Prolonged response to Tyrosine Kinase Inhibitors followed by Immunotherapy in metastatic hepatocellular carcinoma: A rare case report.

The overall prognosis of hepatocellular carcinoma (HCC) is dismal and 5-year survival rate is 14.8%. We report a case of HCC coinfected with hepatitis C virus (HCV) and tumor thrombosis in the portal vein that was initially started on sorafenib followed by lenvatinib and nivolumab. On radiological imaging, there was a good partial response (PR) after starting nivolumab. A female 56 years of age presented with HCC coinfection with HCV, tumor thrombosis growing to the right portal vein. She received 6 months of sorafenib starting from April 2019 and was then switched to lenvatinib due to progressive disease. She continued lenvatinib for 11 months following which she developed new metastatic lesions where she was started on nivolumab. After 4 months of nivolumab, her alpha-fetoprotein decreased and there was a radiological PR. She is currently on nivolumab, with a total duration of response of 24 months on sorafenib followed by lenvatinib and lastly on nivolumab. Hence, tyrosine kinase inhibitors and immunotherapy can be effective lines treatment for advanced HCC and can give durable response duration, and probable radiological PR can be achieved with Nivolumab.

Endocardial fibroelastosis causing sudden death in an infant: Autopsy case report of an unusual lesion.

ABSTRACT: Endocardial fibroelastosis is characterized by proliferation of both elastic and collagenous fibers within the endocardium, causing diffuse or localized thickening. A four-and-a-half-month-old baby was admitted to a local hospital, with a history of seizures for one day. Baby developed features of heart failure and died within one week after admission. At the post-mortem examination, heart was found to be enlarged with dilated ventricles. The endocardium of left ventricle was markedly thickened with a whitish appearance. Histopathology showed a thick layer of collagenous fibrous tissue in the endocardium, which was confirmed by Masson trichrome stain. The cause of death was offered as dilated cardiomyopathy due to endocardial fibroelastosis. The underlying mechanisms of myocardial fibrosis remain unclear. It is hypothesized that genetic, infectious, inflammatory, and nutritional processes are involved in this condition. This case highlights the importance of gross specimen examination and special staining methods to support histopathology after postmortem examination, for ascertaining the cause of death.

Safety assessment of compounded non-FDA-approved hormonal therapy versus FDA-approved hormonal therapy in treating postmenopausal women.

OBJECTIVE: To assess the safety and serum estradiol (E2) and total testosterone (T) concentrations in postmenopausal women treated with Pellet Hormonal Therapy (PHT) and Food and Drug Administration approved Hormonal Therapy (FHT). METHODS: A total of 539 postmenopausal women were identified, including 384 on PHT and 155 on FHT. Data extracted from medical records include demographics, indication for hormone therapy, treatment duration, side effects, serum E2 and T levels, and frequency of laboratory follow-up. RESULTS: The incidence of overall side effects was significantly higher in PHT compared with FHT (221 [57.6%] vs 23 [14.8%], P < 0.00001, odds ratio [95% CI] =8.0[4.5-14.2]). When examining women with an intact uterus prior to hormone therapy initiation, 55.3% (136/246) on PHT vs 15.2% (12/79) on FHT had at least one episode of abnormal uterine bleeding (P < 0.0001, odds ratio [95% CI] = 7.9[3.6-17.0]). Furthermore, a significantly higher proportion of women on PHT (20.3% [50/246]), compared with 6.3% (5/79) on FHT, had a hysterectomy (P = 0.036, odds ratio [95% CI] = 3.2[1.1-9.3]). Both mean (SD, Min-Max) peak E2 (pg/mL) and peak T (ng/dL) are significantly higher in the PHT group than those in the FHT group (E2: 237.70 [168.55, 10-1,111] vs 93.45 [130.77, 5.5-465.8], T: 194.04 [84.94, 4.3-599] vs 15.59 [19.52, 0.2-70], P < 0.00001). Of those on PHT, four women had E2 level > 1,000 pg/mL and nine women with T level > 400 ng/dL. CONCLUSION: Women on PHT had a significantly higher incidence of side effects than FHT as well as a significantly higher supraphysiological level of peak E2 and T during the treatment.

Metastatic Dermatosis in Breast Carcinoma on Adjuvant Trastuzumab: Is Skin a Sanctuary Site in Human Epidermal Growth Factor Receptor-2-Amplified Disease?

