The presenting symptom signatures of incident cancer: evidence from the English 2018 National Cancer Diagnosis Audit.

BACKGROUND: Understanding relationships between presenting symptoms and subsequently diagnosed cancers can inform symptom awareness campaigns and investigation strategies. METHODS: We used English National Cancer Diagnosis Audit 2018 data for 55,122 newly diagnosed patients, and examined the relative frequency of presenting symptoms by cancer site, and of cancer sites by presenting symptom. RESULTS: Among 38 cancer sites (16 cancer groups), three classes were apparent: cancers with a dominant single presenting symptom (e.g. melanoma); cancers with diverse presenting symptoms (e.g. pancreatic); and cancers that are often asymptomatically detected (e.g. chronic lymphocytic leukaemia). Among 83 symptoms (13 symptom groups), two classes were apparent: symptoms chiefly relating to cancers of the same body system (e.g. certain respiratory symptoms mostly relating to respiratory cancers); and symptoms with a diverse cancer site case-mix (e.g. fatigue). The cancer site case-mix of certain symptoms varied by sex. CONCLUSION: We detailed associations between presenting symptoms and cancer sites in a large, representative population-based sample of cancer patients. The findings can guide choice of symptoms for inclusion in awareness campaigns, and diagnostic investigation strategies post-presentation when cancer is suspected. They can inform the updating of clinical practice recommendations for specialist referral encompassing a broader range of cancer sites per symptom.

Impact of previous hepatitis B infection on the clinical outcomes from chronic hepatitis C? A population-level analysis.

Chronic coinfection with hepatitis C virus (HCV) and hepatitis B virus (HBV) is associated with adverse liver outcomes. The clinical impact of previous HBV infection on liver disease in HCV infection is unknown. We aimed at determining any association of previous HBV infection with liver outcomes using antibodies to the hepatitis B core antigen (HBcAb) positivity as a marker of exposure. The Scottish Hepatitis C Clinical Database containing data for all patients attending HCV clinics in participating health boards was linked to the HBV diagnostic registry and mortality data from Information Services Division, Scotland. Survival analyses with competing risks were constructed for time from the first appointment to decompensated cirrhosis, hepatocellular carcinoma (HCC) and liver-related mortality. Records of 8513 chronic HCV patients were included in the analyses (87 HBcAb positive and HBV surface antigen [HBsAg] positive, 1577 HBcAb positive and HBsAg negative, and 6849 HBcAb negative). Multivariate cause-specific proportional hazards models showed previous HBV infection (HBcAb positive and HBsAg negative) significantly increased the risks of decompensated cirrhosis (hazard ratio [HR]: 1.29, 95% CI: 1.01-1.65) and HCC (HR: 1.64, 95% CI: 1.09-2.49), but not liver-related death (HR: 1.02, 95% CI: 0.80-1.30). This is the largest study to date showing an association between previous HBV infection and certain adverse liver outcomes in HCV infection. Our analyses add significantly to evidence which suggests that HBV infection adversely affects liver health despite apparent clearance. This has important implications for HBV vaccination policy and indications for prioritization of HCV therapy.

Anti-envelope antibody responses in individuals at high risk of hepatitis C virus who resist infection.

Injection drug users uninfected by hepatitis C virus (HCV) despite likely repeated exposure through high-risk behaviour are well documented. Factors preventing infection in these individuals are incompletely understood. Here, we looked for anti-HCV-envelope antibody responses in a cohort of repeatedly exposed but uninfected subjects. Forty-two hepatitis C diagnostic antibody- and RNA-negative injection drug users at high risk of exposure were studied and findings compared to healthy controls and cases with chronic HCV infection. Purified IgGs from sera were tested by ELISA for binding to genotype 1a and 3a envelope glycoproteins E1E2 with further testing for IgG and IgM reactivity against soluble E2. Virus-neutralizing activity was assessed using an HCV pseudoparticle system. Uninfected subjects demonstrated significantly greater IgG and IgM reactivities to envelope glycoproteins than healthy controls with IgG from 6 individuals additionally showing significant neutralization. This study is the first to describe humoral immunological responses targeting the HCV envelope, important for viral neutralization, in exposed uninfected individuals. A subset of these cases also had evidence of viral neutralization via anti-envelope antibodies. In addition to confirming viral exposure, the presence of specific anti-envelope antibodies may be a factor that helps these individuals resist HCV infection.

