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.

AKT is indispensable for coordinating Par-4/JNK cross talk in p21 downmodulation during ER stress.

The double-edged role of p21 to command survival and apoptosis is emerging. The current investigation highlights ER stress-mediated JNK activation that plausibly triggers cell death by attenuating endogenous p21 level. Here, we demonstrated that ER stress activator 3-AWA diminishes the p21 levels in cancer cells by averting the senescent phenotype to commence G2/M arrest. In essence, the deceleration in p21 level occurs through ER stress/JNK/Caspase-3 axis via activation/induction of proapoptotic Par-4 and inhibition of AKT. The molecular dynamics studies identified important interactions, which may be responsible for the AKT inhibition and efficacy of 3-AWA towards AKT binding pocket. Interestingly, the p21 deceleration was rescued by incubating the cells with 3-AWA in the presence of an ER stress inhibitor, Salubrinal. Furthermore, we demonstrated that p21 expression decreases solitarily in Par-4+/+ MEFs; albeit, ER stress-induced JNK activation was observed in both Par-4+/+ and Par-4-/- MEFs. Par-4 knockdown or overexpression studies established that ectopic Par-4 along with ER stress are not sufficient to downregulate p21 in PC-3 cells but are adequate for DU-145 cells and that the ER stress inflicted activation of JNK, inhibition of AKT and Par-4 induction are all crucial to p21 downmodulation by 3-AWA. By using isogenic cell lines, such as HCT-116 p53+/+ and HCT-116 p53-/-, we found that deceleration in p21 expression due to ER stress is p53 independent. Moreover, in orthotopic carcinogen-induced rat colorectal carcinoma model, we found that 3-AWA inhibits colorectal tumor growth and formation of colorectal polyps at a tolerable dose, similar to the first-line drug for colorectal cancer-5-fluorouracil.

Reasons why patients fail screening in Indian breast cancer trials.

INTRODUCTION: An increased number of screen failure patients in a clinical trial increases time and cost required for the recruitment. Assessment of reasons for screen failure can help reduce screen failure rates and improve recruitment. MATERIALS AND METHODS: We collected retrospective data of human epidermal growth factor receptor (HER2) positive Indian breast cancer patients, who failed screening for phase 3 clinical trials and ascertained their reasons for screen failure from screening logs. Statistical comparison was done to ascertain if there are any differences between private and public sites. RESULTS: Of 727 patients screened at 14 sites, 408 (56.1%) failed screening. The data on the specific reasons for screen failures was not available at one of the public sites (38 screen failures out of 83 screened patients). Hence, after excluding that site, further analysis is based on 644 patients, of which 370 failed screening. Of these, 296 (80%) screen failure patients did not meet selection criteria. The majority -266 were HER2 negative. Among logistical issues, 39 patients had inadequate breast tissue sample. Sixteen patients withdrew their consent at private sites as compared to six at public sites. The difference between private and public sites for the above three reasons was statistically significant. CONCLUSION: Use of prescreening logs to reduce the number of patients not meeting selection criteria and protocol logistics, and patient counseling to reduce consent withdrawals could be used to reduce screen failure rate.

PAX genes in childhood oncogenesis: developmental biology gone awry?

Childhood solid tumors often arise from embryonal-like cells, which are distinct from the epithelial cancers observed in adults, and etiologically can be considered as 'developmental patterning gone awry'. Paired-box (PAX) genes encode a family of evolutionarily conserved transcription factors that are important regulators of cell lineage specification, migration and tissue patterning. PAX loss-of-function mutations are well known to cause potent developmental phenotypes in animal models and underlie genetic disease in humans, whereas dysregulation and/or genetic modification of PAX genes have been shown to function as critical triggers for human tumorigenesis. Consequently, exploring PAX-related pathobiology generates insights into both normal developmental biology and key molecular mechanisms that underlie pediatric cancer, which are the topics of this review.

Is stenting required before retrograde intrarenal surgery with access sheath.

