Treatment of relapsed/refractory chronic lymphocytic leukemia with Zanubrutinib after progressing on other BTK inhibitors.

Chronic Lymphocytic Leukemia (CLL) is the most common type of leukemia in the US, representing approximately 1.1% of all new cancers diagnosed. Most patients with CLL can be monitored without treatment, and the indicated treatment options include a CD20 monoclonal antibody with or without bruton tyrosine kinase (BTK) inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, and B-cell lymphoma 2 (BCL2) antagonists. We review the case of a 77-year-old female with a long-standing history of CLL predominant lymphocytosis, transfusion -independent anemia, and thrombocytopenia. Patient responded to zanubrutinib after initial failure of idelalisib, rituximab, and acalabrutinib and venetoclax.

Acquired Hemophilia A and ST-Elevation Myocardial Infarction (STEMI): A Rare Presentation and Management Dilemma.

Thrombotic events are a rare complication of recombinant activated factor VII (rFVIIa) therapy in patients with hemophilia. We present a case of a 71-year-old male who developed ST-elevation myocardial infarction after receiving rFVIIa replacement therapy for acquired hemophilia A.

Efficacy and safety of combined endoscopic cyanoacrylate injection and balloon-occluded retrograde transvenous occlusion (BRTOcc) of gastrorenal shunts in patients with bleeding gastric fundal varices.

BACKGROUND: Endoscopic cyanoacrylate (glue) injection of fundal varices may result in life-threatening embolic adverse events through spontaneous gastrorenal shunts (GRSs). Balloon-occluded retrograde transvenous occlusion (BRTOcc) of GRSs during cyanoacrylate injection may prevent serious systemic glue embolization through the shunt. This study aimed to evaluate the efficacy and safety of a combined endoscopic-interventional radiologic (BRTOcc) approach for the treatment of bleeding fundal varices. METHODS: We retrospectively analysed the data of patients who underwent the combined procedure for acutely bleeding fundal varices between January 2010 and April 2018. Data were extracted for patient demographics, clinical and endoscopic findings, technical details, and adverse events of the endoscopic-BRTOcc approach and patient outcomes. RESULTS: We identified 30 patients (13 [43.3%] women; median age 58 [range, 25-92] years) with gastroesophageal varices type 2 (53.3%, 16/30) and isolated gastric varices type 1 (46.7%, 14/30) per Sarin classification, and median clinical and endoscopic follow-up of 151 (range, 4-2,513) days and 98 (range, 3-2,373) days, respectively. The median volume of octyl-cyanoacrylate: Lipiodol injected was 7 (range, 4-22) mL. Procedure-related adverse events occurred in three (10.0%) patients, including transient fever, non-life-threatening pulmonary glue embolism, and an injection-site ulcer bleed. Complete gastric variceal obturation was achieved in 18 of 21 patients (85.7%) at endoscopic follow-up. Delayed variceal rebleeding was confirmed in one patient (3.3%) and suspected in two patients (6.7%). Although no procedure-related deaths occurred, the overall mortality rate was 46.7%, primarily from liver-disease progression and co-morbidities. CONCLUSION: The combined endoscopic-BRTOcc procedure is a relatively safe and effective technique for bleeding fundal varices, with a high rate of variceal obturation and a low rate of serious adverse events.

Deletion of endoplasmic reticulum stress-responsive co-chaperone p58IPK protects mice from diet-induced steatohepatitis.

AIM: Activation of PKR-like endoplasmic reticulum kinase (PERK), an endoplasmic reticulum stress sensor, is a feature of non-alcoholic steatohepatitis (NASH), yet regulators of PERK signaling remain undefined in this context. The protein p58IPK regulates PERK; however, its role in NASH has not been examined. The aim of this study was to assess the in vivo role of p58IPK in the pathogenesis of dietary NASH. METHODS: Parameters of hepatocyte cell death, liver injury, inflammation, fibrosis, indirect calorimetry and PERK activation were assessed in p58IPK knockout (p58ipk-/- ) mice and their wild-type littermate controls. All animals were fed a diet enriched in fat, fructose, and cholesterol (FFC) for 20 weeks. RESULTS: Activation of PERK was attenuated in FFC-fed p58ipk-/- mice. Accordingly, FFC-fed p58ipk-/- mice showed a reduction in hepatocyte apoptosis and death receptor expression, with a significant reduction in serum alanine transaminase values. Correspondingly, macrophage accumulation and fibrosis were significantly lower in FFC-fed p58ipk-/- mice. CONCLUSION: We have shown that, in an in vivo dietary NASH model, p58IPK mediates hepatocyte apoptosis and liver injury, likely through PERK phosphorylation. In the absence of p58IPK , PERK phosphorylation and NASH are attenuated. Inhibition of hepatic p58IPK could be a future target for NASH therapy.

Mmu-miR-615-3p regulates lipoapoptosis by inhibiting C/EBP homologous protein.

Lipoapoptosis occurring due to an excess of saturated free fatty acids such as palmitate is a key pathogenic event in the initiation of nonalcoholic fatty liver disease. Palmitate loading of cells activates the endoplasmic reticulum stress response, including induction of the proapoptotic transcription factor C/EBP homologous protein (CHOP). Furthermore, the loss of microRNAs is implicated in regulating apoptosis under conditions of endoplasmic reticulum (ER) stress. The aim of this study was to identify specific microRNAs regulating CHOP expression during palmitate-induced ER stress. Five microRNAs were repressed under palmitate-induced endoplasmic reticulum stress conditions in hepatocyte cell lines (miR-92b-3p, miR-328-3p, miR-484, miR-574-5p, and miR-615-3p). We identified miR-615-3p as a candidate microRNA which was repressed by palmitate treatment and regulated CHOP protein expression, by RNA sequencing and in silico analyses, respectively. There is a single miR-615-3p binding site in the 3'untranslated region (UTR) of the Chop transcript. We characterized this as a functional binding site using a reporter gene-based assay. Augmentation of miR-615-3p levels, using a precursor molecule, repressed CHOP expression; and under these conditions palmitate- or tunicamycin-induced cell death were significantly reduced. Our results suggest that palmitate-induced apoptosis requires maximal expression of CHOP which is achieved via the downregulation of its repressive microRNA, miR-615-3p. We speculate that enhancement of miR-615-3p levels may be of therapeutic benefit by inhibiting palmitate-induced hepatocyte lipoapoptosis.

