Overall survival in patients with endometrial cancer treated with dostarlimab plus carboplatin-paclitaxel in the randomized ENGOT-EN6/GOG-3031/RUBY trial.

BACKGROUND: Part 1 of the RUBY trial (NCT03981796) evaluated dostarlimab plus carboplatin-paclitaxel compared with placebo plus carboplatin-paclitaxel in patients with primary advanced or recurrent endometrial cancer (EC). At the first interim analysis, the trial met one of its dual primary endpoints with statistically significant progression-free survival benefits in the mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) and overall populations. Overall survival (OS) results are reported from the second interim analysis. PATIENTS AND METHODS: RUBY is a phase III, global, double-blind, randomized, placebo-controlled trial. Part 1 of RUBY enrolled eligible patients with primary advanced stage III or IV or first recurrent EC who were randomly assigned (1 : 1) to receive either dostarlimab (500 mg) or placebo, plus carboplatin-paclitaxel every 3 weeks for 6 cycles followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. OS was a dual primary endpoint. RESULTS: A total of 494 patients were randomized (245 in the dostarlimab arm; 249 in the placebo arm). In the overall population, with 51% maturity, RUBY met the dual primary endpoint for OS at this second interim analysis, with a statistically significant reduction in the risk of death [hazard ratio (HR) = 0.69, 95% confidence interval (CI) 0.54-0.89, P = 0.0020] in patients treated with dostarlimab plus carboplatin-paclitaxel versus carboplatin-paclitaxel alone. The risk of death was lower in the dMMR/MSI-H population (HR = 0.32, 95% CI 0.17-0.63, nominal P = 0.0002) and a trend in favor of dostarlimab was seen in the mismatch repair-proficient/microsatellite stable population (HR = 0.79, 95% CI 0.60-1.04, nominal P = 0.0493). The safety profile for dostarlimab plus carboplatin-paclitaxel was consistent with the first interim analysis. CONCLUSIONS: Dostarlimab in combination with carboplatin-paclitaxel demonstrated a statistically significant and clinically meaningful OS benefit in the overall population of patients with primary advanced or recurrent EC while demonstrating an acceptable safety profile.

Stemless reverse total shoulder arthroplasty: a systematic review of contemporary literature.

PURPOSE: Reverse shoulder prostheses are increasingly used for treatment of rotator cuff tear arthropathy and other degenerative shoulder diseases. In recent years, aiming for bone stock preservation has led to the design of metaphyseal humeral components without a stem. The aims of this study were to evaluate the complication and reintervention rates, as well as the clinical and radiographic outcomes in patients who underwent reverse shoulder arthroplasty (RSA) with stemless implants. METHODS: A systematic review of the literature was completed until May 2020 using PubMed, EMBASE, CINAHL and Cochrane databases, according to PRISMA guidelines. RESULTS: The literature search revealed 2942 studies, of which 13 were included in this review, with a total of 517 patients and a mean follow-up between 6.4 and 101.6 months. The total complication rate was 6.5%, while 3.3% were humeral associated complications. Finally, the rate of shoulders that underwent a reintervention was 6.7%, with 1.4% relating to a humeral component reason. Stemless RSA led to substantial improvements in patient reported outcome measures and range of motion across all studies. Scapular notching was reported in 15.2%, and lucencies around humeral component were reported in 0.8% of shoulders. CONCLUSION: Stemless RSA resulted in low complication and reintervention rates at the mid-term follow-up. The reported clinical and radiological outcomes showed that these prostheses have at least equivalent outcomes with their stemmed counterparts. Further studies are required to investigate the long-term longevity and performance of the stemless humeral implants. LEVEL OF EVIDENCE: Level IV; Systematic Review.

Superior labral anterior to posterior (SLAP) injury in the workplace. / Lesión del labrum superior anteroposterior (SLAP) en el entorno laboral.

