ALK Deletion Exons 2 to 19: Case Report of a Rare ALK Inhibitor-Responsive Lung Cancer Driver Oncogene.

ALK internal deletions of nonkinase domain exons occur in 0.01% of lung cancers with ALK genomic aberrations. We report a lung adenocarcinoma with a previously undescribed somatic ALK deletion of exons 2 to 19 with dramatic and sustained (>23 mo) response to alectinib. Our and other reported cases with ALK nonkinase domain deletions (between introns and exons 1-19) can display positive results in nonsequencing-based lung cancer diagnostic tests (such as immunohistochemistry) used to screen for more common ALK rearrangements. This case report emphasizes that "ALK-driven" lung cancers should be expanded to encompass those harboring not only ALK rearrangements with other genes but also ALK nonkinase domain deletions.

Bromodomain Inhibition Reveals FGF15/19 As a Target of Epigenetic Regulation and Metabolic Control.

Epigenetic regulation is an important factor in glucose metabolism, but underlying mechanisms remain largely unknown. Here we investigated epigenetic control of systemic metabolism by bromodomain-containing proteins (Brds), which are transcriptional regulators binding to acetylated histone, in both intestinal cells and mice treated with the bromodomain inhibitor JQ-1. In vivo treatment with JQ-1 resulted in hyperglycemia and severe glucose intolerance. Whole-body or tissue-specific insulin sensitivity was not altered by JQ-1; however, JQ-1 treatment reduced insulin secretion during both in vivo glucose tolerance testing and ex vivo incubation of isolated islets. JQ-1 also inhibited expression of fibroblast growth factor (FGF) 15 in the ileum and decreased FGF receptor 4-related signaling in the liver. These adverse metabolic effects of Brd4 inhibition were fully reversed by in vivo overexpression of FGF19, with normalization of hyperglycemia. At a cellular level, we demonstrate Brd4 binds to the promoter region of FGF19 in human intestinal cells; Brd inhibition by JQ-1 reduces FGF19 promoter binding and downregulates FGF19 expression. Thus, we identify Brd4 as a novel transcriptional regulator of intestinal FGF15/19 in ileum and FGF signaling in the liver and a contributor to the gut-liver axis and systemic glucose metabolism.

Triple-hit high-grade B-cell lymphoma presenting with ovarian torsion.

We report a case of a previously healthy woman in her early 70s who presented with 2 weeks of episodic abdominal pain and significant weight loss. Imaging of her abdomen revealed acute right ovarian torsion associated with bilateral ovarian enlargement and an indeterminant pelvic mass. An urgent laparoscopic bilateral oophorectomy was performed with pathological results consistent with triple-hit high-grade B-cell lymphoma. She was successfully treated with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab, intrathecal methotrexate and venetoclax with complete remission after three cycles. Ovarian lymphoma is a rare entity and its genetic features have not been well described. We performed a literature review, describe the current knowledge regarding ovarian lymphoma and its therapeutic implication in the genomic age.

Obesity and cholangiocarcinoma: A review of epidemiological and molecular associations.

Cholangiocarcinoma (CCA) is a malignancy of bile duct epithelium, and its incidence is increasing globally. Numerous factors are reported associated with an increased risk of CCA and vary among populations across different areas. Obesity is a major, worldwide public health problem that leads to several complications and is associated with increased cancer risk. Although several epidemiological studies have shown that obesity is likely associated with the increased risk of CCA, this association might be limited to Western countries. Multiple hormones, cytokines, and metabolite perturbations in obese states have been shown to enhance tumorigenicity and metastasis potentials. Understanding the biological linkage of obesity to CCA might lead to novel prevention and therapeutic approaches to CCA treatment. This review summarizes the current evidence and highlights the knowledge gaps regarding the relationship between obesity and CCA from epidemiological and molecular perspectives.

Extended thromboprophylaxis for medically ill patients with cancer: a systemic review and meta-analysis.

