ROR2 Regulates Cellular Plasticity in Pancreatic Neoplasia and Adenocarcinoma.

Cellular plasticity is a hallmark of pancreatic ductal adenocarcinoma (PDAC) starting from the conversion of normal cells into precancerous lesions, to the progression of carcinoma subtypes associated with aggressiveness and therapeutic response. We discovered that normal acinar cell differentiation, maintained by the transcription factor Pdx1, suppresses a broad gastric cell identity that is maintained in metaplasia, neoplasia, and the classical subtype of PDAC in mouse and human. We have identified the receptor tyrosine kinase Ror2 as marker of a gastric metaplasia-like identity in pancreas neoplasms. Ablation of Ror2 in a mouse model of pancreatic tumorigenesis promoted a switch to a gastric pit cell identity that largely persisted through progression to the classical subtype of PDAC. In both human and mouse pancreatic cancer, ROR2 activity continued to antagonize the gastric pit cell identity, strongly promoting an epithelial to mesenchymal transition, conferring resistance to KRAS inhibition, and vulnerability to AKT inhibition.

Transdiaphragmatic sarcomatoid carcinoma of the lung: A case report.

INTRODUCTION: Pulmonary sarcomatoid carcinoma is a very rare primary tumor of the lung. Although usually aggressive, these tumors have not been described previously to invade through the diaphragm into the liver. We present a patient with a pulmonary sarcomatoid carcinoma with transdiaphragmatic spread into the dome of the liver. PRESENTATION OF CASE: An 82-year-old female with a lifetime non-smoking history presented with generalized fatigue, fever, night sweats, cough, and pleuritic chest pain. She had recently traveled to the western United States. Additionally, she had recently undergone periodontal deep cleaning with no peri-procedural antibiotics. Laboratory testing was significant for a leukocytosis of 13.5 white blood cells per microliter and a negative viral panel. Computed tomography and magnetic resonance imaging revealed a large heterogeneous mass extending from the right pulmonary hilum through the diaphragm. Although initial radiology reports suggested hepatic abscess, percutaneous fine needle aspiration was performed. Biopsy revealed pulmonary sarcomatoid carcinoma. She was begun on systemic treatment. DISCUSSION: Pulmonary sarcomatoid carcinoma can exhibit transdiaphragmatic invasion into the liver. This clinical situation can easily be confused with a hepatic abscess, but suspicion should remain for abscess. Clinical suspicion for neoplasm should warrant biopsy when technically possible. CONCLUSION: Although hepatic abscesses can exhibit transdiaphragmatic spread into the chest, pulmonary sarcomatoid carcinoma can also invade the abdomen. Biopsy should be performed during the evaluation and workup of the patient.

Targeted Next-Generation Sequencing Improves the Prognostication of Patients with Disseminated Appendiceal Mucinous Neoplasms (Pseudomyxoma Peritonei).

BACKGROUND: Appendiceal mucinous neoplasms (AMNs) with disseminated disease (pseudomyxoma peritonei) are heterogeneous tumors with variable clinicopathologic behavior. Despite the development of prognostic systems, objective biomarkers are needed to stratify patients. With the advent of next-generation sequencing (NGS), it remains unclear if molecular testing can improve the evaluation of disseminated AMN patients. METHODS: Targeted NGS was performed for 183 patients and correlated with clinicopathologic features to include American Joint Committee on Cancer/World Health Organization (AJCC/WHO) histologic grade, peritoneal cancer index (PCI), completeness of cytoreduction (CC) score, and overall survival (OS). RESULTS: Genomic alterations were identified for 179 (98%) disseminated AMNs. Excluding mitogen-activated protein kinase genes and GNAS due to their ubiquitous nature, collective genomic alterations in TP53, SMAD4, CDKN2A, and the mTOR genes were associated with older mean age, higher AJCC/WHO histologic grade, lymphovascular invasion, perineural invasion, regional lymph node metastasis, and lower mean PCI (p < 0.040). Patients harboring TP53, SMAD4, ATM, CDKN2A, and/or mTOR gene alterations were found to have lower OS rates of 55% at 5 years and 14% at 10 years, compared with 88% at 5 years and 88% at 10 years for patients without the aforementioned alterations (p < 0.001). Based on univariate and multivariate analyses, genomic alterations in TP53, SMAD4, ATM, CDKN2A, and/or the mTOR genes in disseminated AMNs were a negative prognostic factor for OS and independent of AJCC/WHO histologic grade, PCI, CC score, and hyperthermic intraperitoneal chemotherapy treatment (p = 0.006). CONCLUSIONS: Targeted NGS improves the prognostic assessment of patients with disseminated AMNs and identifies patients who may require increased surveillance and/or aggressive management.