BACKGROUND AND OBJECTIVE: Superior labral anterior to posterior (SLAP) injuries are widely recognised as a cause of pain and dysfunction in the shoulders of active patients. The aims of the present study were to analyze SLAP injuries in the workplace, and to evaluate the reliability of physical examination and imaging techniques for the diagnosis of work-related SLAP injuries. MATERIAL AND METHODS: Retrospective chart review of 58 SLAP injuries treated in our occupational health centre from 2005 to 2015 in 815 patients undergoing shoulder arthroscopy. Data were collected on mechanism of injury, clinical proceedings, complementary tests (contrasting the initial magnetic resonance imaging report with that of a radiologist specializing in musculoskeletal pathology), arthroscopy findings and treatments performed. RESULTS: The most common mechanism of injury was acute injury while handling weight, in the majority of cases, above the head. SLAP injury was suspected in 41% of cases through anamnesis and physical exam, in 29% through the initial magnetic resonance imaging report, and in 52% through the specialised radiologist's report. In 78%, associated injuries were present, the most common being rotator cuff injuries. CONCLUSIONS: SLAP injuries in the workplace are rare and are often a diagnostic finding during surgical intervention performed for a different associated injury. Arthro-magnetic resonance imaging and magnetic resonance imaging have lower reliability than physical exams in the diagnosis of work-related SLAP injuries. A radiologist specializing in musculoskeletal pathology could probably improve the reliability of imaging test interpretation in work-related SLAP injuries.

Needlescopic assisted internal ring suturing; a novel application of low-cost home-made instruments for pediatric inguinal hernia repair.

BACKGROUND: Congenital inguinal hernia (CIH) is a commonly performed surgical procedure in infants and children. Single port laparoscopic hernia repair using percutaneous internal inguinal ring (IIR) suturing procedure is a widely employed technique for indirect inguinal hernia repair in children. The majority of extracorporeal techniques use extracorporeal knotting and burying the knot subcutaneously. This may result in many drawbacks. The aim of this multicenter study is to introduce a new technique for pediatric inguinal hernia repair using only needles without any laparoscopic instruments. PATIENTS AND METHODS: This is a multicenter study which was conducted at Pediatric Surgical Departments of Al-Azhar, Mansoura, Alexandria and Tanta Universities during the period from January 2015 to June 2017. 314 patients with CIH underwent Needlescopic Assisted Internal Ring Suturing (NAIRS) after cauterization of the hernia sac at its neck. The main outcome measures were: feasibility, safety of the technique, operative time, recurrence rate, hydrocele and cosmetic results. RESULTS: A total of 314 patients with CIH were corrected by NAIRS. They were 232 males and 82 females. The mean age was 28.12 ± 1.3 months (range 6-120 months). The mean operative time was 12.6 ± 1.7 min (range 8-15 min) for unilateral cases and 18.6 ± 1.7 min (range 14-20 min) for the bilateral repairs. All cases were completed laparoscopically without major intraoperative complications. No recurrence was detected in this study. No wound complications or umbilical hernias developed. Hydrocele occurred in five males (2.16%), without detection of testicular atrophy or iatrogenic ascent of the testis. CONCLUSION: This preliminary study showed that NAIRS after cauterization of the neck of the hernia sac in infants and children is safe, feasible, reproducible with excellent cosmetic results.

Tuberculosis is a Mimicker of JIA: A Rare Case Report.

