Correlation of the Geriatric Assessment with Overall Survival in Older Patients with Cancer.

AIMS: Global guidelines recommend that all older patients with cancer receiving chemotherapy should undergo a geriatric assessment. However, utilisation of the geriatric assessment is often constrained by its time-intensive nature, which limits its adoption in settings with limited resources and high demand. There is a lack of evidence correlating the results of the geriatric assessment with survival from the Indian subcontinent. Therefore, the aims of the present study were to assess the impact of the geriatric assessment on survival in older Indian patients with cancer and to identify the factors associated with survival in these older patients. MATERIALS AND METHODS: This was an observational study, conducted in the geriatric oncology clinic of the Tata Memorial Hospital (Mumbai, India). Patients aged 60 years and older with cancer who underwent a geriatric assessment were enrolled. We assessed the non-oncological geriatric domains of function and falls, nutrition, comorbidities, cognition, psychology, social support and medications. Patients exhibiting impairment in two or more domains were classified as frail. RESULTS: Between June 2018 and January 2022, we enrolled 897 patients. The median age was 69 (interquartile range 65-73) years. The common malignancies were lung (40.5%), oesophagus (31.9%) and genitourinary (12.1%); 54.6% had metastatic disease. Based on the results of the geriatric assessment, 767 (85.4%) patients were frail. The estimated median overall survival in fit patients was 24.3 (95% confidence interval 18.2-not reached) months, compared with 11.2 (10.1-12.8) months in frail patients (hazard ratio 0.54; 95% confidence interval 0.41-0.72, P < 0.001). This difference in overall survival remained significant after adjusting for age, sex, primary tumour and metastatic status (hazard ratio 0.56; 95% confidence interval 0.41-0.74, P < 0.001). In the patients with a performance status of 0 or 1 (n = 454), 365 (80.4%) were frail; the median overall survival in the performance status 0-1 group was 33.0 months (95% confidence interval 24.31-not reached) in the fit group versus 14.4 months (95% confidence interval 12.25-18.73) in the frail patients (hazard ratio 0.50; 95% confidence interval 0.34-0.74, P = 0.001). In the multivariate analysis, the geriatric assessment domains that were predictive of survival were function (hazard ratio 0.68; 95% confidence interval 0.52-0.88; P = 0.003), nutrition (hazard ratio 0.64; 95% confidence interval 0.48-0.85, P = 0.002) and cognition (hazard ratio 0.67; 95% confidence interval 0.49-0.91, P = 0.011). DISCUSSION: The geriatric assessment is a powerful prognostic tool for survival among older Indian patients with cancer. The geriatric assessment is prognostic even in the cohort of patients thought to be the fittest, i.e. performance status 0 and 1. Our study re-emphasises the critical importance of the geriatric assessment in all older patients planned for cancer-directed therapy.

Study of significance of bone marrow microvessel density in myeloproliferative neoplasms in correlation with CD34 blasts, mast cell count and fibrosis.

Background: Myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell diseases characterised by myeloid cell growth from one or more lineages. Angiogenesis, in contrast to other subtypes, plays a substantial role in the pathophysiology of primary myelofibrosis (PMF). Research expressing the correlation of microvessel density (MVD), blasts, fibrosis and mast cell count in MPN cases are rarely conducted. We aimed to study the significance of MVD in correlation with CD34 blasts, mast cells and fibrosis in bone marrow biopsies of MPN patients. Methods: The current research was a cross sectional study conducted on 66 cases diagnosed as MPN during a six-year period. This comprised of 32 chronic myeloid leukemia (CML), 31 PMF and three essential thrombocythemia (ET) cases. Routine staining along with reticulin stain to look for fibrosis and immunohistochemistry (IHC) using CD34 and mast cell tryptase (MCT) were performed. Results: We found increased MVD in PMF, when compared to CML and ET (p = 0.042). Further, mean MVD was observed to be increased with high blast counts (p = 0.036). On follow up, raised mean MVD was seen in those cases with relapse/deceased as compared to disease-free patients, which was highly significant (p = 0.000). Conclusions: Increased MVD score was mostly associated with PMF subtype among all the MPNs. Further, higher MVD was observed to be associated with increased blast count and poor prognosis. With angiogenesis playing a critical role in disease outcome, we now have drugs to regulate angiogenesis that are supported by contemporary research. However, further studies with larger cohorts to establish the theranostic role of MVD in MPNs is recommended.

