Inflammatory Myofibroblastic Tumor of the Esophagus and Stomach Successfully Treated With ALK Inhibitor in a Pediatric Patient: A Case Report and Concise Review of Literature.

An inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal neoplasm of borderline malignant potential. Nearly half of all IMTs have rearrangement of anaplastic lymphoma kinase (ALK) locus on chromosome 2p23 which can be treated with targeted therapy. Herein, we describe an unusual presentation of IMT involving an anatomical region rarely implicated in this disease process. A 15-year-old male patient came to the ER with dysphagia and coffee ground emesis. On esophagogastroscopy, a nodular luminal obstructing 30 × 50 mm mass in the lower esophagus was found, which was continuous with a large, partially circumferential gastric mass extending from the mid-body to the proximal antrum. Biopsies from esophageal and gastric masses revealed submucosal lesions composed of cytologically bland spindle and epithelioid cells, intermingled with inflammatory infiltrate, for which several immunohistochemical (IHC) stains were performed. The molecular study demonstrated ATIC::ALK fusion. Based on morphological, IHC, and molecular study findings, the diagnosis of ALK-positive IMT was rendered. Because surgical excision was deemed infeasible, the patient was started on ALK-inhibiting therapy with crizotinib. The patient responded well with no evidence of residual or recurrent disease on follow-up imaging or surveillance esophagogastroduodenoscopy. Crizotinib was ultimately discontinued after 10 months of therapy, and the patient continues to undergo surveillance imaging for monitoring of disease burden.

Postoperative Outcomes, and Growth and Brain Injury Outcomes in Spontaneous Intestinal Perforation vs Surgical Necrotizing Enterocolitis in Preterm Infants.

OBJECTIVE: To compare the clinical outcomes in preterm infants following surgical necrotizing enterocolitis (sNEC) and spontaneous intestinal perforation (SIP). METHODS: Retro-spective comparison of clinical information in preterm infants with sNEC and SIP admitted between January, 2013 and December 31, 2018. The clinical outcomes were compared in two groups, including postoperative and brain injury detected on brain magnetic resonance imaging (MRI) after clinical and histopathological confirmation of the SIP and the NEC diagnosis. RESULTS: 114 infants had sNEC, and 37 had SIP. Infants with SIP had lower median gestational age [25.1 weeks (23.5, 27.1) vs 26.6 (24.4, 31.0), P=0.03], an earlier mean (SD) age of disease onset [10.1 (11.3) days vs 19.6 (17.9); P<0.001] and lower maternal chorioamnionitis on placental pathology [4 (23.5%) vs 22 (68.8%); P=0.007), received more often Penrose drain therapy (54% vs 33%; P=0.03), had less median (IQR) bowel length loss [3.3 cm (1.72, 4.38) vs 21.4 (9.55, 35.3); P=<0.001] and had more often intact ileocecal valve (91.4% vs 65.7%; P=0.006] compared to those with sNEC. In addition, those with sNEC had lower median (IQR) weight z scores at the time of discharge [-1.88 (-2.80, -1.09) vs -1.14 (-2.22, -0.44); P=0.036] than SIP. There were no significant differences in postoperative ileus, duration of parenteral nutrition, surgical morbidity, length of stay, mortality, white matter, and grey matter injury on brain MRI at term equivalent age in preterm infants with SIP and sNEC. CONCLUSION: In our cohort, preterm infants with SIP and sNEC did not show significant differences in postoperative morbidity and brain MRI abnormalities at term equivalent age. sNEC had lower discharge weight z scores. Larger prospective studies are needed for confirmation of these findings.

Cyclin B3 is a dominant fast-acting cyclin that drives rapid early embryonic mitoses.