BACKGROUND: Flexible ureterorenoscopies continue to assume an increasing role in the armamentarium of the endourologist. In many centers around the world, prior stenting is carried out before retrograde intrarenal surgery (RIRS) to passively dilate the ureter, which facilitates passage of a flexible ureteroscope with or without an access sheath. In our series, the first stage of passive dilatation with prior stenting was totally avoided without compromising the success of the procedure. MATERIALS AND METHODS: From January 2004 to December 2007, 54 patients with 55 renal units underwent RIRS. The patients were between 28 and 65 years old. All patients had renal stones ranging in size from 8 mm to 22 mm. The mean serum creatinine level was 1.1 mg%. The lower ureter was dilated under 'C - arm' fluoroscopy guidance up to 14 FR. An access sheath of 10/12 Fr was passed over the working guide wire. RIRS (7.5/9.3 Fr) was introduced into the access sheath. The stones were fragmented using a holmium laser. The mean operating time was 85 mins (45-130 mins). RESULTS: In 52 out of 55 renal units (94.5%), a flexible ureteroscope could be passed successfully into the kidney through an access sheath. In 3 of the cases (5.4%), the lower ureter could not be dilated. In these patients, the procedure was staged after passing a 6/26 JJ stent. An X-ray KUB was done at the 3-month follow-up visit. A total of 50 renal units (94.3%) were stone free at the 3-month follow-up visit. CONCLUSION: In a majority of the cases, RIRS could be accomplished successfully during the first sitting. Single stage RIRS did not alter the subsequent stone clearance or increase the incidence of morbidity or complications.

Outcome of lupus nephritis in Indian children.

We report the clinicopathological features, treatment and outcome of 54 Indian children (14 boys) with biopsy-proven lupus nephritis followed over a 10-year period. The mean age (SD) at onset of disease was 9.6 +/- 2.6 (range 2.5-14.4) years. Twenty-six (48.1%) patients had class IV nephritis, 7 (13.0%) had class V, whereas class I, II and III nephritis were present in 3 (5.6%), 10 (18.5%) and 6 (11.1%) patients, respectively. Hypertension, haematuria and nephrotic range proteinuria were present in 30 (55.6%), 31 (57.4%) and 28 (51.8%) patients, respectively. Compared with all the other classes combined, there were more boys among patients with class IV nephritis, and hypertension, haematuria, nephrotic syndrome and decreased glomerular filtration rate at presentation were more common. The mean duration of follow-up was 3.1 +/- 2.9 years (median 2.5, range 0.2-10.3 years). Of the 39 patients who were followed-up for at least 1 year, 33 (84.6%) were in complete or partial remission, whereas six (15.4%) had no response to therapy. The incidence of serious infection was 1.5 episodes per 10 patient-years. Nine patients died, of whom four had serious infections or septicaemia, and three developed end-stage renal failure (ESRF). The patient survival rate at 3 years and at last follow-up visit was 88% and 83.3%, respectively, whereas the renal survival rates (without ESRF) were 92% and 94.4% respectively. Cox regression analysis showed no relation of gender, age of onset, presence of hypertension, haematuria and proteinuria, estimated glomerular filtration rate, renal histology and response to therapy to the outcome of death or ESRF. We found lower patient survival rate as compared with data from the developed countries but similar to that seen in developing countries. Serious infections were an important cause of mortality besides renal failure.

Encephalocraniocutaneous lipomatosis: a rare neurocutaneous syndrome.

Encephalocraniocutaneous lipomatosis is a congenital hamartomatous disorder with unique ocular, cutaneous and neurological features. A 13-year-old boy presented with history of mental retardation and delayed developmental milestones. Bulbar conjunctiva of left eye showed hypertrophy with a soft reddish limbal nodule encroaching on the cornea. Dermatological examination showed multiple patches of alopecia, soft papules in the left perioral and periorbital areas, soft masses over the right axilla, trunk and in the lumbosacral region suggestive of lipomas. The CT scan of the brain revealed well-defined, hypodense lesions in both the cerebellar hemispheres suggestive of lipomas. The constellation of these findings led us to a diagnosis of encephalocraniocutaneous lipomatosis.

Treatment of pemphigus with intravenous pulse cyclophosphamide.

BACKGROUND: The complications associated with the use of systemic corticosteroid therapy have prompted a search for alternative agents. However, these agents are themselves associated with increased risk of myelosuppression or malignancy. METHODS: The present study included twenty patients with recalcitrant pemphigus or steroid induced side effects who were treated with intravenous cyclophosphamide pulse therapy. RESULTS: Out of 18 patients who completed the study, 14 showed good to excellent response. Thirteen were able to decrease their daily dose of steroid to 5-10 mg prednisolone while one could stop steroids altogether. Most patients did not experience serious side effects. DISCUSSION: Thus intravenous pulse cyclophosphamide is a promising form of therapy in pemphigus either recalcitrant or intolerant to steroid therapy. The decreased total cumulative dose of cyclophosphamide with intravenous therapy as compared to oral therapy may reduce the incidence of secondary malignancy.

