An Anomaly with Potential as a New Prognostic Marker in CLL with del(13q): Gain of 16p13.3

Deletion 13q [del(13q)] is a favorable prognostic marker if it is detected as a sole abnormality in chronic lymphocytic leukemia (CLL). However the clinical courses of cases with isolated del(13q) are quite heterogeneous. In our study, we investigated copy number variations (CNVs), loss of heterozygosity (LOH), and the size of del(13q) in 30 CLL patients with isolated del(13q). We used CGH+SNP microarrays in order to understand the cause of this clinical heterogeneity. We detected del(13q) in 28/30 CLL cases. The size of the deletion varied from 0.34 to 28.81 Mb, and there was no clinical effect of the deletion size. We found new prognostic markers, especially the gain of 16p13.3. These markers have statistically significant associations with short time to first treatment and advanced disease stage. Detecting both CNVs and LOH at the same time is an advantageous feature of aCGH+SNP. However, it is very challenging for the array analysis to detect mosaic anomalies. Therefore, it is very important to confirm the results by FISH. In our study, we detected approximately 9% mosaic del(13q) by microarray. In addition, the gain of 16p13.3 may affect the disease prognosis in CLL. However, additional studies with more patients are needed to confirm these results.

Management of altered metabolic activity in Drosophila model of Huntington’s disease by curcumin

Huntington’s disease (HD) is a devastating polyglutamine disorder characterized by extensive neurodegeneration and metabolic abnormalities at systemic, cellular and intracellular levels. Metabolic alterations in HD manifest as abnormal body weight, dysregulated biomolecule levels, impaired adipocyte functions, and defective energy state which exacerbate disease progression and pose acute threat to the health of challenged individuals in form of insulin resistance, cardiovascular disease, and energy crisis. To colossally mitigate disease symptoms, we tested the efficacy of curcumin in Drosophila model of HD. Curcumin is the bioactive component of turmeric ( Curcuma longa Linn), well-known for its ability to modulate metabolic activities. We found that curcumin effectively managed abnormal body weight, dysregulated lipid content, and carbohydrate level in HD flies. In addition, curcumin administration lowered elevated reactive-oxygen-species levels in adult adipose tissue of diseased flies, and improved survival and locomotor function in HD flies at advanced disease stage. Altogether, these findings clearly suggest that curcumin efficiently attenuates metabolic derangements in HD flies and can prove beneficial in alleviating the complexities associated with HD.

Prognostic Value of Microvessel Density in Non-Hodgkin Lymphoma: A Meta-Analysis

<b><i>Background:</i></b> Angiogenesis in non-Hodgkin lymphoma (NHL) has been investigated by a variety of studies. However, the correlation between angiogenesis and the occurrence or prognosis of NHL patients remains controversial. <b><i>Methods:</i></b> We performed a systematic and comprehensive retrieval of relevant literatures from PubMed, EMBASE, and Web of Science databases. The quality of the eligible studies was assessed using the Newcastle-Ottawa Scale (NOS). <b><i>Results:</i></b> Fifteen eligible studies containing a total of 1373 NHL patients were included in this study. All the eligible studies were high-quality studies scoring ≥6 points. MVD was not different between NHL and control (SMD = 0.281, 95% CI: −1.410 to 1.972, <i>p</i> = 0.745). High MVD was associated with advanced disease stage (OR = 1.580, 95% CI: 1.080–2.311, <i>p</i> = 0.018) and unfavorable OS (HR = 1.656, 95% CI: 1.366–2.009, <i>p</i> = 0.000) but not with PFS (HR = 1.349, 95% CI: 0.852–2.136, <i>p</i> = 0.201). <b><i>Conclusion:</i></b> This meta-analysis demonstrated that high MVD was related to advanced disease stage and associated with unfavorable OS of NHL patients.

Nephrotoxicity in patients with cancer treated with immune checkpoint inhibitors.

e14558 Background: Despite their efficacy in various cancer types, administration of immune checkpoint inhibitors (ICIs) may be complicated by the development of immune-related adverse events (IrAE). Nephrotoxicity represents a relatively rare but clinically significant adverse event, associated with the administration of ICI. Methods: The medical records of 294 patients with solid tumors or hematological malignancies that received ICIs for at least 4 weeks were retrospectively reviewed. Demographic, clinicopathological, treatment, toxicity and outcome data were recorded. ICI-associated nephrotoxicity was correlated with the remaining clinicopathological parameters as well as with progression-free survival (PFS) and overall survival (OS). Results: The majority of patients were male (70.4%), with bladder cancer or renal cell carcinoma (38.1% and 27.6%, respectively), and stage IV disease (56.8%), and had received ICI as monotherapy (68,7%). Nephrotoxicity during immunotherapy administration was observed in 20/ 294 (6.8%) patients, was mild (grade 1) and reversible in 55% and 75% of these cases, respectively, and was significantly associated with nephrotoxicity from previously administered therapy (p = 0,008), impaired renal function at initiation of ICIs (p = 0.044). and advanced disease stage at diagnosis (p = 0,028). No correlation between ICI-nephrotoxicity and PFS or OS was observed. Conclusions: ICI-associated nephrotoxicity was a relatively infrequent IrAE in our patient population, most commonly mild and reversible, and with no significant effect on survival. Preexisting treatment-related nephrotoxicity, impaired renal function and/or advanced disease stage at diagnosis may represent significant predisposing factors for its development.

