unknown primary origin was withheld. Physical examination of the left upper limb showed a small scar at the level of the thumb. Retrograde investigation revealed resection of a lesion in 2016 with the histopathological diagnosis of an eccrine ductal carcinoma of a sweat gland. Immunohistochemical analysis showed concordance between primary and metastatic lesions.ConclusionAlthough the clinical presentation and the general work‐up are highly suggestive for a metastatic process in the lacrimal gland, the final diagnosis relies on the histopathology or cytology. To the best of our knowledge, metastasis of a primary cutaneous sweat gland carcinoma to the lacrimal gland has not been reported in the literature.

Signaling pathway screening platforms are an efficient approach to identify therapeutic targets in cancers that lack known driver mutations: a case report for a cancer of unknown primary origin

Precision medicine aims to tailor cancer therapies to target specific tumor-promoting aberrations. For tumors that lack actionable drivers, which occurs frequently in the clinic, extensive molecular characterization and pre-clinical drug efficacy studies will be required. A cell line maintained at low passage and a patient- derived xenograft model (PDX) were generated using a fresh biopsy from a patient with a poorly-differentiated neuroendocrine tumor of unknown primary origin. Next-generation sequencing, high throughput signaling network analysis, and drug efficacy trials were then conducted to identify actionable targets for therapeutic intervention. No actionable mutations were identified after whole exome sequencing of the patient’s DNA. However, whole genome sequencing revealed amplification of the 3q and 5p chromosomal arms, that include the PIK3CA and RICTOR genes, respectively. We then conducted pathway analysis, which revealed activation of the AKT pathway. Based on this analysis, efficacy of PIK3CA and AKT inhibitors were evaluated in the tumor biopsy-derived cell culture and PDX, and response to the AKT inhibitor AZD5363 was observed both in vitro and in vivo indicating the patient would benefit from targeted therapies directed against the serine/threonine kinase AKT. In conclusion, our study demonstrates that high throughput signaling pathway analysis will significantly aid in identifying actionable alterations in rare tumors and guide patient stratification into early-phase clinical trials.

Oropharynx-directed ipsilateral irradiation for p16-positive squamous cell carcinoma involving the cervical lymph nodes of unknown primary origin.

The purpose of this study was to present our findings on the use of limited-field, oropharynx-directed ipsilateral irradiation for p16-positive squamous cell carcinoma of unknown primary origin. Between April 2011 and January 2016, 25 patients with a histological diagnosis of p16-positive squamous cell carcinoma were selectively irradiated to the ipsilateral oropharynx and cervical neck for tumors of unknown primary origin. The dose to the oropharynx ranged from 54-60 Gy (median 60 Gy) in 30-33 fractions. Concurrent cisplatin-based chemotherapy was administered to 8 patients (32%). The actuarial 2-year estimates of locoregional control, progression-free survival, and overall survival were 91%, 87%, and 92%, respectively. One patient failed in the contralateral neck. There was no grade 3 + toxicity in either the acute or late setting. Oropharynx-directed, ipsilateral radiation results in disease control that compares favorably with historical controls treated by comprehensive mucosal and bilateral neck radiation.

Ovarian involvement of a desmoplastic small round cell tumor of unknown primary origin with lymph node and lung metastases: A case report.

Desmoplastic small round cell tumors (DSRCTs) were initially characterized as exhibiting divergent differentiation and were extremely aggressive, belonging to the family of 'small round blue cell tumors'. Due to a male predominance, to date, only 15 cases in women have been reported in the English literature. The present study describes a case of DSRCT in a young woman who initially presented with ovarian masses accompanied with lymph node and lung metastases. A correct diagnosis was reached by combining the hematoxylin and eosin, and immunohistochemical staining results. Following surgery, the patient underwent the chemotherapy and, 3 months later, is in a good condition. The study also provides an overview of this uncommon disease.

GATA3 Expression in Normal Skin and in Benign and Malignant Epidermal and Cutaneous Adnexal Neoplasms.

:Initial investigations reported GATA3 to be a sensitive and relatively specific marker for mammary and urothelial carcinomas. Recently, GATA3 expression has been described in several other epithelial tumors. However, there has been only limited investigation of GATA3 expression in cutaneous epithelial tumors. The objective of this study was to examine the immunohistochemical expression of GATA3 in a wide variety of cutaneous epithelial neoplasms. GATA3 expression was evaluated in 99 benign and 63 malignant cutaneous epithelial tumors. GATA3 was consistently and usually strongly expressed in clear cell acanthoma, trichofolliculoma, trichoepithelioma, trichilemmoma, sebaceous adenoma, sebaceoma, apocrine hidrocystoma, apocrine tubular papillary adenoma, hidradenoma papilliferum, and syringocystadenoma papilliferum. Hidradenomas exhibited variable positive staining. Most poromas, syringomas, chondroid syringomas, cylindromas, and spiradenomas were negative or only focally and weakly positive. Focal staining was present in all pilomatrixomas. Thirteen of 14 basal cell carcinomas, 21 of 24 squamous carcinomas, and all 6 sebaceous carcinomas exhibited positive staining. The 1 apocrine carcinoma, both mucinous carcinomas, and 2 of 3 microcystic adnexal carcinomas also exhibited positive staining, whereas the 1 eccrine porocarcinoma and the 1 adenoid cystic carcinoma were negative. One of 11 Merkel cell carcinomas exhibited focal weak staining. Our findings demonstrate that GATA3 is expressed in a wide variety of benign and malignant cutaneous epithelial neoplasms. In addition to carcinomas of breast and urothelial origin and other more recently described GATA3-positive tumors, the differential diagnosis of a metastatic tumor of unknown primary origin that expresses GATA3 should also include a carcinoma of cutaneous epithelial origin.