Comparative Transcriptome Analysis of Iron and Zinc Deficiency in Maize (Zea mays L.).

Globally, one-third of the population is affected by iron (Fe) and zinc (Zn) deficiency, which is severe in developing and underdeveloped countries where cereal-based diets predominate. The genetic biofortification approach is the most sustainable and one of the cost-effective ways to address Fe and Zn malnutrition. Maize is a major source of nutrition in sub-Saharan Africa, South Asia and Latin America. Understanding systems' biology and the identification of genes involved in Fe and Zn homeostasis facilitate the development of Fe- and Zn-enriched maize. We conducted a genome-wide transcriptome assay in maize inbred SKV616, under -Zn, -Fe and -Fe-Zn stresses. The results revealed the differential expression of several genes related to the mugineic acid pathway, metal transporters, photosynthesis, phytohormone and carbohydrate metabolism. We report here Fe and Zn deficiency-mediated changes in the transcriptome, root length, stomatal conductance, transpiration rate and reduced rate of photosynthesis. Furthermore, the presence of multiple regulatory elements and/or the co-factor nature of Fe and Zn in enzymes indicate their association with the differential expression and opposite regulation of several key gene(s). The differentially expressed candidate genes in the present investigation would help in breeding for Fe and Zn efficient and kernel Fe- and Zn-rich maize cultivars through gene editing, transgenics and molecular breeding.

Extra-anatomical complications of antegrade double-J insertion.

INTRODUCTION: Insertion of a double-J (JJ) stent is a common procedure often carried out in the retrograde route by the urologists and the antegrade route by the radiologists. Reported complications include stent migration, encrustation, and fracture. Extra-anatomic placement of an antegrade JJ stent is a rare but infrequently recognized complication. MATERIALS AND METHODS: We performed a retrospective audit of 165 antegrade JJ stent insertions performed over three consecutive years by a single interventional radiologist. All renal units were hydronephrotic at the time of nephrostomy. All procedures were performed under local anaesthetic with antibiotic prophylaxis. RESULTS: Antegrade stent insertion was carried out simultaneously at the time of nephrostomy in 55 of the 165 cases (33%). The remainder were inserted at a mean of 2 weeks following decompression. In five (3%) patients, who had delayed antegrade stenting following nephrostomy, the procedure was complicated by silent ureteric perforation and an extra-anatomic placement of the stent. These complications had delayed manifestations, which included two retroperitoneal abscesses, a pelvic urinoma, a case each of ureterorectal fistula, and ureterovaginal fistula. Risk factors for ureteric perforation include previous pelvic malignancy, pelvic surgery, pelvic radiation, and a history of ureteric manipulation. CONCLUSION: Antegrade ureteric JJ stenting is a procedure not without complications. Extra-anatomic placement of the antegrade stent is a hitherto the infrequently reported complication but needs a high index of suspicion to be diagnosed. Risk factors for ureteric perforation at the time of stent insertion have to be considered to prevent this potential complication.

Extensive in silico analysis of NF1 splicing defects uncovers determinants for splicing outcome upon 5' splice-site disruption.

We describe 94 pathogenic NF1 gene alterations in a cohort of 97 Austrian neurofibromatosis type 1 patients meeting the NIH criteria. All mutations were fully characterized at the genomic and mRNA levels. Over half of the patients carried novel mutations, and only a quarter carried recurrent minor-lesion mutations at 16 mutational warm spots. The remaining patients carried NF1 microdeletions (7%) and rare recurring mutations. Thirty-six of the mutations (38%) altered pre-mRNA splicing, and fall into five groups: exon skipping resulting from mutations at authentic splice sites (type I), cryptic exon inclusion caused by deep intronic mutations (type II), creation of de novo splice sites causing loss of exonic sequences (type III), activation of cryptic splice sites upon authentic splice-site disruption (type IV), and exonic sequence alterations causing exon skipping (type V). Extensive in silico analyses of 37 NF1 exons and surrounding intronic sequences suggested that the availability of a cryptic splice site combined with a strong natural upstream 3' splice site (3'ss)is the main determinant of cryptic splice-site activation upon 5' splice-site disruption. Furthermore, the exonic sequences downstream of exonic cryptic 5' splice sites (5'ss) resemble intronic more than exonic sequences with respect to exonic splicing enhancer and silencer density, helping to distinguish between exonic cryptic and pseudo 5'ss. This study provides valuable predictors for the splicing pathway used upon 5'ss mutation, and underscores the importance of using RNA-based techniques, together with methods to identify microdeletions and intragenic copy-number changes, for effective and reliable NF1 mutation detection.