In many species, early embryonic mitoses proceed at a very rapid pace, but how this pace is achieved is not understood. Here we show that in the early C. elegans embryo, cyclin B3 is the dominant driver of rapid embryonic mitoses. Metazoans typically have three cyclin B isoforms that associate with and activate Cdk1 kinase to orchestrate mitotic events: the related cyclins B1 and B2 and the more divergent cyclin B3. We show that whereas embryos expressing cyclins B1 and B2 support slow mitosis (NEBD to Anaphase ~ 600s), the presence of cyclin B3 dominantly drives the ~3-fold faster mitosis observed in wildtype embryos. CYB-1/2-driven mitosis is longer than CYB-3-driven mitosis primarily because the progression of mitotic events itself is slower, rather than delayed anaphase onset due to activation of the spindle checkpoint or inhibitory phosphorylation of the anaphase activator CDC-20. Addition of cyclin B1 to cyclin B3-only mitosis introduces an ~60s delay between the completion of chromosome alignment and anaphase onset, which likely ensures segregation fidelity; this delay is mediated by inhibitory phosphorylation on CDC-20. Thus, the dominance of cyclin B3 in driving mitotic events, coupled to introduction of a short cyclin B1-dependent delay in anaphase onset, sets the rapid pace and ensures fidelity of mitoses in the early C. elegans embryo.

Outcomes by disease onset, sex, and intervention in neonates with SIP and surgical NEC.

BACKGROUND: Outcomes of infants following surgical necrotizing enterocolitis (NEC) and spontaneous intestinal perforation (SIP) categorized by the age of onset, interventions, and sex are not well defined. METHODS: Retrospective comparison of infants categorized by age of onset (NEC at <10, 10-20, and >20 days) and SIP at <7 versus ≥7 days), sex, and intervention [Penrose Drain (PD) vs. laparotomy]. RESULTS: A total of 114 infants had NEC and 37 had SIP. On multinomial logistic regression, infants with NEC/SIP onset >20 days had significantly lower odds of small bowel involvement (aOR = 0.07, 95% CI: 0.01-0.33, p = 0.001), higher necrosis (aOR = 3.59, 95% CI: 1.34-9.65, p = 0.012) and higher CRP (p = 0.004) than onset <10 days. Initial laparotomy was associated with more bowel loss (24.1 cm [12.3; 40.6] vs.12.1 [8.00; 23.2]; p = 0.001), small and large intestine involvement (47.1% vs 17.2%; p = 0.01), and ileocecal valve resection (42% vs. 19.4%; p = 0.036) than initial PD therapy. Females underwent fewer small bowel resections (52.3% vs 73.6%; p = 0.025) but had higher surgical morbidity (53.7% vs. 24.7%.; p = 0.001) than males. CONCLUSION: Clinical, radiological, and histopathological presentation and outcomes in preterm infants with surgical NEC/SIP are associated with age of disease onset, sex, and initial intervention. IMPACT: Neonates with surgical NEC onset >20 days had more severe necrosis, inflammation, kidney injury, and bowel loss than those with <10 days. Initial laparotomy was associated with later age onset, more bowel loss, and ileocecal valve resection compared to initial PD treatment, but not with differences in mortality or length of stay. Female sex was associated with lower maturity, more placental malperfusion, less often small bowel involvement, lower pre-NEC hematocrit as well as higher surgical morbidity than males. Whether the management of surgical NEC and SIP should differ by the age of onset requires further investigation.

Deep Learning in Phosphoproteomics: Methods and Application in Cancer Drug Discovery.

Protein phosphorylation is a key post-translational modification (PTM) that is a central regulatory mechanism of many cellular signaling pathways. Several protein kinases and phosphatases precisely control this biochemical process. Defects in the functions of these proteins have been implicated in many diseases, including cancer. Mass spectrometry (MS)-based analysis of biological samples provides in-depth coverage of phosphoproteome. A large amount of MS data available in public repositories has unveiled big data in the field of phosphoproteomics. To address the challenges associated with handling large data and expanding confidence in phosphorylation site prediction, the development of many computational algorithms and machine learning-based approaches have gained momentum in recent years. Together, the emergence of experimental methods with high resolution and sensitivity and data mining algorithms has provided robust analytical platforms for quantitative proteomics. In this review, we compile a comprehensive collection of bioinformatic resources used for the prediction of phosphorylation sites, and their potential therapeutic applications in the context of cancer.

