Real-world treatment patterns and quality of life among patients with locally advanced or metastatic urothelial carcinoma living in Saudi Arabia, South Korea, Taiwan, and Turkey.

OBJECTIVES: To evaluate demographic and clinical characteristics, treatment patterns, and quality of life in patients with locally advanced or metastatic urothelial carcinoma in Asia. METHODS: Data were drawn from the Adelphi Real World Metastatic Urothelial Carcinoma Disease Specific Programme™, a cross-sectional survey of medical oncologists/urologists and their adult patients in Saudi Arabia, South Korea, Taiwan, and Turkey. Exploratory patient-reported outcomes included the EQ-5D visual analog scale, European Organisation for Research and Treatment of Cancer Quality of Life of Patient Questionnaire global health, and Brief Pain Inventory. Analyses were descriptive. RESULTS: Overall, 175 physicians reported data for 988 patients. Mean (standard deviation) patient age was 66.3 (10.8) years, 77% were men, and 82% had bladder tumors at diagnosis. Of patients receiving first- (n = 988), second- (n = 290), and third-line (n = 87) treatments, 81%, 35%, and 59% received chemotherapy, respectively, and 17%, 63%, and 34% received programmed cell death protein 1/ligand 1 inhibitors, respectively. Patient-reported (n = 319) mean (standard deviation) EQ-5D visual analog scale score was 51.8 (15.6), European Organisation for Research and Treatment of Cancer Quality of Life of Patient Questionnaire global health status score was 44.6 (19.9), and Brief Pain Inventory score was 6.5 (1.9; n = 315). CONCLUSION: The most common first- and second-line treatments for locally advanced or metastatic urothelial carcinoma were chemotherapy and programmed cell death protein 1/ligand inhibitors, respectively. At third line, 10% of patients received best supportive care alone, underscoring an unmet need for effective third-line treatment options. Patients in all regions reported quality-of-life impairment.

Design, synthesis and biological evaluation studies of novel small molecule ENPP1 inhibitors for cancer immunotherapy.

Ecto-nucleotide pyrophosphatase/phosphodiesterases 1 (ENPP1 or NPP1), is an attractive therapeutic target for various diseases, primarily cancer and mineralization disorders. The ecto-enzyme is located on the cell surface and has been implicated in the control of extracellular levels of nucleotide, nucleoside and (di) phosphate. Recently, it has emerged as a critical phosphodiesterase that hydrolyzes cyclic 2'3'- cGAMP, the endogenous ligand for STING (STimulator of INterferon Genes). STING plays an important role in innate immunity by activating type I interferon in response to cytosolic 2'3'-cGAMP. ENPP1 negatively regulates the STING pathway and hence its inhibition makes it an attractive therapeutic target for cancer immunotherapy. Herein, we describe the design, optimization and biological evaluation studies of a series of novel non-nucleotidic thioguanine based small molecule inhibitors of ENPP1. The lead compound 43 has shown good in vitro potency, stability in SGF/SIF/PBS, selectivity, ADME properties and pharmacokinetic profile and finally potent anti-tumor response in vivo. These compounds are a good starting point for the development of potentially effective cancer immunotherapy agents.

Clinical Profile of Asymptomatic Bacteriuria in Type 2 Diabetes Mellitus: An Eastern India Perspective.

INTRODUCTION: Asymptomatic bacteriuria (ASB), believed to precede symptomatic urinary tract infection (UTI) in diabetes mellitus, has geographical variation in microbial pattern and risk factors. However, data from the Eastern part of India are still lacking. MATERIALS AND METHODS: A prospective longitudinal study was performed over 80 otherwise healthy type 2 diabetes patients with a follow-up for one year to (1) estimate the prevalence of ASB and its association with age, gender, duration of diabetes, and renal and glycemic status; and (2) identify the antibiotic sensitivity pattern of uropathogens as well as evaluate the usefulness of microbial pattern as a predictor of symptomatic UTI. RESULTS: ASB was prevalent in 21.25% of type 2 diabetes population in our study. Klebsiella sp emerged as the commonest cause among males. The only risk factor for ASB was found to be long-standing type 2 diabetes. There was no association with age, gender, or recent glycemic status. Bacteriuric patients with worse baseline HbA1C values were at greater risk of UTI. Female diabetic patients with ASB due to Escherichia coli had significantly greater risk of developing UTI within one year. CONCLUSION: A large-scale prospective study reproducing similar findings will genuinely obviate the need to review recommendations on screening of ASB due to E. coli in females with long-standing diabetes and poor glycemic control. Early adoption of stringent HbA1C lowering strategy and measures to improve genital hygiene can help prevent symptomatic UTI in these patients.

