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Purpose Discordance between HER2 expression in tumor tissue (tHER2) and HER2 status on circulating tumor cells (cHER2) has been reported. It remains largely underexplored whether patients with tHER2 − /cHER2 + can benefit from anti-HER2 targeted therapies. Methods cHER2 status was determined in 105 advanced-stage patients with tHER2 − breast tumors. Association between cHER2 status and progression-free survival (PFS) was analyzed by univariate and multivariate Cox models and survival differences were compared by Kaplan–Meier method. Results Compared to the patients with low-risk cHER2 (cHER2 +  < 2), those with high-risk cHER2 (cHER2 +  ≥ 2) had shorter survival time and an increased risk for disease progression (hazard ratio [HR] 2.16, 95% confidence interval [CI] 1.20–3.88, P  = 0.010). Among the patients with high-risk cHER2, those who received anti-HER2 targeted therapies had improved PFS compared with those who did not (HR 0.30, 95% CI 0.10–0.92, P  = 0.035). In comparison, anti-HER2 targeted therapy did not affect PFS among those with low-risk cHER2 (HR 0.70, 95% CI 0.36–1.38, P  = 0.306). Similar results were obtained after adjusting covariates. A longitudinal analysis of 67 patients with cHER2 detected during follow-ups found that those whose cHER2 status changed from high-risk at baseline to low-risk at first follow-up exhibited a significantly improved survival compared to those whose cHER2 remained high-risk (median PFS: 11.7 weeks vs. 2.0 weeks, log-rank P  = 0.001). Conclusion In advanced-stage breast cancer patients with tHER2 − tumors, cHER2 status has the potential to guide the use of anti-HER2 targeted therapy in patients with high-risk cHER2.

Background Intraoperative frozen section (IFS) is routinely utilized by many surgeons during pancreaticoduodenectomy. However, its utility has not been rigorously studied. Methods Patients who underwent pancreaticoduodenectomy between 2006 and 2015 were identified from institutional data. Measures of diagnostic accuracy of frozen section and multivariate logistic regression are reported. Results The cohort included 1076 patients. Of resected specimens, 73.3% were malignant. IFS and final pathologic review (the gold standard) were discrepant for (1) pathologic diagnosis or (2) resection margin status in 5.3% and 3.3% of cases. The sensitivity, specificity, and accuracy of IFS for histologic determination of malignancy were 97.2%, 95.3%, and 96.7% respectively. For resection margins, they were 92.3%, 99.3%, and 96.8%, respectively. Positive bile duct and neck margins were revised intraoperatively 62% and 65% of the time, respectively; positive uncinate margins were never resected but led surgeons to avoid revision of a second positive margin in 13% of cases (4.2% of all PDA). Operative changes were rarely noted in the presence of benign disease ( n  = 11, 1.0%); conversion to total pancreatectomy based on positive margins was performed in just 13 cases (1.2%). Upon multivariable analysis, a positive neck margin proved to be the greatest predictor for a revised resection margin (AOR 16.9 [4.8–59.8]), whereas a positive uncinate margin or a diagnosis of chronic pancreatitis was protective against IFS-driven operative changes (AOR 0.25 [0.09–0.73]; AOR 0.16 [0.13–0.19]). Conclusions IFS is highly accurate and guides reresection of margins. However, selective omission of IFS may be justified for cases where benign disease is suspected.

Whereas VHL inactivation is a primary event in clear cell renal cell carcinoma (ccRCC), the precise mechanism(s) of how this interacts with the secondary mutations in tumor suppressor genes, including PBRM1 , KDM5C / JARID1C , SETD2 , and/or BAP1 , remains unclear. Gene expression analyses reveal that VHL, PBRM1, or KDM5C share a common regulation of interferon response expression signature. Loss of HIF2α, PBRM1, or KDM5C in VHL-/- cells reduces the expression of interferon stimulated gene factor 3 (ISGF3), a transcription factor that regulates the interferon signature. Moreover, loss of SETD2 or BAP1 also reduces the ISGF3 level. Finally, ISGF3 is strongly tumor-suppressive in a xenograft model as its loss significantly enhances tumor growth. Conversely, reactivation of ISGF3 retards tumor growth by PBRM1-deficient ccRCC cells. Thus after VHL inactivation, HIF induces ISGF3, which is reversed by the loss of secondary tumor suppressors, suggesting that this is a key negative feedback loop in ccRCC.

