Everolimus plus octreotide long-acting repeatable in advanced neuroendocrine tumors in the routine tertiary cancer care setting: An Indian experience.

BACKGROUND: Neuroendocrine tumors (NETs) are rare, heterogeneous, indolent tumors that are relatively insensitive to systemic chemotherapy. Therapeutic strategies for NETs broadly include somatostatin analogs, antiangiogenic therapy, and most recently, mammalian target of rapamycin inhibition. Combination therapy has shown promising antitumor activity and good tolerability in the randomized phase III trials. AIM: The aim was to evaluate the safety and efficacy of Everolimus plus Octreotide long-acting repeatable (LAR) in patients with advanced NETs in the routine tertiary cancer care setting in India in this postapproval, noninterventional trial. PATIENTS AND METHODS: Patients presenting to selected centers between 2011 and 2013 with histologically confirmed low-, intermediate- or high-grade advanced NETs who may have had prior exposure to cytotoxic chemotherapy (≤2 lines) were treated with oral Everolimus (10 mg/day) plus intramuscular Octreotide LAR (30 mg once every 28 days) until disease progression or unacceptable toxicity was seen. Patients were evaluated every 3 months for a response to therapy as per Response Evaluation Criteria in Solid Tumors. RESULTS: Everolimus plus Octreotide LAR was associated with a clinical benefit rate of 69% (best evaluable responses: Stable disease [SD] in 10 patients [63%], partial response in 1 patient [6%]). The average duration of therapy was 4.8 cycles, and 3 (17%) patients continued therapy for ≥12 cycles (all achieved SD). The therapy was found to be well-tolerated in all patients. CONCLUSIONS: Everolimus plus Octreotide LAR appears to be safe and efficacious in patients with advanced NETs who may have had prior exposure to chemotherapy - a finding consistent with recently conducted major trials.

Prevalence of KRAS mutations in metastatic colorectal cancer: A retrospective observational study from India.

BACKGROUND: One of the genetic alterations implicated in tumor progression in colorectal cancers (CRCs) are abnormalities in Kristen Rat Sarcoma (KRAS) gene. Evaluation of KRAS mutation status is an important prognostic factor and has predictive value in deciding first line therapy based on monoclonal antibodies such as Cetuximab and Panitumumab in metastatic CRCs. MATERIALS AND METHODS: In this retrospective study, we analyzed 7 different somatic mutations in Exon 2 of KRAS gene in 299 unselected incidental CRC patients who visited the hospital for clinical management during the period 2009-2013. Most of the tumors were primarily originating from colon and rectum; nevertheless, there were a few from rectosigmoid, sigmoid, ceacum and anal canal in the study group. Genomic DNA extracted from paraffin embedded tumor tissues was screened for 7 point mutations located in Codons 12 and 13 of KRAS gene, using Scorpions amplified refractory mutation system real time polymerase chain reaction technology. Statistical analysis was performed to assess bivariate relationship between different variables that includes: mutation status, mutation type, tumor location, tumor morphology, age and sex. RESULTS: Prevalence of mutation in Codons 12 and 13 was 42.8% in the study group. Well-differentiated tumors had significantly more mutation positivity than moderately and poorly differentiated tumors (P = 0.001). 92% of the mutations were from Codon 12 and 8% in Codon 13. Glycine to Arginine was relatively more common in rectosigmoid followed by ceacum, while Glycine to Alanine mutation was relatively more prevalent in sigmoid, followed by rectum and rectosigmoid. CONCLUSION: The results suggest a prevalence of KRAS mutation at 42.8% in Indian population indicating that this testing is very crucial for targeted therapy management in metastatic CRC in India. Further analysis on mutation status of other homologues such as NRAS and downstream partner, v-raf murine sarcoma viral oncogene homolog B1, would add value to understanding the role of anti-epidermal growth factor receptor therapy in CRC management.