Jaundice and anaemia as presenting features of an incomplete autoimmune polyglandular syndrome type II.

The coexistence of adrenal failure with either autoimmune thyroid disease and/or type 1 diabetes is defined as autoimmune polyglandular syndrome (APS) type 2 or Schmidt's syndrome. Vitiligo, hypergonadotropic hypogonadism, chronic autoimmune hepatitis, alopecia, pernicious anaemia and seronegative arthritis may also be present. We present a case of 45-year-old Indian man with progressive jaundice and asthenia for 3 months. He was also found to have pallor, icterus, dry coarse skin and delayed relaxation of ankle jerk. Investigations showed pancytopaenia with megaloblastic changes due to pernicious anaemia, autoimmune hypothyroidism and autoimmune adrenalitis with evolving adrenal insufficiency. Upper gastrointestinal endoscopy guided biopsy showed evidence of gastric mucosal atrophy. Patient responded well to hydroxocobalamin and thyroxine replacement. Detailed workup to check for evolving APS II is prudent in a hypothyroid patient presenting with pallor and jaundice. It may alert physicians to possible adrenal crisis in the future, especially after starting levothyroxine replacement in these patients.

Inhibition of crosstalk between Bcr-Abl and PKC signaling by PEITC, augments imatinib sensitivity in chronic myelogenous leukemia cells.

Chronic myelogenous leukemia (CML), a clonal hyperproliferation of immature blood cells accounts for 20% of adult leukemia cases. Reciprocal translocation of chromosomes 9 and 22, results into Bcr-Abl fusion and is responsible for expression of a tyrosine kinase protein p210(bcr/abl), which mediates several survival pathways and confer therapeutic resistance. Protein kinase C (PKC), a family of serine threonine kinases play an important role in the process of leukemogenesis. A crosstalk between Bcr-Abl and PKC signaling has been documented. Therefore, targeting p210(bcr/abl) and its associated signaling proteins using non-toxic natural means will be an effective strategy for antileukemic therapy. Aim of the present study is to investigate whether PEITC, a natural isothiocyanate in combination with imatinib mesylate (IM), a tyrosine kinase inhibitor could increase the therapeutic efficacy of IM by modulating the expression of p210(bcr/abl). Enhanced cytotoxic efficacy of IM by PEITC was further validated using another myelogenous leukemia cell line, KU812. It was observed that PEITC in combination with IM efficiently downregulated the expression of p210(bcr/abl) in chronic myelogenous leukemia cell lines (K-562). PEITC inhibited the expressions of PKCα, PKCßII and PKCζ (both phosphorylated and total form). Expression of Raf1 and ERK1/2, two important target proteins in PKC signaling cascade was diminished. The result indicated that PEITC ultimately reduced expression of Raf1 and ERK1/2 through Bcr-Abl and PKC inhibition. This result was further confirmed by UCN-01, a selective PKC inhibitor and IM; indicating an association between p210(bcr/abl) and PKC with Raf1 and ERK1/2. PEITC thus may have enormous potential in synergistic therapy of leukemia by enhancing drug efficacy.

In search of natural remediation for cervical cancer.

Cancer is a serious global health issue. Cancer of the cervix is one of the leading gynecological malignancies worldwide; though it is more prevalent in the developing countries. Fruitful approaches are needed to control cervical cancer. Awareness through proper education, screening and early detection may pave a way to combat the disease process in the first place. Surgery, chemotherapy and radiotherapy are some of the common modes of treatment for cervical cancer. Conventional medical treatments often are not able to eliminate the offending growth fully and are not free from complications. Side effects very often are disastrous. Therefore, it is high time to focus our attention to bring about a novel way to tackle the problem. Advocating holistic approach using plant derived phytochemicals may address this health problem. These molecules show potent anticancer potential and are free from toxicity. Adjunctive therapies using phytochemicals may prove to be of tremendous importance. Plants are a prime source of effective drugs for the treatment of various forms of cancer. Many of these compounds are well characterized and have led the researchers to develop potential chemotherapeutic agents. Neutraceuticals may not replace the conventional treatment regimen, but they may enhance the efficacy of chemotherapy and radiotherapy.