Adjusting for the Confounding Effects of Treatment Switching-The BREAK-3 Trial: Dabrafenib Versus Dacarbazine.

BACKGROUND: Patients with previously untreated BRAF V600E mutation-positive melanoma in BREAK-3 showed a median overall survival (OS) of 18.2 months for dabrafenib versus 15.6 months for dacarbazine (hazard ratio [HR], 0.76; 95% confidence interval, 0.48-1.21). Because patients receiving dacarbazine were allowed to switch to dabrafenib at disease progression, we attempted to adjust for the confounding effects on OS. MATERIALS AND METHODS: Rank preserving structural failure time models (RPSFTMs) and the iterative parameter estimation (IPE) algorithm were used. Two analyses, "treatment group" (assumes treatment effect could continue until death) and "on-treatment observed" (assumes treatment effect disappears with discontinuation), were used to test the assumptions around the durability of the treatment effect. RESULTS: A total of 36 of 63 patients (57%) receiving dacarbazine switched to dabrafenib. The adjusted OS HRs ranged from 0.50 to 0.55, depending on the analysis. The RPSFTM and IPE "treatment group" and "on-treatment observed" analyses performed similarly well. CONCLUSION: RPSFTM and IPE analyses resulted in point estimates for the OS HR that indicate a substantial increase in the treatment effect compared with the unadjusted OS HR of 0.76. The results are uncertain because of the assumptions associated with the adjustment methods. The confidence intervals continued to cross 1.00; thus, the adjusted estimates did not provide statistically significant evidence of a treatment benefit on survival. However, it is clear that a standard intention-to-treat analysis will be confounded in the presence of treatment switching-a reliance on unadjusted analyses could lead to inappropriate practice. Adjustment analyses provide useful additional information on the estimated treatment effects to inform decision making. IMPLICATIONS FOR PRACTICE: Treatment switching is common in oncology trials, and the implications of this for the interpretation of the clinical effectiveness and cost-effectiveness of the novel treatment are important to consider. If patients who switch treatments benefit from the experimental treatment and a standard intention-to-treat analysis is conducted, the overall survival advantage associated with the new treatment could be underestimated. The present study applied established statistical methods to adjust for treatment switching in a trial that compared dabrafenib and dacarbazine for metastatic melanoma. The results showed that this led to a substantially increased estimate of the overall survival treatment effect associated with dabrafenib.

Elevated interferon-stimulated gene transcription in peripheral blood mononuclear cells occurs in patients infected with genotype 1 but not genotype 3 hepatitis C virus.

Hepatitis C virus (HCV) can be classified into seven distinct genotypes that are associated with differing pathologies and respond differently to antiviral therapy. In the UK, genotype 1 and 3 are present in approximately equal proportions. Chronic infection with HCV genotype 3 is associated with increased liver steatosis and reduced peripheral total cholesterol levels, which potentially influences peripheral immune responses. To understand these differences, we investigated host gene transcription in peripheral blood mononuclear cells by microarray and quantitative PCR in patients with genotype 1 (n = 22) or genotype 3 infection (n = 22) and matched healthy controls (n = 15). Enrichment of genes involved in immune response and inflammatory pathways were present in patients infected with HCV genotype 1; however, no differences in genes involved in lipid or cholesterol metabolism were detected. This genotype-specific induction of genes is unrelated to IL28B genotype or previous treatment failure. Our data support the hypothesis that genotype 1 infection drives a skewed Type I interferon response and provides a foundation for future investigations into the host-pathogen interactions that underlie the genotype-specific clinical outcomes of chronic HCV infection.

