A 71-year-old man presented to the hospital with chest pain and dyspnea worsening over the past few months. His medical and surgical history included end-stage renal disease with deceased donor kidney transplant five years ago, well-controlled human immunodeficiency virus infection, and hepatitis C virus infection complicated by hepatocellular carcinoma (HCC) which was treated with surgical resection two years ago. Imaging revealed a large, loculated right pleural effusion, a calcified right mediastinal mass, multiple liver lesions, and lytic bony lesions of ribs, spine, and pelvis. Biopsy of a liver lesion revealed well-differentiated HCC. Endobronchial ultrasound-guided biopsy of the calcified mediastinal mass was nondiagnostic. Thoracentesis of the right pleural effusion revealed an exudative effusion with no malignant cells observed on cytology after multiple samples. An indwelling pleural catheter was placed, and the patient was discharged with plans for outpatient therapy for metastatic HCC.

TOPIC: Disorders of the Pleura TYPE: Medical Student/Resident Case Reports INTRODUCTION: Pleural fibrosis results in adhesions between the visceral and parietal pleura, obliterating the pleural cavity. Severe cases can lead to restrictive lung disease, hypercapnic respiratory failure, and death. Known etiologies include asbestosis, neoplasms, hemothorax, connective tissue diseases, radiation, trauma, drugs, and infection [1]; unexplained cases are deemed cryptogenic. CASE PRESENTATION: A 48-year-old female presented with chronic dyspnea. Past surgical history: March 2004 at age 31 she underwent right thoracotomy for fibrothorax; January 2005 she underwent decortication of left thorax; pathology from both surgeries: fibrosis without specific diagnosis or etiology. Past medical history: hypertension, Human Immunodeficiency Virus (HIV) on Highly Active Antiretroviral Therapy (HAART). Vital Signs: afebrile, pulse 110, BP 140/93, SpO2 was 91%. Physical exam: elevated jugular venous pressure and markedly diminished breath sounds bilaterally. Arterial blood gas 7.38/61/65/36. Chest x-ray and CT: chronic bilateral pleural thickening. Pulmonary Function Tests (PFTs): restrictive pattern with TLC 41%, DLCO 47% predicted.Extensive workup for etiology of the pleural fibrosis in 2004 and 2005 was negative; young age argues against occupational exposure; even after many years of follow up, she never developed connective tissue disorders. She has been HIV positive since before 2004, but had no opportunistic infections and remained well controlled on HAART. Right heart catheterization in 2014 showed mean PA pressure of 27. DISCUSSION: Given extensive negative workup, we diagnosed the patient with cryptogenic fibrosing pleuritis. HIV has not been described to lead to fibrosing pleurisy in the absence of infection. Prior case reports of patients with similar symptomatology are generally in older smokers or ex-smokers; in one case report, three improved with pleural decortication and one had a good response to corticosteroids [2]. A case was described in 26-year-old male with cryptogenic fibrosing pleuritis for whom decortication was unsuccessful [3]. Our case adds to the published literature by providing many years of follow up including PFTs and imaging. She showed no progression in the pleural disease, no development of fibrosis in other areas, and stability in pulmonary function testing. Bilateral decortication did improve her PFT and functional status, though she remains severely restricted with chronic hypoxemic respiratory failure and pulmonary hypertension. CONCLUSIONS: The cause and optimal treatment for cryptogenic fibrosing pleuritis remains unclear. REFERENCE #1: Huggins JT, Sahn SA. Causes and management of pleural fibrosis. Respirology. 2004;9:441–7. doi: 10.1111/j.1440-1843.2004.00630.x. REFERENCE #2: Buchanan DR, Johnston ID, Kerr IH, Hetzel MR, Corrin B, Turner-Warwick M. Cryptogenic bilateral fibrosing pleuritis. Br J Dis Chest. 1988 Apr;82(2):186-93. doi: 10.1016/0007-0971(88)90042-3. PMID: 3166932. REFERENCE #3: Verweel E, Noble Jl, Zoelen CG, Maat A, Thijsse W, Gerritsen P, Bakker J. Failure to wean caused by cryptogenic fibrosing pleuritis and bilateral lung trapping: case report. Rev Bras Ter Intensiva. 2007 Dec;19(4):504-8. English. doi: 10.1590/s0103-507x2007000400018. PMID: 25310172. DISCLOSURES: No relevant relationships by Ammar Alhaddad, source=Web Response No relevant relationships by Daniel Baram, source=Web Response No relevant relationships by Prasantha Vemu, source=Web Response

The 12q13-q14 chromosomal region is recurrently amplified in 25% of fusion-positive (FP) rhabdomyosarcoma (RMS) cases and is associated with a poor prognosis. To identify amplified oncogenes in FP RMS, we compared the size, gene composition, and expression of 12q13-q14 amplicons in FP RMS with those of other cancer categories (glioblastoma multiforme, lung adenocarcinoma, and liposarcoma) in which 12q13-q14 amplification frequently occurs. We uncovered a 0.2 Mb region that is commonly amplified across these cancers and includes CDK4 and 6 other genes that are overexpressed in amplicon-positive samples. Additionally, we identified a 0.5 Mb segment that is only recurrently amplified in FP RMS and includes 4 genes that are overexpressed in amplicon-positive RMS. Among these genes, only serine hydroxymethyltransferase 2 (SHMT2) was overexpressed at the protein level in an amplicon-positive RMS cell line. SHMT2 knockdown in amplicon-positive RMS cells suppressed growth, transformation, and tumorigenesis, whereas overexpression in amplicon-negative RMS cells promoted these phenotypes. High SHMT2 expression reduced sensitivity of FP RMS cells to SHIN1, a direct SHMT2 inhibitor, but sensitized cells to pemetrexed, an inhibitor of the folate cycle. In conclusion, our study demonstrates that SHMT2 contributes to tumorigenesis in FP RMS and that SHMT2 amplification predicts differential response to drugs targeting this metabolic pathway.