Critical telomere shortening (for example, secondary to partial telomerase deficiency in the rare disease dyskeratosis congenita) causes tissue pathology, but underlying mechanisms are not fully understood. Mice lacking telomerase (for example, mTR −/− telomerase RNA template mutants) provide a model for investigating pathogenesis. In such mice, after several generations of telomerase deficiency telomeres shorten to the point of uncapping, causing defects most pronounced in high-turnover tissues including intestinal epithelium. Here we show that late-generation mTR −/− mutants experience marked downregulation of Wnt pathway genes in intestinal crypt epithelia, including crypt base columnar stem cells and Paneth cells, and in underlying stroma. The importance of these changes was revealed by rescue of crypt apoptosis and Wnt pathway gene expression upon treatment with Wnt pathway agonists. Rescue was associated with reduced telomere-dysfunction-induced foci and anaphase bridges, indicating improved telomere capping. Thus a mutually reinforcing feedback loop exists between telomere capping and Wnt signalling, and telomere capping can be impacted by extracellular cues in a fashion independent of telomerase. Mice lacking telomerase provide a model to study pathogenesis caused by critical telomere shortening. Here, the authors provide evidence that telomere shortening causes downregulation of Wnt signalling in intestinal crypts and that defects can be partially rescued by treatment with Wnt agonists.

Basal cell carcinoma (BCC) is the most common skin cancer, and its incidence is increasing. Though metastatic BCC (mBCC) is uncommon, the literature demonstrates a 0.0028%-0.55% rate of metastasis. We report on a patient treated at our institution who was found to have mBCC with osseous metastases. To our knowledge, this is the first report of mBCC in the orthopaedic literature. Orthopaedic oncologists should consider mBCC in patients diagnosed with carcinoma of unknown origin, with a known history of BCC, or individuals with light skin pigmentation and age 50 or greater. This can help clinicians make the correct diagnosis and provide the appropriate treatment.

Abstract Introduction Melanomas and tumors with high microsatellite instability (MSI-H) carry heavy tumor mutation burden. The resulting neo-antigens elicit a host immune response in an attempt to contain the tumor. Immune checkpoint pathways (PD-1/PD-L1 and CTLA-4) downregulate T-cell activation, limiting damage to healthy tissue during physiologic immune response. Tumors take advantage of these pathways as a mechanism of immune escape. Checkpoint inhibitors (CPIs) such as Nivolumab (PD-1 inhibitor) and others inhibit these pathways, allowing immune-mediated destruction of tumor cells. Unsurprisingly, these drugs are associated with a spectrum of immune-related adverse effects (irAEs). We report a case of a patient with MSI-H metastatic melanoma who developed an unusual irAE during nivolumab immunotherapy. Case Report A 35-year-old man with a history of ocular melanoma presented with omental metastasis. The metastatic focus was MSI-H by NGS with deficient MSH1/PMS2 by immunohistochemistry. Nivolumab therapy was initiated. Initial follow-up imaging showed complete response. At 7 months, clinical exam and PET imaging showed new skin nodules, hypermetabolic mediastinal lymphadenopathy, and a hypermetabolic vertebral (L3) lesion concerning for disease progression. Biopsies from all three sites revealed sarcoidosis-like granulomatous inflammation. Special stains for fungus and mycobacteria and microbial cultures were negative. The patient was asymptomatic and did not require antisarcoid treatment. He remains in remission for melanoma. Conclusion Sarcoidosis-like reaction is a rare irAE of CPIs that can clinically/radiologically mimic metastatic disease. Bone involvement as seen in our patient is extremely rare. Importantly, biopsy/histopathological examination is required to rule out disease progression. Infectious causes for granulomas should be excluded as these patients are immunocompromised. Evidence suggests that irAE with CPIs may be associated with better outcomes. MSI-H status is infrequent in melanomas but is hypothesized to be a predictive biomarker for CPI response. Our patient is predicted to do well.