Strong Annexin A10 Expression Supports a Pancreatic Primary and Combined Annexin A10, Claudin 18, and SOX2 Expression Supports an Esophagogastric Origin in Carcinomas of Unknown Primary.

Primary tumor site determination for gastrointestinal (GI) tract and pancreaticobiliary (PB) tree carcinomas that present as metastasis of unknown primary can be problematic. Annexin A10 (ANXA10), claudin 18 (CLDN18), and trefoil factor 1 (TFF1) have been identified through expression profiling as markers of gastric lineage commitment; sex-determining region Y (SRY)-box transcription factor 2 (SOX2) expression has been reported in several tumor types, including gastric adenocarcinomas. We evaluated the diagnostic utility of immunohistochemistry for ANXA10, CLDN18, SOX2, and TFF1 for determining the site of origin for GI/PB adenocarcinomas. Immunohistochemistry for all 4 markers was performed on tissue microarrays including 559 GI/PB tumors and 421 other tumors. H-scores were calculated as the product of the intensity (0 to 3) and extent (percentage, 0% to 100%) of staining. Positive staining was defined as >5% staining. ANXA10 expression was most frequent in pancreatic adenocarcinomas when compared with all other GI/PB tumors (96.4% vs. 43.5%, P <0.001). Strong staining for ANXA10 (H-score ≥200) distinguished pancreatic ductal adenocarcinoma from intrahepatic cholangiocarcinoma and adenocarcinomas of the gallbladder and colorectum (69.6% vs. 0%, P <0.001). Triple positivity for ANXA10, CLDN18, and SOX2 was more frequent in esophagogastric tumors than in other GI/PB tumors (22.6% vs. 4.1%; P <0.001). TFF1 expression was observed in nearly all tumor types. Staining for ANXA10, CLDN18, and SOX2 as part of a panel may aid in distinguishing esophagogastric adenocarcinomas from lower GI/PB tumors. ANXA10 staining may be particularly useful in distinguishing pancreatic adenocarcinomas from intrahepatic cholangiocarcinoma and adenocarcinomas of the gallbladder and colorectum.

Clinical Correlates of Cerebellar Injury in Preterm Infants with Surgical Necrotizing Enterocolitis.

Objective: Determine the risk factors of cerebellar injury in infants with surgical necrotizing enterocolitis (NEC). Methods: Retrospective study compared clinical/pathological information between surgical NEC infants with and those without cerebellar injury. Results: Infants with cerebellar injury (21/65, 32.3%) had significantly more hemorrhagic and the reparative lesions on the intestinal histopathology, had patent ductus arteriosus (PDA) more often, received red cell transfusion frequently, had blood culture positive sepsis and grew gram positive organisms more often and had cholestasis frequently following NEC than those without cerebellar injury. On multilogistic regression, the positive blood culture sepsis (OR 3.9, CI 1.1-13.7, p = 0.03), PDA (OR 4.5, CI 1.0-19.9, p = 0.04) and severe hemorrhage (grade 3-4)(OR 16.9, CI 2.1-135.5, p = 0.007) were independently associated with higher risk of cerebellar injury. Conclusion: The cerebellar injury was most likely associated with positive blood culture sepsis following NEC, PDA, and severe hemorrhage lesions (grade 3-4) in infants with surgical NEC.

Clinical and histopathological correlates of intestinal repair in preterm infants following surgical necrotizing enterocolitis.