Epidermal growth factor receptor mutation in non-small-cell lung carcinomas: a retrospective analysis of 1036 lung cancer specimens from a network of tertiary cancer care centers in India.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutation plays a vital role in the prognosis of patients with lung cancer. However, there is a dearth of studies on EGFR mutation in Indian population. In this retrospective study conducted at a network of tertiary cancer care centers across India, we evaluated the proportion of EGFR mutation in patients with non-small-cell lung carcinomas (NSCLC). MATERIALS AND METHODS: A total of 1036 cases of non-small lung cancer were assessed for EGFR mutation status using Scorpion amplified refractory mutation system real time polymerase chain reaction method from fine needle aspiration cytology core biopsy, pleural fluid and cell blocks. For a few cases, macro dissection of tumor from H and E slides was also performed for EGFR analysis. EGFR Status was assessed for the most commonly known driver mutations in Exons 18, 19, 20 and 21, which contributes to a total of 29 somatic mutations including the resistance mutation T790M. RESULTS: Around 39% of the cohort was female and 61% were male. Mutation was positive in 40.3% and negative (wild type) in 59.7%. There was 1.8% mutation in exon 18, 24.6% in exon 19, 1.6% in exon 20 and 12.8% in exon 21. 38.2% had a mutation in a single site and 1.1% had a mutation in two sites. Overall mutation was significant in females (50.5% vs. 33.9%) compared with males (χ2 = 28.3, P < 0.001). Mutation was significant in exon 21 (16.8% vs. 10.3%, χ2 = 9.44, P = 0.002) and exon 19 (30.7% vs. 20.7%, χ2 = 13.2, P < 0.001) in females compared with males. CONCLUSION: EGFR is expressed differentially/mutated in patients with NSCLC. Further studies to unravel the predictors for acquired genetic alterations of EGFR are needed.

Dynamics of water in synthetic saponite clays: effect of trivalent ion substitution.

Saponite clay belongs to the phyllosilicate family and is comprised of layers of Si(IV) tetrahedra and Al(III) or Mg(II) octahedra with definite interlayer spacing. In these systems, the trivalent ion substitutions in the tetrahedral layers lead to negative charge on the layers. Here we report the dynamics of water contained in [Si(6.97)Al(1.03)][Ni(6.00)]O(20)(OH)(4)[Na(1.03)]·28H(2)O (SAP-1) and [Si(7.13)Fe(0.86)][Ni(6.00)]O(20)(OH)(4)[Na(0.86)]·14H(2)O (SAP-2) saponite clays in the temperature range 200-310 K as studied by quasielastic neutron scattering technique. Particularly the effect of the ion substitution towards the dynamics of water is addressed here. Data analysis is carried out using the relaxing cage model. The existence of distribution in relaxation times indicated that the water molecules in saponite clay have a different local environment which leads to complex diffusion behavior. It is found that water exists in a supercooled state in the temperature range up to 235 K. However, some of the water molecules are found to be immobile in the temperature range 240-285 K. The fraction of immobile water decreases with increase in temperature. At higher temperatures, some of the water molecules in the hydration shells or those near the surface start participating in the diffusion process and at 293 K, almost all water molecules contribute to the dynamics. Diffusivity of water in both SAP-1 and SAP-2 are found to be lower in comparison to the bulk, and within the two samples of saponite clay diffusivity in SAP-1 is found to be lower compared to SAP-2; this has been explained on the basis of the charge on the tetrahedral layers and the charge balancing cations in the interlayer spacing.

Clinicopathologic profile of 470 giant cell tumors of bone from a cancer hospital in western India.

Over 20 years, 470 cases of giant cell tumor of bone diagnosed at a tertiary cancer hospital were analyzed. Male predominance (57%), predilection for bones around the knee joint (42%), and occurence in the 21- to 30-year-old age group (49.1%) with 6% being in the immature skeleton are well known facts. Accurate diagnosis was possible in 66% and 88% of cases on radiology and biopsy, respectively. Tumors measured 6 to 20 cm and, in 402 cases, showed "usual" histology comprising uniformly scattered multinucleate giant cells amidst mononuclear stromal cells, together imparting a syncitium-like appearance. Presence of osteoid, hemorrhage, and aneurysmal bone cyst-like areas; spindle cells in sheets (devoid of giant cells); or storiform pattern and intravascular osteoclasts were less common. The less common histologic features posed diagnostic difficulty in the setting of a small biopsy. Treatment included intralesional curettage (33.19%), marginal excision (4.2%), wide excision (31%), or radical surgeries (14.25%). Recurrences seen in 170 cases were multiple in 47 cases. Metastases largely to the lung were recorded in 24 cases. The histology of all the tumors, namely, primary, recurrent, or metastatic was identical. Statistical analysis using the computer software SPSS (SPSS Inc, Chicago, Ill)was performed with particular reference to the unusual histologic features vs recurrence and metastasis by chi(2) test. The only statistically significant factors were occurrence in the axial skeleton vs appendicular skeleton (P = .001) and primary treatment elsewhere vs at this hospital (P = .045), each of these being associated with increased frequency for local recurrence but not metastasis.

Artificial neural networks: useful aid in diagnosing acute appendicitis.