Hospitalized medically ill patients with cancer are at increased risk of both venous thromboembolism and bleeding. The safety and efficacy of extended thromboprophylaxis in patients with cancer are unclear. We conducted a systematic review and meta-analysis of the literature using of MEDLINE, EMBASE, and the Cochrane CENTRAL databases to identify cancer subgroups enrolled in randomized controlled trials evaluating extended thromboprophylaxis following hospitalization. The primary outcomes were symptomatic and incidental venous thromboembolic events and hemorrhage (major hemorrhage and clinically relevant nonmajor bleeding). Four randomized controlled trials reported the outcomes of extended thromboprophylaxis in 3655 medically ill patients with active or history of cancer. The rates of venous thromboembolic events were similar between the extended-duration and standard-duration groups (odds ratio [OR], 0.85; 95% confidence interval [CI], 0.61-1.18; I2 = 0%). However, major and clinically relevant nonmajor bleeding occurred significantly more frequently in the extended-duration thromboprophylaxis group (OR, 2.10; 95% CI, 1.33-3.35; I2 = 8%). Extended thromboprophylaxis in hospitalized medically ill patients with cancer was not associated with a reduced rate of venous thromboembolic events but was associated with increased risk of hemorrhage. This study protocol was registered on PROSPERO as #CRD42020209333.

Trim the gut, lose the weight - and the bone.

Vertical sleeve gastrectomy (VSG) is an effective therapeutic approach for obesity and type 2 diabetes but is associated with osteoporosis. In this issue of the JCI, Li et al. report that VSG rapidly reduces bone mass, as observed in humans, via rapid demineralization and decreased bone formation, independent of weight loss or Ca2+/vitamin D deficiency. VSG also reduces bone marrow adipose tissue, in part via increased granulocyte-colony stimulating factor (G-CSF). The interplay between VSG-mediated effects on systemic metabolism and bone biology remain to be investigated. These findings suggest novel mechanisms and therapeutic targets for bariatric surgery-induced osteoporosis.

SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms.

Pharmacologic inhibition of the renal sodium/glucose cotransporter-2 induces glycosuria and reduces glycemia. Given that SGLT2 inhibitors (SGLT2i) reduce mortality and cardiovascular risk in type 2 diabetes, improved understanding of molecular mechanisms mediating these metabolic effects is required. Treatment of obese but nondiabetic mice with the SGLT2i canagliflozin (CANA) reduces adiposity, improves glucose tolerance despite reduced plasma insulin, increases plasma ketones, and improves plasma lipid profiles. Utilizing an integrated transcriptomic-metabolomics approach, we demonstrate that CANA modulates key nutrient-sensing pathways, with activation of 5' AMP-activated protein kinase (AMPK) and inhibition of mechanistic target of rapamycin (mTOR), independent of insulin or glucagon sensitivity or signaling. Moreover, CANA induces transcriptional reprogramming to activate catabolic pathways, increase fatty acid oxidation, reduce hepatic steatosis and diacylglycerol content, and increase hepatic and plasma levels of FGF21. Given that these phenotypes mirror the effects of FGF21 to promote lipid oxidation, ketogenesis, and reduction in adiposity, we hypothesized that FGF21 is required for CANA action. Using FGF21-null mice, we demonstrate that FGF21 is not required for SGLT2i-mediated induction of lipid oxidation and ketogenesis but is required for reduction in fat mass and activation of lipolysis. Taken together, these data demonstrate that SGLT2 inhibition triggers a fasting-like transcriptional and metabolic paradigm but requires FGF21 for reduction in adiposity.

Prevalence of thyroid diseases in familial adenomatous polyposis: a systematic review and meta-analysis.