OBJECTIVE: We sought to determine the clinical and histopathological factors linked with intestinal repair and its correlation with clinical outcomes in preterm infants following surgical necrotizing enterocolitis (NEC). METHODS: A retrospective study has compared clinical and histopathological characteristics between preterm infants with histopathological reparative changes versus non-reparative changes in resected intestinal tissue following surgical treatment of NEC. Reparative changes were defined as microscopic evidence of neovascularization, increased fibroblasts or myofibroblasts, and epithelial regeneration during histopathological examination of the most affected area of resected intestinal tissue. RESULTS: The infants with reparative changes (53/148) had significantly lower median birth weight (725 [650-963] vs. 920 [690-1320]; p = .018), higher likelihood of patent ductus arteriosus (38/53 [71.7%] vs. 48/95 [50.5%]; p = .012), longer TPN days (99 [56-147] vs. 76.5 [39-112.5]; p = .034), higher CRP levels (7.3 [3.2-13] vs. 2.6 [1.1-7.8]; p = .011) at NEC onset, and more short bowel syndrome (27/53 [54.0%] vs. 28/95 [32.2%]; p = .012). Those with reparative changes also received more Penrose drain therapy (21/53 [39.6%] vs. 14/95 [14.7%]; p = .011) and had a longer median time to laparotomy (108 h [28-216] vs. 24 [12-96]; p = .003). Epithelial regeneration observed in 6/53 (11.3%) infants lagged fibroblast proliferation and neovascularization changes in the submucosa/muscularis intestinal layers. On a multivariable logistic regression model which included histopathological and clinical factors, inflammation with a percentage <25% area involvement, time from NEC diagnosis to surgery, and Apgar score < 6 at 5 min were independently and significantly associated with higher odds reparative changes. CONCLUSION: In neonates with surgical NEC, the histopathological findings in the resected bowel are significantly associated with clinical characteristics, other histopathological findings, and outcomes. The presence of reparative changes consistent with healing is significantly associated with Apgar score, Penrose drain therapy, longer time from NEC diagnosis to surgery, and lower burden of inflammation in the resected bowel tissue in multivariable analyses. Routine histopathological grading of resected bowel and optimal use of Penrose drain therapy warrant further investigation in the care of neonates with surgical NEC.

Intestinal Resection is More Likely to be Effective in Necrotizing Enterocolitis Extending to Colon than in Disease Limited to the Small Intestine.

Background: The prognosis in surgical necrotizing enterocolitis (NEC) has focused on the total length of the resected bowel; the relative impact of small intestinal vs colonic resection is not well studied. Objective: We hypothesized that intestinal resections may reduce mortality and length of hospital stay (LOS) more likely in infants who have NEC extending into the colon than in those with disease limited to the small intestine. We also investigated the relationship between gestational maturation and NEC-related mortality. Methods: A retrospective study of 153 patients compared demographic, clinical, and histopathological information in infants who had NEC limited to the small intestine vs disease with colonic involvement. Results: Our 153 infants had a mean (±standard deviation) gestational age of 27.4 ± 3.4 weeks and a birth weight of 987 ± 505 g. NEC was limited to the small intestine in 103 (67.3%) infants and extended into the colon in 50 (32.7%). Infants with small intestinal NEC needed shorter bowel resections of 28 ± 31.9 cm than 42.2 ± 40.7 cm in those with colonic involvement (p = 0.02). The LOS was longer in NEC limited to the small intestine than in disease with colonic lesions (96 ± 88.1 vs 69.7 ± 19.1 days; p <0.05). In small intestinal NEC, mortality decreased to <50% beyond a gestational age (GA) >37 weeks. In contrast, infants with NEC that involved the colon had mortality <50% mortality beyond 27.3 weeks' GA (p = 0.008). Conclusions: Bowel resections may be more likely associated with shorter LOS in surgical NEC that involves both the small bowel and colon, even when longer segments of the gastrointestinal tract are removed, than in disease limited to the small intestine.

Clinical Correlates of Moderate-to-Severe Bronchopulmonary Dysplasia in Preterm Infants following Surgical Necrotizing Enterocolitis.