Urethral metastasis: an uncommon presentation of a colonic adenocarcinoma.

INTRODUCTION: Metastases to the urethra are a rare clinical entity. To our knowledge there are less than ten case reports described in the literature. In this report, however we describe a case of urethral metastases from a colonic cancer origin where the urethral lesion was the presenting symptom. CASE REPORT: A 69-year-old woman presented with a swelling at the urethral opening. Per vaginal examination revealed a hard tender lesion situated at the external urethral meatus with contact bleeding. Excision biopsy revealed adenocarcinoma. Immunohistochemical staining demonstrated that the tumour cells were strongly suggestive of a metastatic lesion from the colon. Subsequent investigations revealed that the patient did indeed have a sigmoid adenocarcinoma and underwent chemotherapy with a view to anterior resection and pelvic exenteration. DISCUSSION: Metastases to the urethra are rare. Treatment options have to be individualised to the extent of the disease and the symptoms of the patient. Immunohistochemical staining can help to a certain extent to point the direction towards the possible primary lesion. Atypical presentations of urethral lesions should be viewed with suspicion. A biopsy of the lesion is the only way of confirming diagnosis.

The ErbB-4 s80 intracellular domain is a constitutively active tyrosine kinase.

The ErbB-4 receptor tyrosine kinase homo- and heterodimerizes following heregulin binding, which provokes increased levels of tyrosine autophosphorylation. Unique to the ErbB family, ErbB-4 is then proteolytically cleaved by alpha- and gamma-secretase to produce an 80 kDa intracellular domain (s80 ICD) fragment. This fragment is found in both the cytoplasm and nucleus of many normal and cancer cells and can interact with transcription factors in the cytoplasm and nucleus. Since the s80 ICD lacks ectodomain sequences known to play a major role in dimerization of ErbB family members, we asked whether the s80 ICD is an active tyrosine kinase. Here, we demonstrate that the s80 ICD is a constitutively active tyrosine kinase and can form homodimers. The s80 ICD is autophosphorylated in cells and can phosphorylate an exogenous substrate in vitro. Also, the s80 ICD can coassociate and dimers are detected by chemical crosslinking. This is the first example of constitutive kinase activation and dimerization totally within the cytoplasmic domain of an ErbB receptor and suggests that the s80 ICD may function to phosphorylate substrates in the cytoplasm or nucleus.

Tinospora cordifolia induces enzymes of carcinogen/drug metabolism and antioxidant system, and inhibits lipid peroxidation in mice.

The present study is an effort to identify a potent chemopreventive agent against various diseases (including cancer) in which oxidative stress plays an important causative role. Here, we investigated the effect of a hydroalcoholic (80% ethanol: 20% distilled water) extract of aerial roots of Tinospora cordifolia (50 and 100mg/kg body wt./day for 2 weeks) on carcinogen/drug metabolizing phase-I and phase-II enzymes, antioxidant enzymes, glutathione (GSH) content, lactate dehydrogenase and lipid peroxidation in liver of 8-week-old Swiss albino mice. The modulatory effect of the extract was also examined on extrahepatic organs, i.e., lung, kidney and forestomach, for the activities of GSH S-transferase (GST), DT-diaphorase (DTD), superoxide dismutase (SOD) and catalase. Significant increases in the levels of acid-soluble sulfhydryl (-SH) and cytochrome P(450) contents, and enzyme activities of cytochrome P(450) reductase, cytochrome b(5) reductase, GST, DTD, SOD, catalase, GSH peroxidase (GPX) and GSH reductase (GR) were observed in the liver. Both treated groups showed decreased malondialdehyde (MDA) formation. In lung SOD, catalase and GST; in kidney SOD and catalase; and in forestomach SOD, DTD and GST showed significant increase at both dose levels of treatment. BHA (0.75%, w/w in diet), a pure antioxidant compound, was used as a positive control. This group showed increase in hepatic levels of GSH content, cytochrome b(5), DTD, GST, GR and catalase, whereas MDA formation was inhibited significantly. In the BHA-treated group, the lung and kidney showed increased levels of catalase, DTD and GST, whereas SOD was significantly increased in the kidney and forestomach; the latter also showed an increase in the activities of DTD and GST. The enhanced GSH level and enzyme activities involved in xenobiotic metabolism and maintaining antioxidant status of cells are suggestive of a chemopreventive efficacy of T. cordifolia against chemotoxicity, including carcinogenicity, which warrants further investigation of active principle (s) present in the extract responsible for the observed effects employing various carcinogenesis models.