Thyroid cancer (TC) is a known extra-intestinal manifestation and contributes to the mortality and morbidity in patients with familial adenomatous polyposis (FAP). Its exact prevalence is not well established and recent studies have shown an increasing number of TC in this patient population. The prevalence of benign thyroid masses and endocrinologic thyroid disorders are also poorly described. We conducted a systematic review and meta-analysis by using a random-effects model to characterize TC and estimated the prevalence of thyroid diseases in FAP patients. Twelve studies (n = 9821) were included. Pooled prevalence of TC, benign thyroid masses, and endocrinologic thyroid disorders in FAP were 2.6% [95% confidence interval (CI) 1.3-4.8], 48.8% [95% CI 33.8-64.0], and 6.9% [95% CI 4.5-10.3] respectively. Subgroup analyses revealed higher prevalence of TC in studies with fewer participants, studies that used screening ultrasound to diagnose TC, and studies that were published after 2002. TC diagnosis preceded the diagnosis of FAP in 34% of the patients. The means age at diagnosis of FAP and TC were 29 and 31 years, respectively. 95% of the patients were female and the most common pathology was of papillary subtype (83.3%). Most mutations (79.2%) were located at the 5' end of APC gene. In summary, benign thyroid disorders are common in FAP, yet, TC is an uncommon phenomenon. Certain patient subset, such as young female with APC mutation at the 5' end, might benefit from routine surveillance ultrasound.

Clinical inertia causing new or progression of diabetic retinopathy in type 2 diabetes: A retrospective cohort study.

BACKGROUND: Clinical inertia is a failure to intensify treatment according to evidence-based guidelines, and can have both short- and long-term adverse effects for type 2 diabetes (T2D). The aim of the present study was to demonstrate the effects of clinical inertia on glycemic control and diabetes-related complications. METHODS: A retrospective cohort study was conducted at a university-based hospital in Thailand. Medical records were evaluated retrospectively from January 2010 to December 2014. Patients were classified into two groups: clinical inertia and non-inertia. Clinical inertia was defined as failure to initiate insulin within 3 months in patients with HbA1c ≥9 % who were already taking two oral antidiabetic agents. RESULTS: From 1206 records, 98 patients with mean HbA1c of 10.3 % were identified and enrolled in the study. The median follow-up time of these patients was 29.5 months and 68.4 % were classified into the clinical inertia group. The mean (± SD) HbA1c decrement in the clinical inertia and non-inertia groups was 0.82 ± 1.50 % and 3.02 ± 1.80 %, respectively, at 6 months (P < 0.001) and 1.46 ± 1.85 % and 3.04 ± 1.76 %, respectively, at the end of study (P < 0.001). Clinical inertia was associated with a significantly shorter median time to progression of diabetic retinopathy (DR); log rank test, P = 0.02 and a higher incidence of DR progression (10 vs 2.2 cases per 1000 person-months; P = 0.003). The adjusted incidence rate ratio for DR progression in the clinical inertia group was 4.92 (95 % confidence interval 1.11-21.77; P = 0.036). Being treated by general practitioners was the strongest risk factor associated with clinical inertia. CONCLUSIONS: Clinical inertia can cause persistently poor glycemic control and speed up the progression of DR in T2D.

Diabetes Mellitus Treated with Medical Nutritional Therapy and Self Blood Glucose Monitoring: A Randomized Controlled Trial.

OBJECTIVE: To assess the effect of Medical Nutritional Therapy (MNT) combined with self blood glucose monitoring (SBGM) in the clinical outcomes of patients with type 2 diabetes. MATERIAL AND METHOD: A randomized controlled trial was conducted on patients with uncontrolled, not-using insulin type 2 diabetes at Her Royal Highness Princess Maha Chakri Sirindhorn Medical Center Sixty patients were recruited and randomized equally into intervention group (MNT with SBGM) and control group (usual care). The primary endpoint was improvement of hemoglobin A1c (HbA1c) at 12 and 24 weeks. RESULTS: At 12 and 24 weeks the intervention group had significantly improved their glycemic control in comparison to control group (median decrement of HbA1c at 12 weeks 0.72% vs. 0.15%; p < 0.001 and at 24 weeks 0.85% vs. 0.20%; p < 0.001). Oral hypoglycemic agents were reduced or discontinued in 7 patients in the intervention group and 1 patient in control group who achieved HbA1c goal after 24 weeks (p = 0.037). After 24 weeks, body weight was significantly decreased from baseline (2.3 kg, p < 0.001) in the intervention group while only non-significant decrease was observed in control group (0.1 kg, p = 0.632). CONCLUSION: MNT combined with SBGM is an effective non-pharmacological intervention for patients with uncontrolled type 2 diabetes.