Optimizing Rehabilitation and Return to Sport in Athletes With Anterior Knee Pain Using a Biomechanical Perspective.

Anterior knee pain represents one of the most common athletic knee conditions and arguably also one of the most complex. The patellofemoral joint is at the center of several forces, and alterations in any of these force vectors due to muscular imbalance, soft-tissue tightness or laxity, and altered functional movement patterns can all combine to create a painful anterior knee. While typically anterior knee pain is not a surgical entity, the orthopaedic surgeon with an understanding of these biomechanical intricacies is best positioned to provide comprehensive evidence-based care for the patient with anterior knee pain. LEVEL OF EVIDENCE: V, expert opinion.

Tumor Size Differences Between Preoperative Endoscopic Ultrasound and Postoperative Pathology for Neoadjuvant-Treated Pancreatic Ductal Adenocarcinoma Predict Patient Outcome.

BACKGROUND & AIMS: The assessment of therapeutic response after neoadjuvant treatment and pancreatectomy for pancreatic ductal adenocarcinoma (PDAC) has been an ongoing challenge. Several limitations have been encountered when employing current grading systems for residual tumor. Considering endoscopic ultrasound (EUS) represents a sensitive imaging technique for PDAC, differences in tumor size between preoperative EUS and postoperative pathology after neoadjuvant therapy were hypothesized to represent an improved marker of treatment response. METHODS: For 340 treatment-naïve and 365 neoadjuvant-treated PDACs, EUS and pathologic findings were analyzed and correlated with patient overall survival (OS). A separate group of 200 neoadjuvant-treated PDACs served as a validation cohort for further analysis. RESULTS: Among treatment-naïve PDACs, there was a moderate concordance between EUS imaging and postoperative pathology for tumor size (r = 0.726, P < .001) and AJCC 8th edition T-stage (r = 0.586, P < .001). In the setting of neoadjuvant therapy, a decrease in T-stage correlated with improved 3-year OS rates (50% vs 31%, P < .001). Through recursive partitioning, a cutoff of ≥47% tumor size reduction was also found to be associated with improved OS (67% vs 32%, P < .001). Improved OS using a ≥47% threshold was validated using a separate cohort of neoadjuvant-treated PDACs (72% vs 36%, P < .001). By multivariate analysis, a reduction in tumor size by ≥47% was an independent prognostic factor for improved OS (P = .007). CONCLUSIONS: The difference in tumor size between preoperative EUS imaging and postoperative pathology among neoadjuvant-treated PDAC patients is an important prognostic indicator and may guide subsequent chemotherapeutic management.

Cyclosporine-Induced Kaposi Sarcoma in a Patient With Ulcerative Colitis.

Kaposi sarcoma (KS) is an angioproliferative neoplasm associated with human herpesvirus-8. Gastrointestinal KS has been well documented in immunosuppressed solid organ transplant patients, with only 26 iatrogenic cases published in patients with inflammatory bowel disease. We report a 24-year-old patient with ulcerative colitis, maintained on cyclosporine for 2 years, who presented with watery, nonbloody diarrhea and weight loss. Colonoscopy revealed human herpesvirus-8-positive hemorrhagic nodules throughout the colon and terminal ileum, with diffuse lymphadenopathy on computed tomography consistent with KS. As gastrointestinal KS may present with symptoms that mimic inflammatory bowel disease, it is critical to maintain suspicion in patients on prolonged immunosuppression to reduce complications.

Apetamin Hepatotoxicity: Potential Consequences of Purchasing a Body Enhancement Drug Off the Internet.

We report Apetamin (cyproheptadine lysine and vitamin syrup), a non-US Food and Drug Administration-approved weight gain supplement, causing drug-induced autoimmune hepatitis. A 40-year-old previously healthy woman presented with fatigue, right-sided abdominal discomfort, and jaundice 6 weeks after starting Apetamin, which she learned from social media for figure augmentation. Labs were significant for elevated transaminases, positive smooth muscle antibody, and increased immunoglobulins. Biopsy indicated drug-induced autoimmune hepatitis. Symptoms improved with prednisone, azathioprine, and stopping Apetamin which contains cyproheptadine, a known hepatotoxin. The case reveals the influence of social media and its impact on health and the importance of a complete drug history.

Multidisciplinary management of the pregnant patient in haemorrhagic shock secondary to an undiagnosed ruptured liver adenoma.