BACKGROUND: [corrected] The purpose of the study was to assess the role of artificial neural networks (ANNs) in the diagnosis of appendicitis in patients presenting with acute right iliac fossa (RIF) pain and comparing its performance with the assessment made by experienced clinicians and the Alvarado score. METHODS: After training and testing an ANN, data from 60 patients presenting with suspected appendicitis over a 6-month period to a teaching hospital was collected prospectively. Accuracy of diagnosing appendicitis by the clinician, the Alvarado score, and the ANN was compared. RESULTS: The sensitivity, specificity, and positive and negative predictive values of the ANN were 100%, 97.2%, 96.0%, and 100% respectively. The ability of the ANN to exclude accurately the diagnosis of appendicitis in patients without true appendicitis was statistically significant compared to the clinical performance (p=0.031) and Alvarado score of >or=6 (p=0.004) and nearly significant compared to the Alvarado score of >or=7 (p=0.063). CONCLUSIONS: ANNs can be an effective tool for accurately diagnosing appendicitis and may reduce unnecessary appendectomies.

Intraperitoneal chemotherapy as first-line treatment in the management of epithelial ovarian cancer.

Recent evidence has suggested improved outcomes following incorporation of intraperitoneal chemotherapy administration with intravenous systemic chemotherapy as first-line treatment of small volume residual epithelial ovarian cancer. This review focuses on the mechanism of actions of the chemotherapeutic drugs and reviews the possible reasons for the superior outcomes of intraperitoneal chemotherapy.

Apoptosis and chemo-resistance in colorectal cancer.

Systemic chemotherapy plays an integral part in treating advanced colorectal cancer. However 50% of patients respond poorly or have disease progression due to resistance to chemotherapeutic agents. This article reviews the pathways that regulate apoptosis, apoptotic mechanisms through which chemotherapeutic agents mediate their effect and how deregulation of apoptotic proteins may contribute to chemo-resistance. Also discussed are potential therapeutic strategies designed to target these proteins and thereby improve response rates to chemotherapy in colorectal cancer.

Differentiated thyroid cancer invading the hypopharynx: A case report.

Most thyroid cancers (90-95%) are well differentiated. Well differentiated cancers of the thyroid are usually confined to the thyroid capsule, making them amenable to isolated thyroid resection. Invasion of the upper aerodigestive tract by these cancers is infrequent and hypopharyngeal invasion is still rare. We report a 51 year old man with thyroid cancer invading the hypopharynx, who was successfully managed with complete resection along with a partial pharyngectomy. He is asymptomatic and disease free eighteen months after surgery. We advocate aggressive surgical extirpation of thyroid carcinoma invading the upper aerodigestive tract.

Genome scan of schizophrenia families in a large Veterans Affairs Cooperative Study sample: evidence for linkage to 18p11.32 and for racial heterogeneity on chromosomes 6 and 14.

Genome-wide linkage analyses of schizophrenia have identified several regions that may harbor schizophrenia susceptibility genes but, given the complex etiology of the disorder, it is unlikely that all susceptibility regions have been detected. We report results from a genome scan of 166 schizophrenia families collected through the Department of Veterans Affairs Cooperative Studies Program. Our definition of affection status included schizophrenia and schizoaffective disorder, depressed type and we defined families as European American (EA) and African American (AA) based on the probands' and parents' races based on data collected by interviewing the probands. We also assessed evidence for racial heterogeneity in the regions most suggestive of linkage. The maximum LOD score across the genome was 2.96 for chromosome 18, at 0.5 cM in the combined race sample. Both racial groups showed LOD scores greater than 1.0 for chromosome 18. The empirical P-value associated with that LOD score is 0.04 assuming a single genome scan for the combined sample with race narrowly defined, and 0.06 for the combined sample allowing for broad and narrow definitions of race. The empirical P-value of observing a LOD score as large as 2.96 in the combined sample, and of at least 1.0 in each racial group, allowing for narrow and broad racial definitions, is 0.04. Evidence for the second and third largest linkage signals come solely from the AA sample on chromosomes 6 (LOD = 2.11 at 33.2 cM) and 14 (LOD = 2.13 at 51.0). The linkage evidence differed between the AA and EA samples (chromosome 6 P-value = 0.007 and chromosome 14 P-value = 0.004).

Modest evidence for linkage and possible confirmation of association between NOTCH4 and schizophrenia in a large Veterans Affairs Cooperative Study sample.