Cystic tuberculosis of the bone is a rare form of tuberculosis (TB). The condition presents like Juvenile idiopathic arthritis (JIA) of children. In children, the lesions symmetrically involve the peripheral skeleton, which are less sclerotic than adults. A case report is presented here where the patient presented with i) the extensive involvement of bones with cystic lesion, ii) Hand & feet involvement with multiple bony exostosis iii) Synovial swelling of multiple joints and 4) fever for 6 months. Swelling of the joints was disproportionately greater than pain. For the last 6 month patient developed low grade fever with evening rise of temperature & dry cough. There was associated anorexia & significant weight loss. Patient was moderately anaemic & there was cervical lymphadenopathy on both sides. The chest examination revealed features suggestive of consolidation in the right lung. Regarding MSK findings there was swelling of both knee & right wrist with G-II tenderness, sublaxation of both anterior and posterior cruciate ligament with mild effusion. Bony exostosis at the base of left index finger & at the base of right middle finger was found. Investigation shows low Hb, very high ESR, positive tuberculin test. X-ray Chest suggestive of consolidation, FNA of right cervical lymph node consistent with tuberculosis. X-ray Pelvis has shown expansile mixed sclerotic radiolucent areas with interval septation involving upper part of both femoral shafts. MRI findings of right knee joint were suggestive of tuberculous osteomyelitis. At this stage the patient was put on Anti-TB chemotherapy. After 2 month and 4 month of follow up with Anti-TB drug both MSK & lung condition was improved significantly. Ultimately the patient was diagnosed as cystic tuberculosis of bone & continued Anti-TB drugs.

Nicotine improves ethanol-induced impairment of memory: possible involvement of nitric oxide in the dorsal hippocampus of mice.

In the present study, the possible involvement of nitric oxide (NO) systems in the dorsal hippocampus in nicotine's effect on ethanol-induced amnesia and ethanol state-dependent memory was investigated. Adult male mice were cannulated in the CA1 regions of the dorsal hippocampus and trained on a passive avoidance learning task for memory assessment. We found that pre-training intraperitoneal (i.p.) administration of ethanol (1 g/kg) decreased inhibitory avoidance memory when tested 24 h later. The response induced by pre-training ethanol was significantly reversed by pre-test administration of the drug. Similar to ethanol, pre-test administration of nicotine (0.4 and 0.8 µg/mouse, intra-CA1) alone and nicotine (0.2, 0.4 and 0.8 µg/mouse) plus an ineffective dose of ethanol also significantly reversed the amnesia induced by ethanol. Ethanol amnesia was also prevented by pre-test administration of L-arginine (1.2 µg/mouse, intra-CA1), a NO precursor. Interestingly, an ineffective dose of nicotine (0.2 µg/mouse) in combination with a low dose of L-arginine (0.8 µg/mouse) synergistically improved memory performance impaired by ethanol given before training. In contrast, pre-test intra-CA1 microinjection of L-NAME (NG-nitro-L-arginine methyl ester), a nitric oxide synthase (NOS) inhibitor (0.4 and 0.8 µg/mouse), which reduced memory retrieval in inhibitory avoidance task by itself, in combination with an effective dose of nicotine (0.4 µg/mouse) prevented the improving effect of nicotine on memory impaired by pre-training ethanol. Moreover, intra-CA1 microinjection of L-NAME reversed the L-arginine-induced potentiation of the nicotine response. The results suggest the importance of NO system(s) in the CA1 regions of the dorsal hippocampus for improving the effect of nicotine on the ethanol-induced amnesia.

Susceptibility-weighted MR imaging for diagnosis of capillary telangiectasia of the brain.

BACKGROUND AND PURPOSE: BCT is a benign entity, whose appearance on conventional MR imaging makes its differentiation from neoplastic, inflammatory, or subacute ischemic disease challenging. SWI is sensitive to susceptibility effects from deoxyhemoglobin with excellent spatial resolution. Only scarce case reports have described the utility of SWI in cases of BCT. Our aim was to show the diagnostic value of SWI applied to a larger series of cases. MATERIALS AND METHODS: This was an observational retrospective study of 33 BCTs in 27 consecutive patients examined from August 2009 to January 2011 with MR imaging, including SWI. Morphology, signal intensity characteristics, and additional vascular malformations were analyzed. Preceding or follow-up examinations were available in 18 patients with a median time interval of 14.5 months (range, 2-115 months). RESULTS: Twenty-five pontine and 8 supratentorial BCTs demonstrated distinct signal-intensity loss on SWI in combination with postcontrast enhancement. Mean lesion diameter was 4.9 mm (range, 1.5-17 mm). Thirty-nine percent showed slight signal-intensity changes on T1 and/or T2; the remainder were isointense to normal brain. In 30%, a prominent draining vessel was observed. Additional cerebral vascular malformations were found in 5 patients. CONCLUSIONS: SWI represents a valuable tool for confirmation of presumed BCT. Demonstration of signal-intensity loss on SWI in an enhancing focal brain lesion, otherwise unremarkable on conventional MR images, is highly specific for BCT, thus excluding serious pathology and reassuring the patient and referring physician. This is particularly helpful for BCT in less typical locations.