Immunohistochemical staining for IMP3 in patients with duodenal papilla tumors: assessment of the potential for diagnosing endoscopic resectability and predicting prognosis

Background Endoscopic papillectomy of duodenal papillary tumors (PT) is indicated for adenomas or well-differentiated adenocarcinomas that do not involve the sphincter of Oddi. However, there is currently no reliable pre-operative method to diagnose the infiltration in the sphincter of Oddi.’ Insulin-like growth factor 2 mRNA protein 3 (IMP3) staining is reportedly associated with advanced disease stage and clinical outcomes in many carcinomas. The aim of this retrospective study was to investigate the ability of diagnosing sphincter of Oddi involvement in PT and predicting the prognoses using IMP3 immunohistochemistry. Methods Twenty-five resected specimens from patients with PT and 24 biopsy specimens from the same patients excluding one were immunostained for IMP3. The percentage of positive cells in the tumor was evaluated and compared with the final pathological diagnosis and prognosis. Results The final pathological diagnoses were adenoma in 5 patients and adenocarcinoma in 20 patients (no sphincter of Oddi involvement in 5 and involvement in 15). The ability to diagnose sphincter of Oddi involvement based on the percentage of IMP3-positive cells in resected specimens and tissue biopsies was the area under the curve 0.8 and 0.78, respectively, of the receiver operating characteristic curve, and the accuracies were 80.0% and 75.0% (cutoff value: 10%), respectively. Moreover, patients with an IMP3-positive cell rate of ≥ 10% had a significantly worse prognosis (log-rank test P = 0.01). Conclusion IMP3 immunostaining of resected and biopsy specimens from PT patients enables the diagnosis of sphincter of Oddi involvement objectively and is also effective in predicting the prognosis.

Patisiran in hATTR Amyloidosis: Six-Month Latency Period before Efficacy

Hereditary amyloidosis associated with mutations in the transthyretin gene (hATTR) is a progressive devastating disease, with a fatal outcome occurring within 10years after onset. In recent years, TTR gene silencing therapy appeared as a promising therapeutic strategy, showing evidence that disease progression can be slowed and perhaps reversed. We report here 18 subjects affected by hATTR amyloidosis treated with patisiran, a small interfering RNA acting as TTR silencer, and evaluated with a PND score, the NIS and NIS-LL scale, and a Norfolk QOL-DN questionnaire at baseline and then every 6 months. A global clinical stabilizationwas observed for the majority of the patients, with mild-moderate improvements in some cases, even in advanced disease stage (PND score > 2). Analysis of NIS, NIS-LL and Norfolk QOL-DN results, and PND score variation suggest the possible presence of a 6-month latency period prior to benefit of treatment.

Human alpha-synuclein overexpressing MBP29 mice mimic functional and structural hallmarks of the cerebellar subtype of multiple system atrophy

Multiple system atrophy (MSA) is a rare, but fatal atypical parkinsonian disorder. The prototypical pathological hallmark are oligodendroglial cytoplasmic inclusions (GCIs) containing alpha-synuclein (α-syn). Currently, two MSA phenotypes are classified: the parkinsonian (MSA-P) and the cerebellar subtype (MSA-C), clinically characterized by predominant parkinsonism or cerebellar ataxia, respectively. Previous studies have shown that the transgenic MSA mouse model overexpressing human α-syn controlled by the oligodendroglial myelin basic protein (MBP) promoter (MBP29-hα-syn mice) mirrors crucial characteristics of the MSA-P subtype. However, it remains elusive, whether this model recapitulates important features of the MSA-C-related phenotype. First, we examined MSA-C-associated cerebellar pathology using human post-mortem tissue of MSA-C patients and controls. We observed the prototypical GCI pathology and a preserved number of oligodendrocytes in the cerebellar white matter (cbw) accompanied by severe myelin deficit, microgliosis, and a profound loss of Purkinje cells. Secondly, we phenotypically characterized MBP29-hα-syn mice using a dual approach: structural analysis of the hindbrain and functional assessment of gait. Matching the neuropathological features of MSA-C, GCI pathology within the cbw of MBP29-hα-syn mice was accompanied by a severe myelin deficit despite an increased number of oligodendrocytes and a high number of myeloid cells even at an early disease stage. Intriguingly, MBP29-hα-syn mice developed a significant loss of Purkinje cells at a more advanced disease stage. Catwalk XT gait analysis revealed decreased walking speed, increased stride length and width between hind paws. In addition, less dual diagonal support was observed toward more dual lateral and three paw support. Taken together, this wide-based and unsteady gait reflects cerebellar ataxia presumably linked to the cerebellar pathology in MBP29-hα-syn mice. In conclusion, the present study strongly supports the notion that the MBP29-hα-syn mouse model mimics important characteristics of the MSA-C subtype providing a powerful preclinical tool for evaluating future interventional strategies.