Curcumin augments the efficacy of antitumor drugs used in leukemia by modulation of heat shock proteins via HDAC6.

Heat shock proteins (HSPs) and histone deacetylase 6 (HDAC6) are induced under oxidative stress, which promotes oncogenesis. HSPs are regulated by heat shock factor1 (HSF1). HDAC6, a class IIb deacetylase, plays an essential role in tumorigenesis and cell stress response. HSPs, HSF1 and HDAC6 are up-regulated in cancer. In the present study, we explored the effect of curcumin, a phytochemical, on HSPs (27, 70, 90), HSF1 and HDAC6 in two different leukemia cell lines (K-562 and HL-60). The association between HDAC6, HSPs, and intrinsic oxidative stress was also investigated. Overexpression of HSPs (27, 70, 90), HSF1, and HDAC6 in leukemia cells were down-regulated by curcumin, and the effects on HSPs 27and 70 were less than that on HSP 90. This resulted in cell cycle arrest at the G2/M stage, leading to apoptosis. Different cell cycle regulatory proteins (p53, p21, cyclin B1, CDK1, Cdc25C) and some apoptosis-related proteins (Bcl-2, Bax, Bid, Bad, Apaf1, AIF and Cyt c) were altered by curcumin. Increased ROS levels in leukemia cells were quenched by curcumin. A probable association between high ROS level and the overexpression of the tumor markers was established in this study. Thus, curcumin enhanced the efficacy of anti-tumor drugs imatinib-mesylate and cytarabine through the inhibition of the tumor markers.

Effect of ethanolic extract of leaves of Paederia foetida Linn. on acetic acid induced colitis in albino rats.

OBJECTIVES: To evaluate the effect of ethanolic extract of leaves of Paederia foetida on acetic acid induced colitis in albino rats. MATERIALS AND METHODS: Ethanolic extract of Paederia foetida (EEPF) was prepared by percolation method. Acute toxicity test was done by using Organization for Economic Cooperation and Development guidelines. Albino rats were divided into four groups of five animals each. Groups A and B received 3% gum acacia. Groups C and D received EEPF 500 mg/kg body weight (BW) and 5-aminosalisylic acid 100 mg/kg BW respectively. Colitis was induced by transrectal administration of 4% acetic acid on 5(th) day. All animals were sacrificed after 48 h of colitis induction and distal 10 cm of the colon was dissected. Colon was weighed for disease activity index (DAI) and scored macroscopically and microscopically. Biochemical assessment of tissue myeloperoxidase (MPO), catalase (CAT) and superoxide dismutase (SOD) was done in colonic tissue homogenate and malondialdehyde (MDA) was estimated in serum. RESULTS: P. foetida showed significant (P < 0.05) reduction in DAI, macroscopic and microscopic lesion score as well as significant (P < 0.05) improvement in MPO, MDA, CAT, and SOD level as compared to Group B. CONCLUSIONS: The ethanolic extract of leaves of P. foetida showed significant amelioration of experimentally induced colitis, which may be attributed to its anti-inflammatory and antioxidant property.

A case of adult onset Still's disease with flare of arthritis.

Adult onset Still's disease is a febrile illness of unknown aetiology, accounting for about 6% cases of fever of unknown origin. It was first described by Eric GL Bywater in 1971, and since then few case series have been reported from India and other parts of the globe. A case of adult onset Still's disease who presented with fever and polyarthralgia of 18 months duration with flare of joint symptoms during fever spikes has been reported.

Quality of life as a key indicator of patient satisfaction and treatment compliance in people with type 2 diabetes mellitus in the IMPROVE study: a multicentre, open label, non-randomised, observational trial.