Treatment of aggressive fibromatosis: the experience of a single institution.

AIMS: Aggressive fibromatosis is a locally aggressive infiltrative low-grade tumour, although pathologically benign, and it does not metastasise, yet it can cause serious local distressing symptoms by virtue of local destruction and impairment of local function. The aim of this study was to emphasise the role of radiotherapy and adequate surgery in the treatment of fibromatosis in patients presenting with newly diagnosed or recurrent disease and to analyse our treatment results over 15 years for this rare tumour type. MATERIALS AND METHODS: Fifty-four patients with confirmed diagnosis of aggressive fibromatosis treated at King Faisal Specialist Hospital between 1990 and 2006 were identified from our local cancer registry. Forty-seven patients had surgery: complete resection (R0) in 20 patients, incomplete surgery (R1/2) in 27 patients, and seven patients had biopsy only. Forty-five patients were treated with radiotherapy: 38 patients were treated with postoperative radiotherapy, three patients were treated with preoperative radiotherapy and four patients had radiotherapy as the only treatment. The radiotherapy dose ranged between 45 and 60Gy (median 50.4Gy). Three patients did not receive any form of treatment apart from biopsy, but were still included in the final analysis. RESULTS: Fifty-two per cent (28/54 patients) of our patient population had tumour recurrence when first presented to King Faisal Specialist Hospital. The median age was 29.5 years (range 2-63 years). The most common site of involvement was the extremities (28 patients). Among the 54 patients (with primary and recurrent presentation) there were 10 local recurrences, all of which were within the original primary site. The 5-year progression-free survival and overall survival rates for the whole group were 75 and 95%, respectively. Univariate and multivariate Cox regression analysis showed that the depth of invasion significantly affected progression-free survival. CONCLUSION: Aggressive fibromatosis is effectively treated with surgery and postoperative radiotherapy. Patients first presenting with tumour recurrence may still have local tumour control comparable with newly diagnosed patients.

Measurement of vaginal length: Reliability of the vaginal sound--a Gynecologic Oncology Group study.

A decrease in vaginal length associated with treatments for gynecological malignancies, particularly pelvic radiotherapy, negatively impacts sexuality. Research into this important problem has been hampered by a lack of instrumentation to measure vaginal length. The Gynecologic Oncology Group recently evaluated the reliability of an instrument, the "vaginal sound," designed to measure vaginal length. Eighty-eight physicians and nurses attended a training session in the use of the vaginal sound that included a clinical practicum with live models. Reliability was assessed at the time of the practicum. The instrument performed well, with vaginal lengths in models without cancer in the upper range of normal as documented by Masters and Johnson. The vaginal sound also appeared to be sensitive to hypothesized changes in vaginal length. Interrater reliability was high with intraclass correlation coefficients of 0.88 among instructors and 0.76 among trainees. In conclusion, the vaginal sound is a simple, yet reproducible measure and adds methodologic rigor to studies of vaginal length.

Prostatic and peripheral blood selenium levels after oral supplementation.