Cerebrospinal fluid adenosine deaminase levels and adverse neurological outcome in pediatric tuberculous meningitis.

BACKGROUND: There is a lack of data on the prognostic significance of changes in cerebrospinal fluid (CSF) parameters in tuberculous meningitis. Our objective was to determine whether changes in CSF parameters are associated with poor neurological outcome in tuberculous meningitis. PATIENTS AND METHODS: We conducted a prospective cohort study on children admitted with a diagnosis of tuberculous meningitis to Government General Hospital in Kakinada, India. On admission, CSF parameters including cell count with fraction of lymphocytes and neutrophil leukocytes, glucose, protein, lactic dehydrogenase (LDH), and adenosine deaminase (ADA) levels were measured. We compared levels in children with and without adverse neurological outcome. RESULTS: A total of 26 children was enrolled over a 2-year period. Ten had an adverse neurological outcome. Six had permanent neurological deficits (four hemiplegia and two cranial nerve palsies), two a hydrocephalus and two died. There was no significant (p>0.05) difference in age, gender and in CSF parameters, including cell count, lymphocyte and neutrophil leukocyte fraction, glucose, protein, and LDH levels between patients with and without adverse neurological outcome. Patients with adverse outcome had with a mean (SD) of 17.1 (3.2) IU/l a significantly higher ADA level than patients without, who had a mean (SD) level of 11.3 (2.7) IU/l (p<0.001, t-test). CONCLUSION: Adverse neurological outcome in childhood tuberculous meningitis is associated with increased cerebrospinal fluid adenosine deaminase levels.

Chemopreventive effects of mustard (Brassica compestris) on chemically induced tumorigenesis in murine forestomach and uterine cervix.

As there is a strong correlation between diet and cancer, the dietary constituents that inhibit mutagenesis and/or carcinogenesis are of paramount importance for the prevention of human cancer. In the present study, cancer chemopreventive potentials of different doses of mustard (Brassica compestris) seed mixed diets were evaluated against benzo(a)pyrene [B(a)P]-induced forestomach tumorigenesis and 3-methylcholantrene (MCA)-induced uterine cervix tumorigenesis. Results showed a significant inhibition of stomach tumour burden (tumours/ mouse) by mustard seeds. Tumour burden was 7.08 +/- 2.47 in the B(a)P-treated control group, whereas it was reduced to 1.36 +/- 1.12 (P<0.001) by the 2.5% dose and 1.18 +/- 0.87 (P<0.001) by the 5% dose of mustard seeds. The cervical carcinoma incidence, as compared to MCA-treated control group (73.33%), was reduced to nil (P<0.05) by the 5% diet of mustard seeds and to 13.33% (P<0.05) by the 7.5% diet of mustard seeds. The effect of the 2.5% and 5% mustard seed mixed diets was also examined on the antioxidant enzymes, glutathione content, lactate dehydrogenase (LDH) and lipid peroxidation in the liver of Swiss albino mice. The glutathione-S-transferase-specific activity was increased (P<0.05) by the 2.5% dose, whereas there was no significant change in the activity of DT-diaphorase. In antioxidant systems, significant elevation of the specific activities of superoxide dismutase and catalase was observed with both doses of mustard seeds (P<0.05). The level of reduced glutathione (GSH) measured as nonprotein sulphydryl content was elevated by the 2.5% dose of mustard seeds only (P<0.05). Lipid peroxidation measured as formation of thiobarbituric acid reactive substances production showed significant inhibition (P<0.05) by the 5% dose of mustard seed mixed diet. LDH activity was decreased significantly (P<0.05) by both the doses. The results strongly suggest the cancer chemopreventive potentials of mustard seeds and their ability to enhance the antioxidant defence system and in turn provide protection against the toxic effects of carcinogens. It is likely that the use of mustard seeds in the diet may contribute to reducing the risk of cancer incidence and burden in the human population.