Hepatoid Adenocarcinoma of the Stomach: Current Perspectives and New Developments

Hepatoid adenocarcinoma of the stomach (HAS) is a rare malignant tumor, accounting for only 0.17–15% of gastric cancers. Patients are often diagnosed at an advanced disease stage, and their symptoms are similar to conventional gastric cancer (CGC) without specific clinical manifestation. Morphologically, HAC has identical morphology and immunophenotype compared to hepatocellular carcinoma (HCC). This is considered to be an underestimation in diagnosis due to its rare incidence, and no consensus is reached regarding therapy. HAS generally presents with more aggressive behavior and worse prognosis than CGC. The present review summarizes the current literature and relevant knowledge to elaborate on the epidemic, potential mechanisms, clinical manifestations, diagnosis, management, and prognosis to help clinicians accurately diagnose and treat this malignant tumor.

Oral administration of repurposed drug targeting Cyp46A1 increases survival times of prion infected mice

Prion diseases are fatal, infectious, and incurable neurodegenerative disorders caused by misfolding of the cellular prion protein (PrPC) into the infectious isoform (PrPSc). In humans, there are sporadic, genetic and infectious etiologies, with sporadic Creutzfeldt-Jakob disease (sCJD) being the most common form. Currently, no treatment is available for prion diseases. Cellular cholesterol is known to impact prion conversion, which in turn results in an accumulation of cholesterol in prion-infected neurons. The major elimination of brain cholesterol is achieved by the brain specific enzyme, cholesterol 24-hydroxylase (CYP46A1). Cyp46A1 converts cholesterol into 24(S)-hydroxycholesterol, a membrane-permeable molecule that exits the brain. We have demonstrated for the first time that Cyp46A1 levels are reduced in the brains of prion-infected mice at advanced disease stage, in prion-infected neuronal cells and in post-mortem brains of sCJD patients. We have employed the Cyp46A1 activator efavirenz (EFV) for treatment of prion-infected neuronal cells and mice. EFV is an FDA approved anti-HIV medication effectively crossing the blood brain barrier and has been used for decades to chronically treat HIV patients. EFV significantly mitigated PrPSc propagation in prion-infected cells while preserving physiological PrPC and lipid raft integrity. Notably, oral administration of EFV treatment chronically at very low dosage starting weeks to months after intracerebral prion inoculation of mice significantly prolonged the lifespan of animals. In summary, our results suggest that Cyp46A1 as a novel therapeutic target and that its activation through repurposing the anti-retroviral medication EFV might be valuable treatment approach for prion diseases.

Profile of gynecological malignancies after the start of gynecology oncology surgeries in Sikkim-experience from a tertiary hospital in North East India

Background: North East is the “cancer capital” of India where there is acute lack of oncologists and oncology facilities. Objectives of the study were to evaluate the trends of gynecological malignancies and to evaluate the need for oncology facility in Sikkim.Methods: This is a retrospective desk review conducted in department of obstetrics and gynecology at Sikkim Manipal institute of medical sciences, India, for a period of three years after the start of oncology surgeries. Women operated for any gynecological malignancy were taken into the study while women referred outside for alternative treatment were excluded from the study.Results: A total 29 women with gynecological malignancies were operated during the 3-year period. Of the total, 17 (58%) were women operated for carcinoma ovary, 6 (21%) for cancer cervix and 6 (21%) for carcinoma uterus. Epithelial ovarian cancer was the most common ovarian cancer. 105 women with large complex ovarian masses were operated during the three-year period, however, only 17 women were diagnosed with cancer of which 8 women had stage I disease while 9 women had advanced disease (stage III-IV). 12 women underwent primary debulking surgery while 5 women underwent interval debulking surgery. Average age for cervical cancer was 48 years, average age for ovarian cancer was 46 years while 52 years was the average age for cancer uterus. Conclusions: High number of gynecological malignancies operated in the only center offering minimum oncological surgical facility points towards the need for a specialized center providing all the needs for treating oncology cases in Sikkim