Attenuation of the effect of progesterone and 4'-chlordiazepam on stress-induced immune responses by bicuculline.

The present study investigates the effect of progesterone, a pregnane precursor of neurosteroids, and 4'-chlordiazepam (4'-CD), a specific ligand for mitochondrial diazepam binding inhibitor receptor (MDR) involved in neurosteroidogenesis, on restraint stress (RS)-induced modulation of humoral and cell-mediated immune responses. RS produced a significant reduction in anti-sheep red blood cells (SRBC) antibody titre, a measure of humoral immune response, and % leucocyte migration inhibition (LMI) and foot-pad thickness test, measures of cell-mediated immune responses. These effects of RS on immune responses were effectively blocked by pretreating the animals with progesterone (10 mg/kg, sc) or 4'-CD (0.5 mg/kg, sc) administered just before subjecting the animal to RS. The effect of both progesterone and 4'-CD on RS-induced immune modulation was significantly attenuated by bicuculline (2 mg/kg, ip) but not by flumazenil (10 mg/kg, ip). Unlike its effect on RS-induced immune responsiveness, progesterone (5, 10 mg/kg, sc) when administered to non-stressed animals produced a significant suppression of both humoral and cell-mediated immune responses which was not reversed by bicuculline. However, 4'-CD failed to modulate immune response in naive non-stressed animals. These results suggest that progesterone and 4'-CD affect stress-induced immune responses by modulating GABA-ergic mechanism. However, GABA-A receptor system does not appear to be involved in progesterone-induced immunosuppression in nonstressed animals.

Purification and cDNA cloning of maize Poly(ADP)-ribose polymerase.

Poly(ADP)-ribose polymerase (PADPRP) has been purified to apparent homogeneity from suspension cultures of the maize (Zea mays) callus line. The purified enzyme is a single polypeptide of approximately 115 kD, which appears to dimerize through an S-S linkage. The catalytic properties of the maize enzyme are very similar to those of its animal counterpart. The amino acid sequences of three tryptic peptides were obtained by microsequencing. Antibodies raised against peptides from maize PADPRP cross-reacted specifically with the maize enzyme but not with the enzyme from human cells, and vice versa. We have also characterized a 3.45-kb expressed-sequence-tag clone that contains a full-length cDNA for maize PADPRP. An open reading frame of 2943 bp within this clone encodes a protein of 980 amino acids. The deduced amino acid sequence of the maize PADPRP shows 40% to 42% identity and about 50% similarity to the known vertebrate PADPRP sequences. All important features of the modular structure of the PADPRP molecule, such as two zinc fingers, a putative nuclear localization signal, the automodification domain, and the NAD+-binding domain, are conserved in the maize enzyme. Northern-blot analysis indicated that the cDNA probe hybridizes to a message of about 4 kb.

Modulation of transcription of rRNA genes by rapamycin.

Lymphosarcoma P1798 cells undergo growth arrest when exponentially growing cultures are exposed to 1 micrograms/ml of Rapamycin (Rapa). This growth arrest is accompanied by inhibition of RNA biosynthesis as measured by incorporation of 3H-uridine into the newly synthesized RNA. Approximately 50% inhibition of 3H-uridine incorporation was observed, upon exposure of P1798 cells to 1 microgram/ml Rapa for 24 h. Run-on transcription experiments using nuclei from Rapa-treated cells indicated a dose-dependent inhibition of transcription or rRNA genes. Cells were relieved from this inhibition of transcription when Rapa was removed from the medium. Under similar conditions, transcriptions of U3 snRNA genes remained unaffected. Cytoplasmic extracts prepared from P1798 cells treated with 1 microgram/ml Rapa for 24 h failed to support transcription from cloned mouse rRNA promoter. This treatment does not affect the RNA polymerase I activity of P1798 cells. Addition of a highly purified murine transcription initiation factor specific for RNA polymerase I reconstitutes the extracts from Rapa-treated P1798 cells. Our data indicate that this new immunosuppressive agent modulates transcription of rRNA genes via regulation of specific transcription factor function.

Cyclosporine A inhibits the activity of a TATA box-binding protein that is required for transcription from the adenovirus major late promoter.