Oxidative stress in tumour-bearing fore-stomach and distant normal organs of Swiss albino mice.

Antioxidant status in the tumour-bearing fore-stomach and distant normal organs (liver, spleen, kidney and heart) was investigated in Swiss albino mice. In addition, the cytochrome P450 (cyt P450) system was also examined in the liver. Benzo(a)pyrene [B(a)P] (8 doses of 1 mg/0.1 ml) was administered twice a week for 4 weeks to develop fore-stomach tumour. The animals were sacrificed at the end of 140 days. The specific activities of catalase (CAT), DT-diaphorase (DTD) and glutathione-S-transferase (GST) were found decreased, and the level of reduced glutathione (GSH) and the specific activity of lactate dehydrogenase (LDH) increased in the tumour-bearing fore-stomach; however, no change was observed in superoxide dismutase (SOD) activity. The specific activities of antioxidant enzymes, and levels of GSH were also altered in the normal organs, depending upon the type of tissue. In addition, the contents of cyt P450 and cyt b5, and the activity of NADPH cyt P450 reductase were significantly decreased in the liver. The results suggest increased oxidative stress in the tumour, and disturbance in the cooperative antioxidant functions in the distant normal organs. Inhibition of cyt P450 system reflected the possible adverse effect on drug metabolism function of the liver. Since, the antioxidant potential and the drug metabolism function were altered, the findings may have relevance to the radiation and chemotherapy of cancer.

Chemopreventive potential of Triphala (a composite Indian drug) on benzo(a)pyrene induced forestomach tumorigenesis in murine tumor model system.

The present work is probably the first report on cancer chemopreventive potential of Triphala, a combination of fruit powder of three different plants namely Terminalia chebula, Terminalia belerica and Emblica officinalis. Triphala is a popular formulation of the Ayurvedic system of medicine. Our findings have shown that Triphala in diet has significantly reduced the benzo(a)pyrene [B(a)P] induced forestomach papillomagenesis in mice. In the short term treatment groups, the tumor incidences were lowered to 77.77% by both doses of Triphala mixed diet. In the case of long-term treatment the tumor incidences were reduced to 66.66% and 62.50% respectively by 2.5% and 5% triphala containing diet. Tumor burden was 7.27 +/- 1.16 in the B(a)P treated control group, whereas it reduced to 3.00 +/- 0.82 (p < 0.005) by 2.5% dose and 2.33 +/- 1.03 (p < 0.001) by 5% dose of Triphala. In long-term studies the tumor burden was reduced to 2.17 +/- 0.75 (p < 0.001) and 2.00 +/- 0.71 (p < 0.001) by 2.5% and 5% diet of Triphala, respectively. It was important to observe that Triphala was more effective in reducing tumor incidences compared to its individual constituents. Triphala also significantly increased the antioxidant status of animals which might have contributed to the chemoprevention. It was inferred that the concomitant use of multiple agents seemed to have a high degree of chemoprevention potential.

Genetic susceptibility to tardive dyskinesia in chronic schizophrenia subjects: I. Association of CYP1A2 gene polymorphism.

Understanding the pharmacogenetic basis of developing iatrogenic disorders such as Tardive Dyskinesia (TD) has significant clinical implications. CYP1A2, an inducible gene of the cytochrome P450 family of genes, has been suggested to contribute to the metabolism of typical antipsychotics in subjects with schizophrenia on long-term treatment, and has been considered as a potential candidate gene for development of TD. In this study, we have investigated the significance of CYP1A2 gene polymorphisms in TD susceptibility among chronic schizophrenia sufferers (n=335) from north India. TD was diagnosed in approximately 29% (96/335) of these subjects. Of the 96 TD positives, 28 had been treated with typical antipsychotics alone, 23 with atypical antipsychotics alone and 45 patients had received both classes of drugs during the course of their illness. Out of the six SNPs tested, CYP1A2(*)2, (*)4, (*)5, (*)6 were found to be monomorphic in our population. CYP1A2(*)1C and CYP1A2(*)1F were polymorphic and were analyzed in the study sample. Since these two allelic variants lead to lesser inducibility among smokers, the smoking status of TD patients was also considered for all subsequent analysis. We observed increased severity of TD among TD-Y smokers, who were carriers of CYP1A2(*)1C (G>A) variant allele and had received only typical antipsychotic drugs (F(1,8)=9.203, P=0.016). No significant association of CYP1A2(*)1F with TD was observed irrespective of the class of drug they received or their smoking status. However, we found a significant association of CYP1A2(*)1F with schizophrenia (chi(2)=6.572, df=2, P=0.037).