Management of a ruptured hepatocellular adenoma during pregnancy is a rare and potentially life-threatening entity. Few case reports have described management of the pregnant patient who presents in haemorrhagic shock secondary to a ruptured liver adenoma. A 30-year-old primigravid woman at 31 weeks pregnant presented with abdominal pain and fetal bradycardia. After stat caesarean delivery of the infant, she had continued hemoperitoneum and was in shock secondary to an undiagnosed ruptured liver mass. General surgery was consulted intraoperatively and performed an exploratory laparotomy, packing and temporary closure. She was subsequently taken to interventional radiology (IR) for angioembolisation of the left hepatic artery. After stabilisation, she underwent formal abdominal closure. Management of a ruptured hepatocellular adenoma in pregnancy requires urgent multidisciplinary care including obstetrics gynaecology, general surgery and IR.

Optimization and Standardization of the Immunodeficient Mouse Model for Assessing Fat Grafting Outcomes.

BACKGROUND: Animal models are often used to assess interventions that might improve fat grafting outcomes; however, there is great variability in the models. The authors sought to determine the predictive value of the immunocompromised mouse model for fat grafting so that experiments could be standardized and optimized. METHODS: Human lipoaspirate injections at different volumes and time points were assessed in a nude mouse model and compared with control injections of nonviable fat. Volume retention and explant histologic score were compared. In a separate study, interanimal reproducibility was determined by implanting a highly consistent hydrogel and measuring variability in volume retention. RESULTS: Injection volume significantly affects adipose resorption kinetics at 6 and 12 weeks. Masson trichrome staining revealed that macrophages were unable to infiltrate large (1 ml) grafts, and oil cysts were not absorbed by 18 weeks, which interfered with interpretation of volume retention data. Nonviable tissue was resorbed when grafts were 0.3 ml, and quantification of graft histologic viability correlated well with graft retention at all study time points. Interanimal variability was measured to be 8.44 percent of the mean retention volume for small graft volumes. CONCLUSIONS: Human fat graft retention in the immunodeficient mouse correlates with graft viability in small, 0.3-ml-volume grafts. However, centralized oil cysts in nonviable 1.0-ml grafts were not resorbed by 18 weeks and thus volume measurements were confounded and not significantly different from viable samples. In addition, tissue injury scores increased in initially healthy fat grafts at 18 weeks, possibly because of a delayed immune reaction.

Molecular Diagnostics in the Evaluation of Pancreatic Cysts.

Within the past few decades, there has been a dramatic increase in the detection of incidental pancreatic cysts. It is reported a pancreatic cyst is identified in up to 2.6% of abdominal scans. Many of these cysts, including serous cystadenomas and pseudocysts, are benign and can be monitored clinically. In contrast, mucinous cysts, which include intraductal papillary mucinous neoplasms and mucinous cystic neoplasms, have the potential to progress to pancreatic adenocarcinoma. In this review, we discuss the current management guidelines for pancreatic cysts, their underlying genetics, and the integration of molecular testing in cyst classification and prognostication.

Expression of high affinity folate receptor in breast cancer brain metastasis.

High affinity folate receptor (HFR) can be overexpressed in breast cancer and is associated with poor prognosis, however the expression in breast cancer brain metastases (BCBM) is unknown. The aim of this study was to analyze the rate of HFR expression in BCBM and its role in the prognosis of this high-risk cohort. We analyzed 19 brain metastasis (BM) and 13 primary tumors (PT) from a total of 25 patients. HFR status was assessed by immunohistochemistry. Median follow-up was 4.2 years (range 0.6-18.5). HFR was positive in 4/19 BM (21.1%) and in 1/13 PT (7.7%). Positive samples had low H-scores (range 1-50). 56% of patients had apocrine differentiation. OS was similar between patients with positive HFR (median OS 48 months) and negative HFR (median OS 69 months) (P = 0.25); and between patients with apocrine differentiation (median OS 63 months) and those without apocrine differentiation (median OS 69 months) (P = 0.49). To the best of our knowledge, this is the first analysis of HFR expression in BCBM. While previous studies associated the presence of HFR with worse prognosis; in our cohort HFR was positive in only 21.1% of BM with low levels of positivity. Neither HFR nor apocrine features had impact in OS.

Leaky severe combined immunodeficiency and aberrant DNA rearrangements due to a hypomorphic RAG1 mutation.