Does CD34 Staining Reflect the Angiogenic Process in the Bone Marrow? An Analysis of a Series of Chronic Myeloid Leukemia Patients.

UNLABELLED: Backgorund: Angiogenesis is associated with growth, dissemination and metastasis of tumours. Measurement of Microvascular Density (MVD) is a quantitative method of assessment of angiogenesis and would give a proportional co relate of the angiogenic process in tumours. The aim of this study is to measure the MVD by using CD34 staining in various phases of Chronic Myeloid Leukemia (CML) and type of CML (Granulocytic/Granulocytic Megakaryocytic) (G/GM) and to co-relate micro vascular densities with the grade of fibrosis. MATERIALS AND METHODS: Bone marrow biopsy specimens of 30 CML patients and 20 non-CML (controls) cases that required bone marrow biopsy were subjected to CD34 staining and H&E staining. The mean MVD in CD34 slides was assessed by selecting hot spots and MVD was measured in these fields in high power (40 x magnification) and the mean MVD was calculated by taking the average of four hot spots per field. Grade of fibrosis and phase of CML, type (G/GM) were assessed in H&E slides. The controls were matched with respect to age and gender. RESULTS: Among 30 patients with CML, 21 were in chronic phase, five in accelerated and four in blast crisis. A normal distribution was obtained for MVD of both CML cases and controls using tests for normality. Comparison of mean MVD between CML and controls by student t-test showed a significant increase in MVD of CML cases (p = 0. 00026). However, no significant difference in MVD between the three phases viz, Chronic, accelerated and blast crisis phase (p = 0. 302) was obtained by using one way ANOVA. Comparison of Grade of fibrosis with MVD using independent t-test showed no significant difference in MVD between low (Grade1&2) and high grade (Grade 3&4) (p = . 805). No significant difference in MVD was obtained between G and GM types of CML using independent t-test (p = 0. 381). CONCLUSION: The study shows that there is a significant increase in MVD in CML cases than controls but no significant difference in MVD could be demonstrated between different phases of CML, histological types of CML and grades of fibrosis in CML.

Study of tumour cellularity in locally advanced breast carcinoma on neo-adjuvant chemotherapy.

BACKGROUND: Breast cancer is the most common invasive malignancy which occurs in women worldwide. The advent of neoadjuvant chemotherapy has radically changed the management of locally advanced breast cancer and a complete response is reported to significantly improve disease free survival. Traditionally, clinical response is assessed on basis of tumour size. In this study, an attempt was made to check whether tumour cellularity could be a better prognostic factor and also to check as to what impact the correlation of tumour size with cellularity had on the response assessment in locally advanced breast cancer patients. MATERIALS AND METHODS: Thirty seven patients with locally advanced breast cancer, who were treated by neoadjuvant chemotherapy during the period of December 2008 to May 2009, were selected for the study and from their case records, tumour size, clinical response and demographic details were gathered. Tumour cellularity was assessed prior to chemotherapy in core needle biopsy sections and it was matched with that seen in subsequent mastectomy specimens. Tumour size and cellularity were then correlated with the different treatment response groups and they were statistically analyzed by using the SPSS, version 13.0 software. RESULTS: After neoadjuvant chemotherapy, the tumour size and cellularity were found to be significantly reduced in breast carcinomas (p<0.05, paired t-test). The relative changes in cellularity which were seen were highly variable between individual patients and different clinical response groups, particularly in the partial response and no response categories. The product of cellularity and size dramatically changed the distribution of residual tumour pathology, thus causing a shift towards a complete response. CONCLUSION: The current study showed that the product of tumour size and cellularity may be a better prognostic indicator of clinical response in patients with neoadjuvant chemotherapy treated locally advanced breast cancer and that it would enable a new definition for clinical response in the future.

Etiopathogenesis and neurobiology of narcolepsy: a review.

Narcolepsy is a chronic lifelong sleep disorder and it often leaves a debilitating effect on the quality of life of the sufferer. This disorder is characterized by a tetrad of excessive daytime sleepiness, cataplexy (brief loss of muscle tone following strong emotion), hypnogogic hallucinations and sleep paralysis. There are two distinct subgroups of Narcolepsy: Narcolepsy with cataplexy and Narcolepsy without cataplexy. For over 100 years, clinicians have recognised narcolepsy, but only in the last few decades have scientists been able to shed light on the true cause and pathogenesis of narcolepsy. Recent studies have shown that a loss of the hypothalamic neuropeptide Hypocretin/Orexincauses Narcolepsy with cataplexy and that an autoimmune mechanism may be responsible for this loss. Our understanding of the neurophysiologic aspect of narcolepsy has also significantly improved. The basic neural mechanisms behind sleepiness and cataplexy, the two defining symptoms of narcolepsy have started to become clearer. In this review, we have provided a detailed account of the key aspects of etiopathogenesis and neurobiology of narcolepsy, along with a critical appraisal of the more recent and interesting causal associations.We have also looked at the contributions of neuroimaging to the etiopathogenesis of Narcolepsy.