OBJECTIVE: The aim of the study is to determine clinical correlates of moderate to severe bronchopulmonary dysplasia (BPD) in preterm infants following surgical necrotizing enterocolitis (NEC). STUDY DESIGN: This is a retrospective, single-center cohort study comparing patients with moderate to severe BPD to patients with non/mild BPD among surgical NEC infants. BPD was defined by NIH 2001 consensus definition. RESULTS: Of 92 consecutive neonates with surgical NEC, 77% (71/92) had moderate/severe BPD and 22% (21/92) had non/mild BPD. The patent ductus arteriosus (PDA) was significantly higher in those developing moderate/severe BPD (67.6% [48/71]) than non/mild BPD (28.6% [6/21]; p = 0.001). Postoperatively, infants with moderate/severe BPD had more severe acute kidney injury (AKI; 67.6 [48/71] vs. 28.6% [6/21]; p = 0.001), were intubated longer (40.5 [interquartile (IQR): 12, 59] vs. 6 days [IQR: 2, 13]; p <0.001), received more parenteral nutrition (109 [IQR: 77, 147] vs. 55 days [IQR: 19, 70]; p <0.001), developed higher surgical morbidity (46.5 [33/71] vs. 14.3% [3/21]; p = 0.008), had more intestinal failure (62.5 vs. 13.3%; p <0.001), required a longer hospital stay (161 [IQR: 112, 186] vs. 64 days [IQR: 20, 91]; p <0.001), and were more likely to need home oxygen. In a multivariable analysis, lower birth weight (OR = 0.3, [95% confidence interval (CI): 0.1-0.5]; p = 0.001), PDA (OR = 10.3, [95% CI: 1.6-65.4]; p = 0.014), and longer parenteral nutritional days (OR = 8.8; [95% CI: 2.0-43.0]; p = 0.005) were significantly and independently associated with higher odds of moderate/severe versus non-/mild BPD. CONCLUSION: Development of moderate/severe BPD occurred in the majority of preterm infants with surgical NEC in this consecutive series. Preterm infants with moderate/severe BPD were more likely to have a PDA before NEC. Development of moderate/severe BPD was associated with significantly greater burden and duration of postoperative morbidity following surgical NEC. Identifying surgical NEC infants at increased risk of moderate/severe BPD and developing lung protection strategies may improve surgical NEC outcomes. KEY POINTS: · Three-fourths of preterm infants experienced severe lung injury following surgical NEC.. · The infants with severe moderate/severe BPD were most likely associated with greater duration of postoperative morbidity.. · There is need to understand and develop lung protective strategies in infants with surgical NEC..

Mechanics of microtubule organizing center clustering and spindle positioning in budding yeast Cryptococcus neoformans.

The dynamic process of mitotic spindle assembly depends on multitudes of inter-dependent interactions involving kinetochores (KTs), microtubules (MTs), spindle pole bodies (SPBs), and molecular motors. Before forming the mitotic spindle, multiple visible microtubule organizing centers (MTOCs) coalesce into a single focus to serve as an SPB in the pathogenic budding yeast, Cryptococcus neoformans. To explain this unusual phenomenon in the fungal kingdom, we propose a "search and capture" model, in which cytoplasmic MTs (cMTs) nucleated by MTOCs grow and capture each other to promote MTOC clustering. Our quantitative modeling identifies multiple redundant mechanisms mediated by a combination of cMT-cell cortex interactions and inter-cMT coupling to facilitate MTOC clustering within the physiological time limit as determined by time-lapse live-cell microscopy. Besides, we screen various possible mechanisms by computational modeling and propose optimal conditions that favor proper spindle positioning-a critical determinant for timely chromosome segregation. These analyses also reveal that a combined effect of MT buckling, dynein pull, and cortical push maintains spatiotemporal spindle localization.