Wei and Hemmings [2000: Nat Genet 25:376-377], using 80 British parent-offspring trios, identified a number of NOTCH4 variants and haplotypes that showed statistically significant evidence of association to schizophrenia. Specifically, the 10 repeat allele of a (CTG)(n) marker and the 8 repeat allele of a (TAA)(n) marker demonstrated excess transmission to affected individuals; SNP21 and haplotypes SNP2-(CTG)(n) and SNP12-SNP2-(CTG)(n) also showed significant associations. In an attempt to replicate these findings, we tested for linkage and association between the same five markers used by Wei and Hemmings in 166 families collected from a multi-center study conducted by the Department of Veterans Affairs (DVA) Cooperative Study Program (CSP). The families include 392 affected subjects (schizophrenia or schizoaffective disorder, depressed) and 216 affected sibling pairs. The families represent a mix of European Americans (n = 62, 37%), African Americans (n = 60, 36%), and racially mixed or other races (n = 44, 27%). We identified moderate evidence for linkage in the pooled race sample (LOD = 1.25) and found excess transmission of the 8 (P = 0.06) and 13 (P = 0.04) repeat alleles of the (TAA)(n) marker to African American schizophrenic subjects. The 8 and 13 repeat alleles were previously identified to be positively associated with schizophrenia by Wei and Hemmings [2000: Nat Genet 25:376-377] and Sklar et al. [2001: Nat Genet 28:126-128], respectively.

Effect of metanil yellow and malachite green on DNA synthesis in N-nitrosodiethylamine induced preneoplastic rat livers.

Metanil yellow (MY) and malachite green (MG) are textile dyes, which, despite the ban occurs unsrupulously as food colouring agents. Accordingly they constitute a serious public health hazard and are of sufficient environmental concern. We have earlier reported that both MY and MG have tumor enhancing effects on the development of hepatic preneoplastic lesions induced by N-nitrosodiethylamine in rats. In order to understand the possible mechanisms by which MY and MG enhance tumor development, in this study we have tested the effects of MY and MG on DNA synthesis and PCNA expression in preneoplastic hepatic lesions during N-nitrosodiethylamine (DEN) induced hepatocarcinogenesis in male Wistar (WR) rats. Rats were administered 200 ppm DEN through drinking water for a period of one month. Administration of DEN for a period of one month showed an upregulation of cell cycle regulatory proteins namely cyclin D1, CDK4, cyclin E and CDK2. Accordingly, in other experiments, the animals were further administered MY and MG for a period of one month following one month DEN treatment. The effects of MY and MG were monitored on the basis of cell proliferation markers--DNA synthesis and PCNA expression both by immunohistochemical and immunoblotting. Following DEN administration, MY, MG and PB showed stimulation of DNA synthesis and increased PCNA expression when compared with either the corresponding controls or only DEN treated animals. In the present study, enhancing effect of MY, MG and PB on the cell proliferation markers during DEN-induced hepatic preneoplasia in rats was observed.

Enhanced sequential expression of G1/S cyclins during experimental epatocarcinogenesis and tyrosine phosphorylation.

It is now widely accepted that cancer development is a multistage process, starting from the original cell population and ending with a malignant tumor. However, the mechanisms involved in the progressive growth of cells from normalcy to preneoplasia, and from preneoplasia to malignancy are not clear. Because tyrosine phosphorylation and dephosphorylation reactions are known to play critical roles during normal and abnormal cellular growth, we have studied the tyrosine phosphorylation, tyrosine phosphorylated proteins, and protein phosphatases during the sequential development of liver cancer. The present investigation indicated that enhanced tyrosine phosphorylation and tyrosine phosphorylated proteins, with no change in the levels of tyrosine protein phosphatases may contribute to abnormal cellular proliferation during liver carcinogenesis. We have also seen an increase in the expression of proliferating cell nuclear antigen and G1/S cyclins during tumor development.

Examination of genetic linkage of chromosome 15 to schizophrenia in a large Veterans Affairs Cooperative Study sample.

Previous studies have reported genetic linkage evidence for a schizophrenia gene on chromosome 15q. Here, chromosome 15 was examined by genetic linkage analysis using 166 schizophrenia families, each with two or more affected subjects. The families, assembled from multiple centers by the Department of Veterans Affairs Cooperative Study Program, consisted of 392 sampled affected subjects and 216 affected sibling pairs. By DSM-III-R criteria, 360 subjects (91.8%) had a diagnosis of schizophrenia and 32 (8.2%) were classified as schizo-affective disorder, depressed. Participating families had diverse ethnic backgrounds. The largest single group were northern European American families (n = 62, 37%), but a substantial proportion was African American kindreds (n = 60, 36%). The chromosome 15 markers tested were spaced at intervals of approximately 10 cM over the entire chromosome and 2-5 cM for the region surrounding the alpha-7 nicotinic cholinergic receptor subunit gene (CHRNA7). These markers were genotyped and the data analyzed using semiparametric affecteds-only linkage analysis. In the European American families, there was a maximum Z-score of 1.65 between markers D15S165 and D15S1010. These markers are within 1 cM from CHRNA-7, the site previously implicated in schizophrenia. However, there was no evidence for linkage to this region in the African America kindreds.