Cutaneous metastasis (CM) from internal malignancies is commonly seen. Sometimes, skin metastases can be the first sign of advanced cancer or an indicator of cancer recurrence. Cases of breast cancer with cutaneous progression after or during trastuzumab therapy have been described in the past, frequently associated with systemic disease progression. However, CM during adjuvant trastuzumab therapy is very rare. It has been hypothesized that cancer cells located in the skin survive and take proliferative advantage by virtue of an immune-tolerance mechanism that hampers trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity. We describe a case of human epidermal growth factor receptor-2-overexpressing breast cancer presenting with diffuse CM during adjuvant trastuzumab therapy.

Gold catalyzed double condensation reaction: Synthesis, antimicrobial and cytotoxicity of spirooxindole derivatives.

Microwave assisted synthesis of spirooxindoles via tandem double condensation between isatins and 4-hydroxycoumarin under gold catalysis is reported. The reaction is practical to perform, since the products can be isolated by simple filtration without requiring tedious column chromatography. The scope of this chemistry is exemplified by preparing structurally diverse spirooxindoles (22 examples) in excellent yields. Antimicrobial evaluation of the synthesized compounds revealed that three compounds (3a, 3f and 3s) exhibited significant MIC values in comparison to the standard drugs. Molecular docking studies of these compounds with AmpC-ß-lactamase receptor revealed that 3a exhibited minimum binding energy (-117.819kcal/mol) indicating its strong affinity towards amino acid residues via strong hydrogen bond interaction. All compounds were also evaluated for their in vitro cytotoxicity against COLO320 cancer cells. Biological assay and molecular docking studies demonstrated that 3g is the most active compound in terms of its low IC50 value (50.0µM) and least free energy of binding (-8.99kcal/mol) towards CHK1 receptor, respectively.

Role of supportive maintenance therapy on implant survival: a university-based 17 years retrospective analysis.

OBJECTIVE: The objective of this study was to determine whether professional maintenance appointments were related to a decrease on dental implant loss. METHODS: We performed a retrospective review (1995-2012) of 1020 patient dental charts to collect data including a cadre of different variables such as age, gender, race, diabetes, osteoporosis, jaw location, implant dimensions and professional maintenance therapy. As a patient may have multiple implants which are correlated, we selected one random implant per patient to assure independence of observations assumption of the Cox proportional hazards regression model. Data analysis was performed using Kaplan-Meier survival curves and multivariate analysis using Cox proportional hazards regression analysis. RESULTS: Our results demonstrate that subjects with no maintenance had the lowest cumulative survival rate as compared to subjects with regular maintenance. In a multivariate Cox regression model, regular maintenance patients had the dental implant failure rate reduced by 90% as compared to no maintenance (P = 0.001). If patients had less than one maintenance visit per year, the failure rate was reduced by 60% as compared to no maintenance, but the difference was not statistically significant (P = 0.08). CONCLUSION: From this research, we conclude that a professional administered periodontal maintenance at least on an annual basis is a critical factor for implant survival.

Male Breast Cancer in India: Series from a Cancer Research Centre.

Male breast cancer (MBC) is an uncommon malignancy. The scarcity of cases has reduced the focus of research in this area as compared with female breast cancer. The incidence of breast cancer in males is slowly rising and it becomes important to study the biology of this uncommon illness. Aim of the present work was to study the clinico-pathological behaviour of male breast cancer at a cancer research institute in India. 18 cases of MBC were identified out of 1752 cases of breast cancer registered during a 10 year period. Clinical parameters and histopathological data were analysed. MBC comprised of 1.03 % of total breast cancer cases. Median age of presentation was 60 years. Most of the patients presented to us in advanced stage. Aggressive pattern of disease was recognised with high node positivity, more perineural spread and lymphovascular invasion. Most of the cases were positive for hormone receptors. Breast cancer is seen at a relatively early age in Indian males. Disease is aggressive in nature with high hormone receptor positivity.

A flavonoid isolated from Streptomyces sp. (ERINLG-4) induces apoptosis in human lung cancer A549 cells through p53 and cytochrome c release caspase dependant pathway.