Nuclear extracts from P1798 lymphoma cells support transcription from the adenovirus major late promotor (AdMLP) and the human histone H4 promoter. Nuclear extracts prepared from P1798 cells treated with 1 microgram/ml cyclosporine A for 24 h fail to support transcription from AdMLP, whereas transcription from the histone H4 promoter is unimpaired. Both control and cyclosporine-treated extracts contain proteins that interact with synthetic deoxyoligonucleotides that correspond to the CAAT box, TATA box, and upstream stimulatory element of AdMLP. Cyclosporine had no discernible qualitative or quantitative effect upon such DNA-protein interactions, as observed by gel mobility shift assays. Analysis of 5' deletion mutants of AdMLP indicates that deletion of sequences upstream of the TATA box reduces AdMLP transcription by only 50%. This observation suggests that cyclosporine A, which inhibits AdMLP transcription by > 90%, is unlikely to act through changes in the amount or activity of upstream activators such as upstream stimulatory factor- or CAAT box-binding proteins. On the other hand, deletion of TATA box sequences between -50 and -11 base pairs virtually eliminates transcription from AdMLP in vitro. A partially purified TFIID fraction was obtained from control P1798 nuclear extracts. The TFIID fraction reconstitutes transcription from AdMLP when added to extracts from cyclosporine A-treated cells. Recombinant TATA box-binding protein also reconstitutes transcription from AdMLP in cyclosporine A-treated extracts. These results are consistent with the hypothesis that cyclosporine A regulates the activity of a subset of general transcription factors which are required for initiation from some promoters (such as AdMLP) but not from others (such as histone H4).

Pseudoachondroplastic dysplasia.

Pseudoachondroplasia is a heterogeneous inherited skeletal dysplasia in which dwarfism is a major feature. We report here a case of a 7 year old girl misdiagnosed as rickets, who presented with short stature, lordosis, genu varum and flexion deformities at both the elbows. Skeletal survey revealed epiphyseal and metaphyseal irregularities. A review of literature is also presented.

Copurification of RNA polymerase I and the glucocorticoid-regulated transcription factor IC.

A simple and rapid method to copurify RNA polymerase I and the glucocorticoid-regulated transcription factor, TFIC, is described. This protocol results in 1262-fold purification and 15% total recovery of the enzyme and factors needed to support faithful transcription in vitro from cloned mouse rRNA gene (rDNA). Using this method, proteins involved in rDNA transcription were purified from exponentially growing lymphosarcoma P1798 cells as well as cells treated with 0.1 microM dexamethasone. A combination of transcription and reconstitution assays using G-free cassette-containing constructs and polyacrylamide gel electrophoretic analysis upon silver staining were used to detect TFIC activity as well as the characteristic TFIC polypeptides in control and dexamethasone-treated cell extracts. Treatment of P1798 cells with 0.1 microM dexamethasone for 24 h results in an over 95% reduction of TFIC activity, but no significant differences in the amount of TFIC polypeptides in the final product purified from control and glucocorticoid-treated cells could be detected. Our data indicate that glucocorticoid regulation of transcription of rDNA is mediated via post-translational modulation of the activity of TFIC.

MURCS association--a review of 7 cases.

MURCS association (Mullerian hypoplasia/aplasia, renal agenesis and cervicothoracic somite dysplasia) is emerging as the second most frequent cause of primary amenorrhoea after Turner syndrome. Seven cases have been described and analysed. All cases had absence of uterus and tubes 85% had cervical spine abnormalities such as vertebral fusion, hypoplasia of vertebrae or butterfly vertebrae and short stature and 28% had renal agenesis or ectopy. The latter finding is in contrast to the reports in world literature where the frequency of renal agenesis is higher. There was no familial incidence in these seven cases lending credence to the belief that the association is essentially sporadic.

Glucocorticoid regulation of c-myc promoter utilization in P1798 T-lymphoma cells.

Glucocorticoids rapidly inhibit the expression of c-myc mRNA in P1798 lymphoma cells. Statistically significant decreases can be observed within 5-10 min after the addition of glucocorticoids. Although transcription of c-myc decreases within a few hours after dexamethasone is added to P1798 cell cultures, nuclear run-on transcription cannot be used to demonstrate that the very early changes in mRNA abundance reflect corresponding changes in transcriptional activity. An RNase protection assay has been used to measure the abundance and rates of turnover of the two major c-myc transcripts arising from the P1 and P2 initiation sites. The relative rates of synthesis of the c-myc mRNAs (i.e. transcription) can be calculated from such data. The abundance of the P2 transcript exceeds that of P1 mRNA by 3- to 4-fold in midlog phase cells. The turnover rates of the two c-myc mRNAs are essentially identical (0.02 min-1), indicating that the P2 promoter is 3-4 times stronger than P1. This was confirmed by measuring the relative transcriptional activities of templates containing the individual c-myc promoters in P1798 extracts in vitro. The expression of P1 and P2 mRNAs decreases at different rates in glucocorticoid-treated cells. A 50% decrease in the abundance of P1 mRNA occurs within 1 h after the addition of dexamethasone. Expression of P2 mRNA is reduced by 50% within 4 h. However, the turnover rates of the major c-myc transcripts do not change in glucocorticoid-treated cells. The t1/2 values of P1 and P2 mRNAs are about 25-30 min and not different from the turnover rates measured in control cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucocorticoid regulation of rRNA synthesis.