PURPOSE: The dietary trace element selenium has been proposed to be a potential chemopreventive agent for prostate cancer. Epidemiological studies have suggested an inverse association between blood selenium and prostate cancer incidence. However, to our knowledge no study to date has examined selenium absorption by the prostate. Therefore, we determine whether oral selenium supplementation alters selenium levels within the prostate and/or peripheral blood. MATERIALS AND METHODS: In this prospective trial 51 men undergoing transurethral resection of the prostate for benign prostatic hyperplasia were randomly assigned to serve as controls or receive 200 microg selenium daily orally for 1 month. Sample size was calculated to detect a difference of 30 ng/gm in prostate tissue with a power of 80%. Peripheral blood was obtained at enrollment and subsequently at surgery, when prostate tissue was also sampled. Selenium levels were determined using inductively coupled plasma mass spectrometry. RESULTS: Baseline erythrocyte selenium was within the standard reference range. Supplementation increased erythrocyte (initial median 173 and final median 209 ng/ml, p = 0.008) and prostate (supplement median 241 and control median 196 ng/gm, p = 0.016) levels. Erythrocyte levels at surgery correlated poorly with prostate levels in the control (r = 0.18) and supplement (r = 0.07) groups. CONCLUSIONS: Oral selenium supplementation increases prostatic and peripheral blood levels in men in a nonselenium deficient population. Blood and prostate levels correlated poorly, suggesting that peripheral blood measurements are a poor indicator of prostatic selenium content.

Toxicological aspects of treatment to remove cyanobacterial toxins from drinking water determined using the heterozygous P53 transgenic mouse model.

The presence of toxic cyanobacteria in drinking water reservoirs renders the need to develop treatment methods for the 'safe' removal of their associated toxins. Chlorine has been shown to successfully remove a range of cyanotoxins including microcystins, cylindrospermopsin and saxitoxins. Each cyanotoxin requires specific treatment parameters, particularly solution pH and free chlorine residual. However, currently there has not been any investigation into the toxicological effect of solutions treated for the removal of these cyanotoxins by chlorine. Using the P53(def) transgenic mouse model male and female C57BL/6J hybrid mice were used to investigate potential cancer inducing effects from such oral dosing solutions. Both purified cyanotoxins and toxic cell-free extract cyanobacterial solutions were chlorinated and administered over 90 and 170 days (respectively) in drinking water. No increase in cancer was found in any treatment. The parent cyanotoxins, microcystins, cylindrospermopsin and saxitoxins were readily removed by chlorine. There was no significant increase in the disinfection by-products trihalomethanes or haloacetic acids, levels found were well below guideline values. Histological examination identified no effect of treatment solutions except male mice treated with chlorinated cylindrospermopsin (as a cell free extract). In this instance 40% of males were found to have fatty vacuolation in their livers, cause unknown. It is recommended that further toxicology be undertaken on chlorinated cyanobacterial solutions, particularly for non-genotoxic carcinogenic compounds, for example the Tg. AC transgenic mouse model.

Dynamics and localization of activin A expression in rat gastric ulcers.

BACKGROUND: Activin A, the homodimer of the activin/inhibin betaA subunit, has been shown to participate in cutaneous wound healing. In this study we intended to determine its part in gastric ulceration. METHODS: Activin A expression was studied by immunohistochemistry and in situ hybridization in acetic-acid-induced chronic gastric ulcers in rat. The dynamics of this process were also assessed by quantitative real time RT-PCR and RNase protection assays (RPA). The effects of different doses of this cytokine on epithelial and mesenchymal cell proliferation were quantitated in vitro. RESULTS: Low amounts of activin A and its mRNA were expressed by epithelia, endothelia and fibroblasts in intact gastric tissue. Granulation tissue of gastric ulcers and gastric glands adjacent to the ulcer rim expressed markedly increased amounts of activin protein as well as activin/inhibin betaA mRNA. RPA and RT-PCR studies revealed a more than 3-fold increase in the relative abundance of this mRNA. Activin A did not affect the proliferation rate of fibroblasts and epithelial cells in vitro. CONCLUSIONS: Activin A participates in gastric ulcer healing in a similar fashion as in cutaneous wounding. Its expression on protein and mRNA level is markedly increased in ulcer base and rim.