Abstract Gene amplification, or an increase in copy number of a confined region on the chromosome arm, has been identified as a critical genetic event that contributes to the development of various cancers. There is increased expression of certain genes within the amplified regions, which alters normal cell growth and survival pathways, and contributes to tumorigenesis. Although previous studies show that some regions are amplified in more than one cancer type, direct analyses comparing the size and gene composition of these amplified regions across tumor types have not been performed. In the current study, we used copy number and RNA sequencing data from our published data and The Cancer Genome Atlas (TCGA) to characterize the commonly affected 12q13-q14 and 12q15 chromosomal regions in rhabdomyosarcoma, glioblastoma multiforme, lung adenocarcinoma, and liposarcoma. Based on our analysis of copy number data from high-density single-nucleotide polymorphism arrays, we observed a 0.08 Mb common region of overlap of the 12q13-q14 amplicons and a 0.20 Mb common region of overlap of the 12q15 amplicons across these tumor types. Differential gene expression analysis between amplified and nonamplified samples showed that OS9, TSPAN31, CDK4, CYP27B1, METTL1, EEF1AKMT3, and TSFM were overexpressed by the 12q13-q14 amplicons. Similarly, MDM2 and CPM were overexpressed by the 12q15 chromosomal amplicons. In addition to the common region of overlap, regions of tumor-type specific amplification were also found in our analysis. The 12q13-q14 amplicon in fusion-positive rhabdomyosarcoma extended 0.48 Mb toward the centromere, while the 12q13-q14 amplicons in dedifferentiated liposarcoma and lung adenocarcinoma extended 0.56 Mb and 0.96 Mb, respectively, toward the telomere. For the 12q15 region, the amplicon in lung adenocarcinoma extended 1.3 Mb toward the centromere, while the amplicons in dedifferentiated liposarcoma and fusion-negative rhabdomyosarcoma extended 1.4 Mb and 1.6 Mb, respectively, toward the telomere. Gene expression analyses showed that some genes from these tumor-specific regions of amplification were preferentially overexpressed in the corresponding tumor types. For example, four genes from the fusion-positive rhabdomyosarcoma-specific 12q13-q14 amplicon (NEMP1, NAB2, SHMT2, and R3HDM2) and two genes from the lung adenocarcinoma-specific 12q15 amplicon (MDM1 and RAP1B) were specifically overexpressed in these two tumor types. Our findings indicate that, in addition to common regions of amplification across multiple tumor types, there are tumor-specific amplified regions and overexpressed genes that indicate the presence of unique features within each cancer category affecting these amplification events. Citation Format: Prasantha L. Vemu, Gregory E. Hoy, Wenyue Sun, Jack Shern, Javed Khan, Frederic G. Barr. Comparing amplification of 12q13-q14 and 12q15 chromosomal regions across cancer types through genomic and transcriptome analysis [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 4357.

The PAX3 gene encodes a member of the PAX family of transcription factors that is characterized by a highly conserved paired box motif. The PAX3 protein is a transcription factor consisting of an N-terminal DNA binding domain (containing a paired box and homeodomain) and a C-terminal transcriptional activation domain. This protein is expressed during development of skeletal muscle, central nervous system and neural crest derivatives, and regulates expression of target genes that impact on proliferation, survival, differentiation and motility in these lineages. Germline mutations of the murine Pax3 and human PAX3 genes cause deficiencies in these developmental lineages and result in the Splotch phenotype and Waardenburg syndrome, respectively. Somatic genetic rearrangements that juxtapose the PAX3 DNA binding domain to the transcriptional activation domain of other transcription factors deregulate PAX3 function and contribute to the pathogenesis of the soft tissue cancers alveolar rhabdomyosarcoma and biphenotypic sinonasal sarcoma. The wild-type PAX3 protein is also expressed in other cancers related to developmental lineages that normally express this protein and exerts phenotypic effects related to its normal developmental role.

Evidence of cancer immunosurveillance and immunoediting processes has been primarily demonstrated in mouse models of chemically induced oncogenesis. Although these models are very tractable, they are characterized by high mutational loads that represent a minority of human cancers. In this study, we sought to determine whether cancer immunosurveillance and immunoediting could be demonstrated in a more clinically relevant oncogene-induced model of carcinogenesis, the MMTV- PyMT (PyMT) mammary carcinoma model. This model system in the FVB/NJ strain background was previously used to demonstrate that adaptive immunity had no role in limiting primary cancer formation and in fact promoted metastasis, thus calling into question whether cancer immunosurveillance operated in preventing the development of breast cancer. Our current study in the C57BL/6 strain backgrounds provides a different conclusion, as we report here the existence of an adaptive immunosurveillance of PyMT mammary carcinomas using two independent models of immune deficiency. PyMT mice bred onto a Rag1(-/-) background or immune suppressed by chronic tacrolimus therapy both demonstrated accelerated development of mammary carcinomas. By generating a bank of cell lines from these animals, we further show that a subset of PyMT cell lines had delayed growth after transplantation into wild-type (WT) syngeneic, but not immune-deficient hosts. This reduced growth rate in immunocompetent animals was characterized by an increase in immune cell infiltration and tissue differentiation. Furthermore, loss of the immune cell infiltration that characterized immunoediting of slow growing cell lines, changed them into fast growing variants capable of progressing in the immunocompetent model. In conclusion, our study provides evidence that immunosurveillance and immunoediting of PyMT-derived cell lines modulate tumor progression in this oncogene-induced model of cancer.