The aim of this study was to investigate the anticancer activity of a flavonoid type of compound isolated from soil derived filamentous bacterium Streptomyces sp. (ERINLG-4) and to explore the molecular mechanisms of action. Cytotoxic properties of ethyl acetate extract was carried out against A549 lung cancer cell line using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Cytotoxic properties of isolated compound were investigated in A549 lung cancer cell line, COLO320DM cancer cell line and Vero cells. The compound showed potent cytotoxic properties against A549 lung cancer cell line and moderate cytotoxic properties against COLO320DM cancer cell line. Isolated compound showed no toxicity up to 2000 µg/mL in Vero cells. So we have chosen the A549 lung cancer cell line for further anticancer studies. Intracellular visualization was done by using a laser scanning confocal microscope. Apoptosis was measured using DNA fragmentation technique. Treatment of the A549 cancer cells with isolated compound significantly reduced cell proliferation, increased formation of fragmented DNA and apoptotic body. Activation of caspase-9 and caspase-3 indicated that compound may be inducing intrinsic and extrinsic apoptosis pathways. Bcl-2, p53, pro-caspases, caspase-3, caspase-9 and cytochrome c release were detected by western blotting analysis after compound treatment (123 and 164 µM). The activities of pro-caspases-3, caspase-9 cleaved to caspase-3 and caspase-9 gradually increased after the addition of isolated compound. But Bcl-2 protein was down regulated after treatment with isolated compound. Molecular docking studies showed that the compound bound stably to the active sites of caspase-3 and caspase-9. These results strongly suggest that the isolated compound induces apoptosis in A549 cancer cells via caspase activation through cytochrome c release from mitochondria. The present results might provide helpful suggestions for the design of antitumor drugs toward lung cancer treatment.

Cu(OTf)2 catalyzed three component reaction: efficient synthesis of spiro[indoline-3,4'-pyrano[3,2-b]pyran derivatives and their anticancer potency towards A549 human lung cancer cell lines.

Cu(OTf)2 catalyzed efficient synthesis of spiropyrano[3,2-b]pyran-4(8H)-ones is accomplished via one-pot three component reaction between isatin, kojic acid and active methylenes. This synthetic protocol is operationally simple and affords product with good to excellent yields at a short reaction time. The synthesized compounds were evaluated for their tumor cell growth inhibitory activity against the human lung cancer cell line (A549) and found that 13 compounds exhibited moderate to good anticancer potency. Molecular docking studies were performed for all the synthesized compounds and the results showed that compound 4e showed greater affinity for anaplastic lymphoma kinase (ALK) receptor.

Odor representations in the mammalian olfactory bulb.

A first key step in studying a sensory modality is to define how the brain represents the features of the sensory stimulus. This has proven to be a challenge in olfaction, where even the stimulus features have been a matter of considerable debate. In this review, we focus on olfactory representations in the first stage of the olfactory pathway, the olfactory bulb (OB). We examine the diverging viewpoints on spatially organized versus distributed representations. We then consider how odor sampling through respiration is a key part of the odorant code. Finally, we ask how the bulb handles the challenging task of representing mixtures. We suggest that current evidence points toward a representation that is spatially organized at the inputs but later distributed, with the spatial organization not being used for much computation. Nevertheless, this is a simple representation that effectively represents multiple individual odorants, as well as odor mixtures.

Treatment of thyroid carcinoma: emphasis on high-dose 131I outpatient therapy.

There is an abundance of evidence indicating that the oral administration of sodium (13I)I-iodide is of value in the management of well-differentiated thyroid cancers. The first step in the management of thyroid cancer is near-total removal of the thyroid gland. Destroying any residual functioning thyroid tissue in the neck or metastatic tissue elsewhere in the body using (131)I after surgery decreases the risk of recurrence and death from well-differentiated thyroid cancers. The dosage of radioiodine used for this purpose varies among different centers. Until a few years ago, radioiodine therapy using >1.110 GBq (30 mCi) (131)I required hospitalization of patients to minimize radiation exposure to others. The U.S. Nuclear Regulatory Commission (USNRC) revised Title 10 of the Code of Federal Regulations (10CFR 35.75) in 1997, allowing the release of patients immediately after (131)I therapy if the total effective dose equivalent from the patient to an individual does not exceed 5 mSv (0.5 rem) in any 1 y. With this change, which became effective on May 29, 1997, a patient can be treated with a higher amount of (131)I as an outpatient and leave the premises with proper instructions to keep the radiation exposure to other individuals as low as it is reasonably achievable. The objectives of this article are to (a) briefly review the types of thyroid cancer; (b) provide an overall review of the treatment of thyroid carcinomas, follow-up of these patients, and the prognostic indicators of survival; and (c) explain the radiation safety precautions and the preventive measures that can be taken to minimize the radiation exposure of family members or helpers living with the patient and the general public at large.