Stomach This: Autoimmune Atrophic Pangastritis, a Rare Type of Gastritis.

Atrophic gastritis can be environmental in origin and involve the antrum or autoimmune in origin and involve the body and fundus. We present a rare case of autoimmune atrophic pangastritis, a distinct type of autoimmune gastritis affecting the entire stomach, which should be considered in patients with other autoimmune disorders.

Orc4 spatiotemporally stabilizes centromeric chromatin.

The establishment of centromeric chromatin and its propagation by the centromere-specific histone CENPA is mediated by epigenetic mechanisms in most eukaryotes. DNA replication origins, origin binding proteins, and replication timing of centromere DNA are important determinants of centromere function. The epigenetically regulated regional centromeres in the budding yeast Candida albicans have unique DNA sequences that replicate earliest in every chromosome and are clustered throughout the cell cycle. In this study, the genome-wide occupancy of the replication initiation protein Orc4 reveals its abundance at all centromeres in C. albicans Orc4 is associated with four different DNA sequence motifs, one of which coincides with tRNA genes (tDNA) that replicate early and cluster together in space. Hi-C combined with genome-wide replication timing analyses identify that early replicating Orc4-bound regions interact with themselves stronger than with late replicating Orc4-bound regions. We simulate a polymer model of chromosomes of C. albicans and propose that the early replicating and highly enriched Orc4-bound sites preferentially localize around the clustered kinetochores. We also observe that Orc4 is constitutively localized to centromeres, and both Orc4 and the helicase Mcm2 are essential for cell viability and CENPA stability in C. albicans Finally, we show that new molecules of CENPA are recruited to centromeres during late anaphase/telophase, which coincides with the stage at which the CENPA-specific chaperone Scm3 localizes to the kinetochore. We propose that the spatiotemporal localization of Orc4 within the nucleus, in collaboration with Mcm2 and Scm3, maintains centromeric chromatin stability and CENPA recruitment in C. albicans.

Nuclear migration in budding yeasts: position before division.

Positioning the nucleus to a specific cellular location is a prerequisite for high-fidelity transmission of the genetic material to daughter cells. The cellular location of the nucleus just before its division is variable in budding yeast species which rely on a variety of mechanisms for nuclear division. Dynamic growth and shrinkage kinetics of microtubules (MTs) and forces exerted by the MT plus- and minus-end-directed motor proteins empower nuclear movement. Even though the overall process of nuclear migration is largely conserved across budding yeasts, in-depth molecular analyses of newly emerging model budding yeasts began to reveal striking differences from the paradigms that have been established based on the studies performed in the well-characterized budding yeast Saccharomyces cerevisiae. Here, we highlight the molecular players involved in differential nuclear migration in diverse budding yeasts.

Aurora kinase Ipl1 facilitates bilobed distribution of clustered kinetochores to ensure error-free chromosome segregation in Candida albicans.

Candida albicans, an ascomycete, has an ability to switch to diverse morphological forms. While C. albicans is predominatly diploid, it can tolerate aneuploidy as a survival strategy under stress. Aurora kinase B homolog Ipl1 is a critical ploidy regulator that controls microtubule dynamics and chromosome segregation in Saccharomyces cerevisiae. In this study, we show that Ipl1 in C. albicans has a longer activation loop than that of the well-studied ascomycete S. cerevisiae. Ipl1 localizes to the kinetochores during the G1/S phase and associates with the spindle during mitosis. Ipl1 regulates cell morphogenesis and is required for cell viability. Ipl1 monitors microtubule dynamics which is mediated by separation of spindle pole bodies. While Ipl1 is dispensable for maintaining structural integrity and clustering of kinetochores in C. albicans, it is required for the maintenance of bilobed distribution of clustered kinetochores along the mitotic spindle. Depletion of Ipl1 results in erroneous kinetochore-microtubule attachments leading to aneuploidy due to which the organism can survive better in the presence of fluconazole. Taking together, we suggest that Ipl1 spatiotemporally ensures bilobed kinetochore distribution to facilitate bipolar spindle assembly crucial for ploidy maintenance in C. albicans.