Paclitaxel and platinum chemotherapy for ovarian carcinoma during pregnancy.

BACKGROUND: Ovarian cancer diagnosed during pregnancy is uncommon. Paclitaxel-based chemotherapy during pregnancy has not been reported previously. CASE: A woman with ascites and an adnexal mass diagnosed during pregnancy at 27 weeks gestational age underwent a laparotomy with cytoreductive surgery and was diagnosed with stage IIIC papillary serous ovarian adenocarcinoma. She was treated with three cycles of paclitaxel and cisplatin during pregnancy. At 37 weeks, she underwent a cesarean section, abdominal hysterectomy, and cytoreduction. Three additional cycles of chemotherapy were given. She developed a recurrence within 6 weeks of completing chemotherapy. She received several cycles of chemotherapy, but died of recurrent cancer 29 months after diagnosis. The infant has normal growth and development at 30 months of age. CONCLUSION: This is the first reported case of paclitaxel use during pregnancy.

Expression of decorin and biglycan in rat gastric tissue: effects of ulceration and basic fibroblast growth factor.

BACKGROUND: The small chondroitin/dermatan sulphate proteoglycans decorin and biglycan participate in organizing the network of collagen fibrils and interact with non-collagenous matrix proteins. In addition, via interactions with cytokines they are directly or indirectly involved in signalling, growth and cell differentiation. We aimed to analyse their expression in normal gastric tissue and during gastric ulcer healing. METHODS: Proteoglycan expression was studied by immunohistochemistry and in situ hybridization in acetic acid-induced gastric ulcers in rat during early phases and during chronic ulceration. The effects of treatment with an acid stable mutein of FGF-2 (bFGF) were also studied. RESULTS: In normal gastric tissue, both proteoglycans were most strongly expressed in the submucosal layer. However, some epithelial cells were positive for biglycan and, surprisingly, also for decorin. In the early phase after ulcer induction exclusively decorin became induced in the muscularis mucosae, while biglycan became detectable in this layer only after 2 weeks. There was no up-regulation of either proteoglycan in other layers, nor could an effect of FGF-2 treatment be seen. CONCLUSIONS: The expression of decorin could be observed for the first time in epithelial cells. Decorin, but not biglycan, appears as an early phase reactant in the muscularis mucosae in accordance with its putative role during angiogenesis and the prevention of apoptosis.

The p53 mutational spectrum associated with BRCA1 mutant ovarian cancer.

PURPOSE: Cancer-specific p53 mutational spectra have been identified. Data from murine models and human BRCA1-related hereditary breast cancers suggest that both unique and specific BRCA1-associated p53 mutations may be found in BRCA1-related ovarian cancers. EXPERIMENTAL DESIGN: The p53 mutational spectrum from ovarian cancers containing either somatic or germ-line BRCA1 mutations was compared with that of sporadic ovarian cancers defined as those diagnosed with a negative family history for breast/ovarian cancer in a three-generation pedigree. Tumor DNA was screened over exons 2-11 of the p53 gene by the PCR and single-strand confirmation polymorphism analysis of the amplimers. Cycle-based DNA sequencing from separate reactions was used to confirm p53 mutations. RESULTS: p53 gene mutations were detected in 42 of 86 sporadic ovarian cancers, compared with 13 of 15 cancers with somatic BRCA1 mutations (P = 0.007) and 16 of 20 cancers with germ-line BRCA1 mutations (P = 0.01). p53 null mutations were found in 31.4% of BRCA1 mutant cancers, compared with only 9.3% of the sporadic cancers (P = 0.002). The p53 mutational spectrum of germ-line BRCA1-related cancers was shifted toward transversions, frameshifts, and non-CpG transitions relative to the spectrum of sporadic ovarian cancers. Thirty-three unique ovarian cancer p53 mutations were sequenced. However, the specific p53 mutations in the BRCA1 mutant cancers were no more unique to this cohort than the p53 mutations of the sporadic cancers. CONCLUSIONS: Ovarian cancers containing somatic or germ-line BRCA1 mutations are uniformly accompanied by p53 dysfunction. This finding offers additional support to observations regarding the importance of p53/BRCA1 interactions in ovarian carcinogenesis.

p53 Mutations and microsatellite instability in ovarian cancer: Yin and yang.