Abstract 1118: Activation of MET via diverse exon 14 skipping mutations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors

Abstract Amplification and point mutation in MET are well-characterized oncogenic drivers that confer susceptibility to MET inhibitors, such as crizotinib, particularly in non-small cell lung cancer. Splice site alterations at exon 14 of the MET (METex14) gene result in exon skipping and MET activation through loss of a DpYR motif (Y1003) that recruits the ubiquitin ligase CBL, targeting MET for degradation. METex14 skipping mutations have primarily been detected in lung adenocarcinoma, occurring in ∼3% of cases, but also in neuroblastoma and gastric cancer cell lines. 17 distinct variants have been characterized, however, their full diversity and prevalence across tumor types is unknown. Most importantly, it is unknown whether these mutations confer clinical susceptibility to targeted therapy with multiple MET inhibitors. We report here analysis of 29,714 cancer genomes to identify 168 harboring METex14 splicing mutations, including 101 distinct genomic variants. They are detected most frequently in lung adenocarcinoma (3.1%, 104/3360), but also in other lung neoplasms (2.0%, 40/2022), brain glioma (0.5%, 6/1312), tumors of unknown primary origin (0.4%, 11/2516), and other tumor types (0.03% 7/20504). Lung malignancies with these mutations do not have other characteristic driver mutations, and have a distinct profile of co-occurring mutations, supporting the role of METex14 skipping as the primary drivers of oncogenesis in these specimens. Most importantly, patients with tumors harboring these mutations demonstrate durable response to anti-MET targeted therapy, in several tumor types. These data demonstrate that METex14 splicing mutations define a distinct class of tumors that are responsive to targeted therapy. The diversity of these variants indicates that diagnostic testing via massively parallel sequencing is necessary for detection in a clinical setting. The data also suggest that thousands of cancer genome profiles will be required to discover non-coding cancer drivers with degenerate genomic signatures. Citation Format: Garrett M. Frampton, Siraj Ali, Juliann Chmielecki, Mark Rosenzweig, Timothy Brennan, Zachary Chalmers, Julia Elvin, Alex Fichtenholtz, Kyle Gowan, Joel Greenbowe, Adrienne Johnson, Lily Khaira, Doron Lipson, Caitlin McMahon, Steven Roels, Roman Yelensky, Deborah Morosini, Philip Stephens, Vincent Miller. Activation of MET via diverse exon 14 skipping mutations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1118. doi:10.1158/1538-7445.AM2015-1118

Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors.

Focal amplification and activating point mutation of the MET gene are well-characterized oncogenic drivers that confer susceptibility to targeted MET inhibitors. Recurrent somatic splice site alterations at MET exon 14 (METex14) that result in exon skipping and MET activation have been characterized, but their full diversity and prevalence across tumor types are unknown. Here, we report analysis of tumor genomic profiles from 38,028 patients to identify 221 cases with METex14 mutations (0.6%), including 126 distinct sequence variants. METex14 mutations are detected most frequently in lung adenocarcinoma (3%), but also frequently in other lung neoplasms (2.3%), brain glioma (0.4%), and tumors of unknown primary origin (0.4%). Further in vitro studies demonstrate sensitivity to MET inhibitors in cells harboring METex14 alterations. We also report three new patient cases with METex14 alterations in lung or histiocytic sarcoma tumors that showed durable response to two different MET-targeted therapies. The diversity of METex14 mutations indicates that diagnostic testing via comprehensive genomic profiling is necessary for detection in a clinical setting. Here we report the identification of diverse exon 14 splice site alterations in MET that result in constitutive activity of this receptor and oncogenic transformation in vitro. Patients whose tumors harbored these alterations derived meaningful clinical benefit from MET inhibitors. Collectively, these data support the role of METex14 alterations as drivers of tumorigenesis, and identify a unique subset of patients likely to derive benefit from MET inhibitors.

General pathologist-helper: The new medical app about general pathology

Introduction: Smartphone applications (apps) have become increasingly prevalent in medicine. Due to most pathologists, pathology trainees, technicians, and medical students use smartphones; apps can be a different way for general pathology education. “General pathologist-helper (GP-HELPER)” is a novel app developed as a reference tool in general pathology and especially for general pathologists, developed for Android and iOS platforms. Materials and Methods: “GP-HELPER,” was created using Mobincube website platform. This tool also integrates “FORUM GP-HELPER,” an external website created using Miarroba website (http://forum-gp-helper.mboards.com) and “COMMUNITY GP-HELPER” a multichannel chat created using Chatango website platform. Results: The application was released in July 2015, and it is been periodically updated since then. The app has permanent information (offline data) about different pathology protocols (TNM latest edition, protocols regarding management of tumors of unknown primary origin, and flowcharts for some of the most difficult tumors to diagnose) and a database with more than 5000 immunohistochemistry results from different tumors. Online data have links to more than 1100 reference pathology video lectures, 250 antibodies information, more than 70 pathology association websites, 46 pathology providers, and 78 outstanding pathology journal websites. Besides this information, the app has two interactive places such as “FORUM GP-HELPER” and “COMMUNITY GP-HELPER” that let users to stay in touch everywhere and every time. Expert consult section is also available. Conclusions: “GP-HELPER” pretends to integrate offline and online data about pathology with two interactive external places in order to represent a reference tool for general pathologists and associate members.