Diabetes is a debilitating chronic illness having multiple impacts on physical and mental well-being of patients. When treating chronic conditions like diabetes, psychosocial aspects and quality of life (QoL) have to be considered; however, these receive less attention due to various reasons. Patients with diabetic complications have increased levels of depression and decreased QoL This necessitates evaluating QoL of patient which now is used as a primary or secondary end point in clinical trials eg, Diab-MedSat QoL questionnaire used in diabetes. At some point all diabetic patients may require insulin to control hyperglycaemia and disease progression. The traditional insulin syringe and needle delivery system has been the principal barrier in the treatment of diabetes as it was not well accepted among the patients due to various reasons. A success over this approach has been pen like devices like FlexPen and Novopen3 which are becoming more popular than the conventional syringe-and-needles as they have several advantages like, easy to carry, use, maintain and also reduces administrative errors ensuring accurate doses are delivered. The objective of IMPROVE study is to evaluate the safety and effectiveness of biphasic insulin aspart (NovoMix 30) in normal clinical practice conditions, in India. This is an open label, non-randomised, non-interventional, observational, safety and effectiveness study in approximately 17,995 patients with type 2 diabetes mellitus. A cohort of Indian patients (n = 349) from all 4 geographical locations (North, West, East and South of India) were administered QoL instrument Diab-MedSat at baseline and 346 patients at final visit (n = 346) to assess their satisfaction with the treatment they received. The results were included in the final statistical analysis as additional outcome variables. The Diab-MedSat Novo Nordisk June 2004 English (UK) version is used. The Diab-MedSat has 21 items that need to be answered and it is scored as an overall score (all 21 items) as well as three subscale scores regarding burden (11 items), symptoms (5 items), efficacy (5 items). The complete analysis took into account all 21 items of Diab-MedSat questionnaire with their subscales. Analyses of the cohort showed higher patient satisfaction among the patients administered Diab-MedSat questionnaire from baseline (n = 349) to final visit (n = 346). The mean of overall score was 52.33 (baseline visit) versus 79.03 (final visit). The difference in the overall score and sub parameters like burden, symptoms and efficacy between the baseline and final visits were statistically significant (p-value < 0.001). The mean value of difference in overall score between the baseline visit and final visit was 26.73 +/- 20.83; while the difference for burden, symptoms and efficacy were respectively 27.86 +/- 20.81, 19.75 +/- 20.94 and 32.87 +/- 28.08. A fairly clear picture emerged that the use of biphasic insulin aspart resulted in improved QoL of the patients substantially. This is demonstrated in the results for all the parameters that were used like symptoms, efficacy and burden. The overall number of extremely satisfied patients had increased from 5.4% in the baseline visit to 91% in the final visit. This unambiguously proves that the satisfaction of patients on biphasic insulin aspart (NovoMix 30) is beyond question.

A study to find out the proportion of prediabetes in patients with acute coronary syndrome in a medical college of Kolkata.

Prediabetes is now considered as a definite entity for increased incidence of cardiovascular disease and a potent risk for progression to type 2 diabetes mellitus. As macrovascular disease is the commonest cause of increased mortality in dysglycaemic individuals (prediabetes and diabetes) by 2-4 times as opposed to normal individuals, clinicians do encounter patients with cardiovascular disease of varying severity regularly. There are increased constellation of other cardiovascular risk factors (hypertension, dyslipidaemia, etc), in prediabetes as compared to normal population. Here a study was carried out among 62 acute coronary syndrome patients who were admitted in a tertiary care hospital in Kolkata to find out the proportion of prediabetes in them. Majority of the patients (54.8%) were in the age group of 45-64 years and were males (77.4%). The study showed 48.4% of all acute coronary syndrome patients were prediabetic and 25% were diabetic. The proportion of impaired fasting glucose and impaired glucose tolerance were 19.4% and 22.6% respectively. So, altogether 72.4% patients were dysglycaemic. Out of all acute coronary syndrome patients, non-ST elevated myocardial infarction group had 50% prediabetic patients, ST elevated myocardial infarction group had 50% prediabetic patients and unstable angina group have 45.8% prediabetic patients. So, all patients of acute coronary syndrome should be screened to detect hyperglycaemia in early stage to prevent further development of diabetes mellitus and also further cardiovascular events.

Metabolic emergencies in diabetes.

Hypoglycaemia is the commonest metabolic abnormality faced by diabetic patients on hypoglycaemic therapy including insulin. Diabetic keto-acidosis (DKA) requires prompt diagnosis and all patients arriving emergency with dehydration, shock, coma, severe respiratory difficulty and evidence of any major illness should be tested for capillary blood glucose (CBG) and urinary ketones urgently not to miss DKA. Hyperosmolar non-ketotic state complicates elderly type 2 diabetes with intercurrent infections (respiratory tract infection is commonest) characterised by severe dehydration, severe hyperglycaemia and absence of acidosis and vomiting. Lactic acidosis is extremely rare; may be compounded with comorbidities like tissue hypoxia, septic shock, heart failure--metformin usage inadvertently may precipitate the condition.