OBJECTIVE: We tested the hypothesis that p53 frameshift mutations in ovarian cancer occur as a result of genomic instability rather than as a proximal cause of this process. STUDY DESIGN: Sequencing of the p53 tumor suppressor gene has been carried out on 305 ovarian, fallopian tube, and peritoneal cancers. Two groups of p53 null mutations were identified: (1) those caused by frameshift insertion or deletion mutations (n = 31) and (2) those caused by nonsense mutations (n = 28). As a control group 59 tumors with p53 missense mutations were selected by matching with the p53 null tumors on the basis of patient age at diagnosis, stage and grade of cancer, cancer site, and year of diagnosis. Microsatellite instability was determined from paired normal and tumor tissue deoxyribonucleic acid by means of the following different markers: D2S123, D5S346, D17S250, BAT25, and BAT26. Amplimers from polymerase chain reactions were evaluated on 7% polyacrylamide gels. RESULTS: The p53 null tumors were more likely to be of higher stage and grade. Fallopian tube cancers were more common (P =.02) in the p53 frameshift group. The overall incidence of microsatellite instability was 39%, 36%, and 25% for tumors with p53 frameshift nonsense and missense mutations (P =.30). Microsatellite instability was seen almost exclusively with ovarian cancer (P =.04). CONCLUSIONS: Microsatellite instability is a relatively common event in ovarian cancer and is dependent on marker selection. The p53 frameshift mutations do not appear to occur as a consequence of genomic instability.

Bracken (Pteridium aquilinum)-induced DNA adducts in mouse tissues are different from the adduct induced by the activated form of the Bracken carcinogen ptaquiloside.

Following treatment with bracken fern (Pteridium aquilinum) extract and bracken spores a number of DNA adducts were detected by (32)P-postlabeling. Three of these adducts have been described previously (Povey et al., Br. J. Cancer (1996) 74, 1342-1348) and in this study, using a slightly different protocol, four new adducts, with higher chromatographic mobility, were detected at levels ranging from 50 to 230% of those previously described. When DNA was treated in vitro with activated ptaquiloside (APT) and analysed by butanol extraction or nuclease P1 treatment, only one adduct was detected by (32)P-postlabeling. This adduct was not present in the DNA from mice treated with bracken fern or spores, suggesting either that bracken contains genotoxins other than ptaquiloside or that the metabolism of ptaquiloside produces genotoxins not reflected by activated ptaquiloside. However, as the ATP-derived adduct has been detected previously in ileal DNA of bracken-fed calves, species-specific differences in the metabolism of bracken genotoxins may exist, thereby leading to differences in their biological outcomes.

The prognostic significance of p53 tumor suppressor gene alterations in ovarian carcinoma.

BACKGROUND: The prognostic significance and nature of p53 dysfunction in ovarian carcinoma is unclear. The relation between p53 overexpression, p53 mutations, and their effects on overall survival in primary ovarian carcinoma is explored. METHODS: Tumor specimens from 171 consecutive epithelial ovarian carcinomas were examined for overexpression of p53 protein with DO7 antibody. P53 mutations were determined by direct sequencing. The influences of conventional histopathologic prognostic factors and various p53 molecular alterations on overall survival were assessed. RESULTS: Overall, 48.5% and 57.3% of the samples showed p53 overexpression and p53 mutation, respectively. Although neither p53 overexpression nor the mere presence of a p53 mutation impacted overall survival, the combination did prognosticate survival both in univariate and multivariate models. The authors' results suggest 4 mechanisms that may affect p53 dysfunction in nearly 100% of advanced stage ovarian carcinomas. These include null mutation, nonresponsive p53 (wild-type [wt] p53 sequence, DO7 negative), sequestration (wt p53 sequence, DO7 positive), and missense mutation. Median survival for these groups that constitute sequentially 21.3%, 20.5%, 12.3%, and 45.9% of the 122 Stage III or IV (International Federation of Gynecology and Obstetrics) cancers was 1.49, 1.31, 3.09, and 3.6 years, respectively. The nonresponsive p53 and null sequence tumors grouped together as functionally null convey the worst prognosis relative to missense mutations in a univariate model (P = 0.006). Functionally null p53 (P = 0.002), stage (P = 0.008), and optimal cytoreduction (P = 0.008) were independent prognostic factors by multivariate analysis. CONCLUSIONS: Sequestration of wt p53 is unique to advanced stage ovarian carcinoma. Functionally null p53 represents an independent molecular predictor of compromised survival.