The RAG1/2 endonuclease initiates programmed DNA rearrangements in progenitor lymphocytes by generating double-strand breaks at specific recombination signal sequences. This process, known as V(D)J recombination, assembles the vastly diverse antigen receptor genes from numerous V, D, and J coding segments. In vitro biochemical and cellular transfection studies suggest that RAG1/2 may also play postcleavage roles by forming complexes with the recombining ends to facilitate DNA end processing and ligation. In the current study, we examine the in vivo consequences of a mutant form of RAG1, RAG1-S723C, that is proficient for DNA cleavage, yet exhibits defects in postcleavage complex formation and end joining in vitro. We generated a knockin mouse model harboring the RAG1-S723C hypomorphic mutation and examined the immune system in this fully in vivo setting. RAG1-S723C homozygous mice exhibit impaired lymphocyte development and decreased V(D)J rearrangements. Distinct from RAG nullizygosity, the RAG1-S723C hypomorph results in aberrant DNA double-strand breaks within rearranging loci. RAG1-S723C also predisposes to thymic lymphomas associated with chromosomal translocations in a p53 mutant background, and heterozygosity for the mutant allele accelerates age-associated immune system dysfunction. Thus, our study provides in vivo evidence that implicates aberrant RAG1/2 activity in lymphoid tumor development and premature immunosenescence.

Mouse model of colonic adenoma-carcinoma progression based on somatic Apc inactivation.

Mutations in the adenomatous polyposis coli (APC) gene are pivotal in colorectal tumorigenesis. Existing mouse intestinal tumor models display mainly small intestinal lesions and carcinomas are rare. We defined human CDX2 sequences conferring colon epithelium-preferential transgene expression in the adult mouse. Mice carrying a CDX2P-NLS Cre recombinase transgene and a loxP-targeted Apc allele developed mainly colorectal tumors, with carcinomas seen in 6 of 36 (17%) of mice followed for 300 days. Like human colorectal lesions, the mouse tumors showed biallelic Apc inactivation, beta-catenin dysregulation, global DNA hypomethylation, and aneuploidy. The predominantly distal colon and rectal distribution of tumors seen in mice where one Apc allele was inactivated in epithelial cells from distal ileum to rectum suggests that regional differences in the intestinal tract in the frequency and nature of secondary genetic and epigenetic events associated with adenoma outgrowth have a contributing role in determining where adenomas develop. The presence of large numbers of small intestine tumors seemed to inhibit colorectal tumor development in the mouse, and gender-specific effects on tumor multiplicity in the distal mouse colon and rectum mimic the situation in humans where males have a larger number of advanced adenomas and carcinomas in the distal colon and rectum than females. The mouse model of colon-preferential gene targeting described here should facilitate efforts to define novel factors and mechanisms contributing to human colon tumor pathogenesis, as well as work on tumor-promoting environmental factors and agents and strategies for cancer prevention and treatment.

Tpp1/Acd maintains genomic stability through a complex role in telomere protection.

Telomeres serve to protect the ends of chromosomes, and failure to maintain telomeres can lead to dramatic genomic instability. Human TPP1 was identified as a protein which interacts with components of a telomere cap complex, but does not directly bind to telomeric DNA. While biochemical interactions indicate a function in telomere biology, much remains to be learned regarding the roles of TPP1 in vivo. We previously reported the positional cloning of the gene responsible for the adrenocortical dysplasia (acd) mouse phenotype, which revealed a mutation in the mouse homologue encoding TPP1. We find that cells from homozygous acd mice harbor chromosomes fused at telomere sequences, demonstrating a role in telomere protection in vivo. Surprisingly, our studies also reveal fusions and radial structures lacking internal telomere sequences, which are not anticipated from a simple deficiency in telomere protection. Employing spectral karyotyping and telomere FISH in a combined approach, we have uncovered a striking pattern; fusions with telomeric sequences involve nonhomologous chromosomes while those lacking telomeric sequences involve homologues. Together, these studies show that Tpp1/Acd plays a vital role in telomere protection, but likely has additional functions yet to be defined.

Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells.

Recent advances have highlighted extensive phenotypic and functional similarities between normal stem cells and cancer stem cells. This raises the question of whether disease therapies can be developed that eliminate cancer stem cells without eliminating normal stem cells. Here we address this issue by conditionally deleting the Pten tumour suppressor gene in adult haematopoietic cells. This led to myeloproliferative disease within days and transplantable leukaemias within weeks. Pten deletion also promoted haematopoietic stem cell (HSC) proliferation. However, this led to HSC depletion via a cell-autonomous mechanism, preventing these cells from stably reconstituting irradiated mice. In contrast to leukaemia-initiating cells, HSCs were therefore unable to maintain themselves without Pten. These effects were mostly mediated by mTOR as they were inhibited by rapamycin. Rapamycin not only depleted leukaemia-initiating cells but also restored normal HSC function. Mechanistic differences between normal stem cells and cancer stem cells can thus be targeted to deplete cancer stem cells without damaging normal stem cells.