Spatio-temporal regulation of nuclear division by Aurora B kinase Ipl1 in Cryptococcus neoformans.

The nuclear division takes place in the daughter cell in the basidiomycetous budding yeast Cryptococcus neoformans. Unclustered kinetochores gradually cluster and the nucleus moves to the daughter bud as cells enter mitosis. Here, we show that the evolutionarily conserved Aurora B kinase Ipl1 localizes to the nucleus upon the breakdown of the nuclear envelope during mitosis in C. neoformans. Ipl1 is shown to be required for timely breakdown of the nuclear envelope as well. Ipl1 is essential for viability and regulates structural integrity of microtubules. The compromised stability of cytoplasmic microtubules upon Ipl1 depletion results in a significant delay in kinetochore clustering and nuclear migration. By generating an in silico model of mitosis, we previously proposed that cytoplasmic microtubules and cortical dyneins promote atypical nuclear division in C. neoformans. Improving the previous in silico model by introducing additional parameters, here we predict that an effective cortical bias generated by cytosolic Bim1 and dynein regulates dynamics of kinetochore clustering and nuclear migration. Indeed, in vivo alterations of Bim1 or dynein cellular levels delay nuclear migration. Results from in silico model and localization dynamics by live cell imaging suggests that Ipl1 spatio-temporally influences Bim1 or/and dynein activity along with microtubule stability to ensure timely onset of nuclear division. Together, we propose that the timely breakdown of the nuclear envelope by Ipl1 allows its own nuclear entry that helps in spatio-temporal regulation of nuclear division during semi-open mitosis in C. neoformans.

A Rare Case of Metastasis to the Thyroid Gland from Renal Clear Cell Carcinoma 11 Years after Nephrectomy and Concurrent Primary Esophageal Carcinoma.

Renal cell carcinoma is known to cause metastasis to unusual sites, which can be both synchronous or metachronous. Thyroid gland is a rare site for metastasis, but when it occurs, renal cell carcinoma is the most common primary neoplasm. We report the case of a 81-year-old female patient who had a significant medical history of right clear cell renal carcinoma with adrenal metastasis. She underwent right radical nephrectomy and adrenalectomy followed by radiofrequency ablation of left adrenal metastasis and systemic chemotherapy with sunitinib. Eleven years later, she presented with dysphagia and was found to have distal esophageal adenocarcinoma. On imaging, there was incidental detection of a left renal mass lesion and a right thyroid nodule, which on histopathology and immunohistochemistry were confirmed to be clear cell carcinoma of renal origin.

A Review of Von Hippel-Lindau Syndrome.

Von Hippel-Lindau syndrome (VHL) is a familial neoplastic condition seen in approximately 1 in 36,000 live births. It is caused by germline mutations of the tumor suppressor gene VHL, located on the short arm of chromosome 3. While the majority of the affected individuals have a positive family history, up to 20% of cases arise from de novo mutations. VHL syndrome is characterized by the presence of benign and malignant tumors affecting the central nervous system, kidneys, adrenals, pancreas, and reproductive organs. Common manifestations include hemangioblastomas of the brain, spinal cord, and retina; pheochromocytoma and paraganglioma; renal cell carcinoma; pancreatic cysts and neuroendocrine tumors; and endolymphatic sac tumors. Diagnosis of VHL is prompted by clinical suspicion and confirmed by molecular testing. Management of VHL patients is complex and multidisciplinary. Routine genetic testing and surveillance using various diagnostic techniques are used to help monitor disease progression and implement treatment options. Despite recent advances in clinical diagnosis and management, life expectancy for VHL patients remains low at 40-52 years. This article provides an overview of the major clinical, histological, and radiological findings, as well as treatment modalities.