Department of Veterans Affairs Cooperative Studies Program genetic linkage study of schizophrenia: ascertainment methods and sample description.

To help clarify the genetics of schizophrenia, the Department of Veterans Affairs Cooperative Studies Program has completed data collection for a genetic linkage study of schizophrenia. This article describes the methodological details of the data collection. Subsequent articles will describe the results of our genome scan, which is now in progress. The data collection protocol included the Diagnostic Interview for Genetic Studies, the Family Interview for Genetic Studies, a review of medical records, and the collection of blood for transformation into lymphoblast cell lines. Among relatives of schizophrenic probands, we assessed auditory attention and verbal memory with neuropsychological tests. Among the 166 families ascertained for the study, 143 had a single affected sib-pair, 17 had three affected siblings, one had five affected siblings and five had two sets of affected siblings. There was a total of 216 affected sib-pairs in these families. Using the n-1 rule, these families contain 188 independent affected sib-pairs.

Overexpression of G1/S cyclins and PCNA and their relationship to tyrosine phosphorylation and dephosphorylation during tumor promotion by metanil yellow and malachite green.

Metanil yellow (MY) and Malachite green (MG) are textile dyes, which, despite the ban, occur unscrupulously as food colouring agents. Accordingly they constitute a serious public health hazard and are of sufficient environmental concern. We have earlier reported that both MY and MG have tumor promoting effects on the development of hepatic preneoplastic lesions induced by N-nitrosodiethylamine in rats. In order to understand the possible mechanism(s) by which metanil yellow (MY) and malachite green (MG) promotes liver tumor development, we have studied the tyrosine phosphorylation and protein phosphatases during tumor promotion. We have also investigated the possible overexpression of G1/S cyclins and PCNA during tumor promotion by MY and MG. The present investigation indicates that enhanced tyrosine phosphorylation is associated with no change in levels of tyrosine protein phosphatases. We have also observed an increase in the expression of PCNA and G1/S cyclins during tumor promotion. These factors collectively may contribute to the abnormal cell proliferation during tumor promotion by MY and MG.

Effect of risperidone on QT interval and QT dispersion in the elderly.

Risperidone, a relatively new antipsychotic medication, is widely used in elderly adults and is reported to have fewer side effects than existing antipsychotic drugs. Recent studies, however, have reported prolongation of QT interval and corrected QT interval, both with the prescribed dose of risperidone and with overdose. Because QT dispersion measured on the surface electrocardiogram (ECG) recently has been shown to be a marker of future arrhythmic events and to predict mortality in elderly patients in a variety of clinical situations, this study was conducted to investigate the effect of risperidone on QT dispersion and corrected QT dispersion in a group of elderly patients. These patients also were evaluated for occurrence of sudden death and/or symptoms suggestive of ventricular arrhythmia. Although risperidone prolonged QT interval, it had no significant effect on QT dispersion. Further, during the follow-up period there were no incidences of sudden death or symptoms suggestive of ventricular arrhythmia. These results indicate that risperidone can be used safely in elderly patients, who are often taking several medications, without risk of increased QT dispersion.

Function for Hedgehog genes in zebrafish retinal development.

The hedgehog (hh) genes encode secreted signaling proteins that have important developmental functions in vertebrates and invertebrates. In Drosophila, expression of hh coordinates retinal development by propagating a wave of photoreceptor differentiation across the eye primordium. Here we report that two vertebrate hh genes, sonic hedgehog (shh) and tiggy-winkle hedgehog (twhh), may perform similar functions in the developing zebrafish. Both shh and twhh are expressed in the embryonic zebrafish retinal pigmented epithelium (RPE), initially in a discrete ventral patch which then expands outward in advance of an expanding wave of photoreceptor recruitment in the subjacent neural retina. A gene encoding a receptor for the hedgehog protein, ptc-2, is expressed by retinal neuroepithelial cells. Injection of a cocktail of antisense (alphashh/alphatwhh) oligonucleotides reduces expression of both hh genes in the RPE and slows or arrests the progression of rod and cone photoreceptor differentiation. Zebrafish strains known to have mutations in Hh signaling pathway genes similarly exhibit retardation of photoreceptor differentiation. We propose that hedgehog genes may play a role in propagating photoreceptor differentiation across the developing eye of the zebrafish.