The glutathione S-transferase M1 genotype in ovarian cancer.

Glutathione S-transferase mu-1 (GSTM1) is a polymorphic member of the mu class gene family of the glutathione S-transferases. Individuals who are GSTM1 null have increased susceptibility to lung and colon cancer. We hypothesized that: (a) GSTM1 null individuals might also be at increased risk for development of ovarian cancer; and (b) the GSTM1 genotype would influence response to chemotherapy. One hundred and forty-six individuals with invasive epithelial ovarian cancer were genotyped using a three-primer PCR reaction specific for the GSTM1 gene and an internal control glutathione S-transferase mu-4 (GSTM4). The products were analyzed on agarose gels. Healthy individuals without a family history of ovarian, breast, or colon cancer served as unmatched controls (n = 80). The results show that age at diagnosis, histological type, and stage of ovarian cancer were all independent of GSTM1 genotype. The frequency of the GSTM1 null genotype in the ovarian cancer cohort was similar to that in the control population, 51% versus 58%, P > 0.05. Likewise, median survival for individuals with advanced stage ovarian cancer was independent of GSTM1 genotype. We concluded that the GSTM1 null genotype does not increase ovarian cancer risk. These findings suggest that GSTM1 does not play a significant role in detoxifying environmental factors that influence ovarian carcinogenesis and does not play an important role in the resistance of ovarian cancer to chemotherapy.

Effect of basic fibroblast growth factor on gastric ulcer healing and its own mRNA expression.

BACKGROUND: The application of an acid-stable mutein of basic fibroblast growth factor (bFGF) called CS23 results in acceleration of ulcer healing. The modes by which this cytokine exerts these effects are not yet completely understood. AIM: To describe the pattern of bFGF-mRNA expression during ulcer healing and to examine the effects of exogenously applied CS23 on gastric ulcer healing in an animal model. METHODS: The speed of healing of gastric ulcers, expression of extracellular matrix gene mRNAs such as pro alpha(I) collagen (by non-radioactive in situ hybridization), cellular proliferation evidenced by the display of PCNA (by immunohistochemistry), angiogenesis, and the feedback of this growth factor on its own mRNA expression pattern were used to evaluate the effects of CS23 on rat gastric ulcer healing in an animal model. RESULTS: CS23 accelerates gastric ulcer healing at 7, 14 and 21 days after ulcer induction. We found an increase in connective tissue beneath the ulcer bed in treated animals in comparison to controls. The expression of PCNA as well as pro alpha(I) collagen mRNA was markedly increased in ulcers, yet there was no distinct difference between treatment arms. In contrast, the density of microvessels was significantly increased in the submucosa of ulcers by CS23 application. bFGF-mRNA expression is up-regulated in the submucosa during early ulcer healing; this increase diminishes within days but can be restituted by the exogenous application of CS23. CONCLUSIONS: CS23 speeds gastric ulcer healing and significantly increases the density of microvessels in the ulcerated tissue without affecting the numbers of proliferating cells or the transcription of collagen mRNA. In addition, it augments the expression of bFGF-mRNA during the later stages of healing, suggesting a positive feedback loop.