Glucocorticoids inhibit transcription of the genes encoding rRNA (rDNA) in P1798 lymphoma cells. This is due to a decrease in the amount or activity of a transcription factor, called TFIC. TFIC has been purified to apparent homogeneity and the properties of this protein have been investigated in detail. TFIC is tightly associated with RNA polymerase I. The data indicate that TFIC is a bona fide initiation factor that is required for formation of the first phosphodiester bond of nascent pre-rRNA. Extracts from dexamethasone-treated cells are devoid of this factor and cannot form initiated complexes in vitro.

Glucocorticoid inhibition of transcription from adenovirus major late promoter.

Glucocorticoids inhibit proliferation of lymphosarcoma P1798 cells in culture. This is accompanied by inhibition of expression of class I as well as some class II genes. We have used the technique of transcription in vitro and the adenovirus major late promoter (AdMLP) to investigate molecular mechanisms of glucocorticoid inhibition of transcription of class II genes. Nuclear extracts from exponentially growing P1798 cells support faithful transcription from AdMLP. However, treatment of P1798 cells with 10(-7) M dexamethasone (a synthetic glucocorticoid) for 24 h impairs the ability of nuclear extracts prepared from such cells to support faithful transcription from AdMLP. Transcription from the human histone H4 gene promoter is unaffected by dexamethasone treatment. Gel mobility shift assays using synthetic oligonucleotide probe indicate no difference in the CAAT box binding activity of control and dexamethasone-treated cell extracts. Similarly, dexamethasone treatment does not affect the upstream stimulatory factor activity of P1798 cells. Furthermore, up-stream stimulatory factor purified from control cell extracts is unable to reconstitute the glucocorticoid-treated cell extracts for transcription from AdMLP. Fractionation of the control cell extracts on Sepharose S yields two protein fractions, neither of which supports transcription from AdMLP. However, one of these fractions, S-II, confers upon glucocorticoid-treated cell extracts the ability to support faithful transcription from AdMLP. We conclude that glucocorticoids regulate the transcription from AdMLP by regulating the activity of a trans-acting transcription factor which copurifies with fraction S-II.

Hormonal regulation of transcription of rDNA. Purification and characterization of the hormone-regulated transcription factor IC.

Glucocorticoids reversibly inhibit transcription of ribosomal RNA genes in murine lymphosarcoma P1798 cells in culture. Inhibition of rDNA transcription is due to reduction in the amount or activity of an RNA polymerase I transcription factor called transcription factor IC (TFIC). TFIC has been purified over 100,000-fold. The highly purified preparation contains neither RNA polymerase I activity nor any of the conventional RNA polymerase I subunits. TFIC activity co-purifies with three polypeptides of approximately 55, 50, and 42 kDa molecular mass. These polypeptides are present in a stoichiometric ration of 1:1:1.

Hormonal regulation of transcription of rDNA. Formation of initiated complexes by RNA polymerase I in vitro.

This paper describes studies of initiation of transcription by RNA polymerase I in vitro. The protocols take advantage of the observation that active transcription complexes precipitate when incubated with S100 extracts. The pellets contain less than 5% of the protein present in unfractionated extracts and are stable to centrifugal washing. This permits rapid manipulation of the reaction conditions and facilitates kinetic studies of aspects of the initiation reaction. An initiated complex has been defined which forms rapidly at 30 degrees C and is associated with formation of the first phosphodiester bond of nascent rRNA. Once formed, initiated complexes are capable of elongation in the presence of heparin or KCl in concentrations sufficient to preclude subsequent initiation. One can therefore estimate the number of initiated complexes formed in a given reaction by measuring the number of full length transcripts recovered in a KCl or heparin-start reaction. The number of such complexes formed correlates well with the formation of a presumptive initiator trinucleotide ApCpU.