Occurrence of cyclopiazonic acid in feeds and feedstuffs in Tamil Nadu, India.

Out of 100 samples (67 randomly collected and 33 known to contain aflatoxin) of feeds and feedstuffs examined, 40 showed cyclopiazonic acid (CPA) activity, i.e., maize 10/26, groundnut cake 10/20, sunflower seed cake 7/10, sorghum 4/10, wheat 1/1, little millet 1/1, rice 1/1, deoiled rice bran 0.1, fishmeal 0/1, chick mash 1/3, grower mash 0/7, layer mash 3/11, broiler mash 2/6 and cattle feed 0/2, concentrations ranged from 0.4 to 12, 0.5 to 20, 0.3 to 20, 0.3 to 20, 20, 10, 10, 1.5, 1 to 15, 8 and 15 ppm, respectively. Co-occurrence of CPA was found in 14 of 33 aflatoxin-containing samples.

Influence of dietary rice culture material containing cyclopiazonic acid on certain serum biochemical parameters of broiler chickens.

Three hundred and forty-eight Vencob broiler chickens were fed diets containing Penicillium griseofulvum rice culture material with 0, 12.5, 25 and 50 ppm of the mycotoxin cyclopiazonic acid (CPA) for 28 days. Serum samples were collected from 9 birds in each group at weekly intervals to study the effect of sublethal doses of CPA on certain serum biochemical parameters. Significant reductions in weight gains (p < 0.01) and feed consumptions (p < 0.05) were observed at 25 and 50 ppm. Exocrine pancreas showed degenerative and necrotic changes in CPA fed chickens. The CPA had significant (p < 0.05) influence on serum total protein, albumin, cholesterol, amylase and lipase levels. CPA did not affect serum glucose levels. There was a decline in levels of total serum protein and albumin in CPA fed groups. But serum cholesterol, amylase and lipase showed dose-dependent increases.

Gradient methods for the optimization of dynamical systems containing neural networks.

An extension of the backpropagation method, termed dynamic backpropagation, which can be applied in a straightforward manner for the optimization of the weights (parameters) of multilayer neural networks is discussed. The method is based on the fact that gradient methods used in linear dynamical systems can be combined with backpropagation methods for neural networks to obtain the gradient of a performance index of nonlinear dynamical systems. The method can be applied to any complex system which can be expressed as the interconnection of linear dynamical systems and multilayer neural networks. To facilitate the practical implementation of the proposed method, emphasis is placed on the diagrammatic representation of the system which generates the gradient of the performance function.

Identification and control of dynamical systems using neural networks.

It is demonstrated that neural networks can be used effectively for the identification and control of nonlinear dynamical systems. The emphasis is on models for both identification and control. Static and dynamic backpropagation methods for the adjustment of parameters are discussed. In the models that are introduced, multilayer and recurrent networks are interconnected in novel configurations, and hence there is a real need to study them in a unified fashion. Simulation results reveal that the identification and adaptive control schemes suggested are practically feasible. Basic concepts and definitions are introduced throughout, and theoretical questions that have to be addressed are also described.

Five and ten year estimated survival and disease-free rates after intraperitoneal chromic phosphate; stage I ovarian adenocarcinoma.

From 1975 to 1982, 25 evaluable patients with FIGO Stage I ovarian cancer were treated with intraperitoneal chromic phosphate (32P). All patients underwent total abdominal hysterectomy, bilateral salpingo-oophorectomy with (28%) or without (72%) omentectomy, with no other surgical staging procedures prior to referral. Patients were restaged by laparoscopy (inspection of diaphragms, abdomen, and pelvis), biopsy of suspicious lesions, and peritoneal cytologic washings prior to intraperitoneal chromic phosphate therapy. For the 25 patients, the estimated 5- and 10-year recurrence-free rates and the 5- and 10-year survival rates are 84% and 75%, respectively. Excellent 10-year recurrence-free rates were achieved for Stages IA and IC, nonruptured cysts, and Grade I and II tumors. In contrast, very low 10-year survival rates were achieved for patients with Stage IB, ruptured cysts, or Grade III tumors.