Multimodality tumor control and living donor transplantation for unresectable hepatocellular carcinoma.

Liver transplantation (LT) is an acceptable mode of treatment for selected patients with unresectable hepatocellular carcinoma (HCC). However, due to the scarcity of cadaveric donor organs, it is considered desirable for patients to opt for living donor liver transplantation (LDLT) or, for those not being transplanted soon, to have some form of tumor control therapy. Such an approach in our program is analyzed and reported. At our institution, 42 LTs were performed between October 1999 and April 2003. Of these, 18 recipients (15 men, 3 women) had 27 HCC. The average number and size of HCC was 1.59 (1 to 4) and 2.31 (0.2 to 6.5) cm, respectively. Thirteen (72%) patients were transplanted primarily for the HCC, whereas five (28%) others were incidental HCC cases. Seven patients (5 LRLT, 2 cadaveric LT) were transplanted soon after listing, and thus did not require tumor control therapy. Six patients waited for 11 (6 to 19) months before LT. Three patients underwent microwave coagulation therapy, and one had additional alcohol injections. One patient received the novel PIAF (cisplatin, interferon, adriamycin, and 5-FU) chemotherapy regimen followed by selective internal irradiation (SIR) treatment. One patient received conformal radiation therapy and another received SIR treatment before LT. Besides 2 postoperative deaths, the remaining 16 patients have been well, with a mean follow-up of 20.4 (3.6 to 41.2) months. In conclusion, for patients with unresectable HCC, in areas with poor cadaveric donor rate, living donation should be the first option. If a suitable live donor is not available, aggressive multimodality therapy is recommended while waiting for cadaveric LT.

Cancer preventive potential of Momordica charantia L. against benzo(a)pyrene induced fore-stomach tumourigenesis in murine model system.

Bitter melon ( Momordica charantia Linnaeus) fruit extract was tested against 3,4 benzo(a)pyrene [B(a)P] induced forestomach papillomagenesis in Swiss albino mice. Extract of M. charantia in two concentrations, 2.5 and 5% of standard mice feed was used for the short-term and long-term studies. A significant decrease in tumour burden was observed in short and long-term treatment. Also, total tumour incidence reduced to 83.33% with 2.5% dose and 90.90% with 5% dose in short term treatment, while in long-term treatment tumor incidence decreased to 76.92% with 2.5% dose and 69.23% with 5% dose of M. charantia. The possible mechanism involved in the cancer chemoprevention has also been discussed.

Chemomodulatory action of Brassica compestris (var sarason) on hepatic carcinogen metabolizing enzymes, antioxidant profiles and lipid peroxidation.

The effect of two different doses (400 and 800 mg/kg body wt/day for 15 days) of a 95% ethanolic extract of the seeds of Brassica compestris (var sarason) was examined on carcinogen metabolizing phase-I and phase-II enzymes,antioxidant enzymes and glutathione content and lipid peroxidation in the liver of Swiss albino mice. Positive control mice were treated with butylated hydroxyanisole (BHA). Significant elevation in the levels of cytochrome p450 (p<0,.05), cytochrome b5 (p < 0.05) glutathione s-transferase (p<0.01), DT-diaphorase (p<0.05), superoxide dismutase (p<0.01), catalase (p < 0.001) and reduced glutathione (p<0.001) was noted in the group treated with 800 mg/kg body wt. of Brassica extract in comparison with the negative control group. Brassica compestris acted as a bifunctional inducer since it induced both phase - I and phase - H enzyme systems. Since phase-I and phase-II enzymes are considered to be reliable markers for evaluating the chemoprevention efficacy of particular test materials,these findings are suggestive of potential chemopreventive roles for Brassica seed extract.