Functional and radiographic outcomes following distal ulna implant arthroplasty.

PURPOSE: To determine the outcome of ulnar head endoprostheses in the treatment of distal radioulnar joint instability, arthrosis, or both. METHODS: We conducted a retrospective review of 47 patients to analyze the outcome of a single ulnar head replacement over a 10-year period. All patients reported pain or instability at the distal radioulnar joint. Standardized assessments included a patient-rated pain score, forearm range of motion, grip strength, and Mayo wrist score. We examined preoperative and postoperative radiographs for final implant position, loosening, and osteolysis. RESULTS: We observed 47 patients for a median of 56 months (minimum, 16 mo). There was a statistically significant decrease in pain scores from 4.6 to 2.2 and improvement in the mean Mayo wrist score from 14 to 69 points after surgery. There was no significant improvement in forearm rotation and wrist function. Kaplan-Meier analysis demonstrated 83% survival at 6 years. A total of 14 patients (30%) required additional surgical procedures after primary arthroplasty. Risk factors for failure included history of previous surgery, use of an extended collar, lucency greater than 2 mm around the implant stem, and pedestal formation at the tip of the implant. CONCLUSIONS: Distal ulna implant arthroplasty reduces pain and improves function in patients with distal radioulnar joint instability, arthrosis, or both.

Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial.

BACKGROUND: Results from phase II studies in patients with stage IIIA non-small-cell lung cancer with ipsilateral mediastinal nodal metastases (N2) have shown the feasibility of resection after concurrent chemotherapy and radiotherapy with promising rates of survival. We therefore did this phase III trial to compare concurrent chemotherapy and radiotherapy followed by resection with standard concurrent chemotherapy and definitive radiotherapy without resection. METHODS: Patients with stage T1-3pN2M0 non-small-cell lung cancer were randomly assigned in a 1:1 ratio to concurrent induction chemotherapy (two cycles of cisplatin [50 mg/m(2) on days 1, 8, 29, and 36] and etoposide [50 mg/m(2) on days 1-5 and 29-33]) plus radiotherapy (45 Gy) in multiple academic and community hospitals. If no progression, patients in group 1 underwent resection and those in group 2 continued radiotherapy uninterrupted up to 61 Gy. Two additional cycles of cisplatin and etoposide were given in both groups. The primary endpoint was overall survival (OS). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00002550. FINDINGS: 202 patients (median age 59 years, range 31-77) were assigned to group 1 and 194 (61 years, 32-78) to group 2. Median OS was 23.6 months (IQR 9.0-not reached) in group 1 versus 22.2 months (9.4-52.7) in group 2 (hazard ratio [HR] 0.87 [0.70-1.10]; p=0.24). Number of patients alive at 5 years was 37 (point estimate 27%) in group 1 and 24 (point estimate 20%) in group 2 (odds ratio 0.63 [0.36-1.10]; p=0.10). With N0 status at thoracotomy, the median OS was 34.4 months (IQR 15.7-not reached; 19 [point estimate 41%] patients alive at 5 years). Progression-free survival (PFS) was better in group 1 than in group 2, median 12.8 months (5.3-42.2) vs 10.5 months (4.8-20.6), HR 0.77 [0.62-0.96]; p=0.017); the number of patients without disease progression at 5 years was 32 (point estimate 22%) versus 13 (point estimate 11%), respectively. Neutropenia and oesophagitis were the main grade 3 or 4 toxicities associated with chemotherapy plus radiotherapy in group 1 (77 [38%] and 20 [10%], respectively) and group 2 (80 [41%] and 44 [23%], respectively). In group 1, 16 (8%) deaths were treatment related versus four (2%) in group 2. In an exploratory analysis, OS was improved for patients who underwent lobectomy, but not pneumonectomy, versus chemotherapy plus radiotherapy. INTERPRETATION: Chemotherapy plus radiotherapy with or without resection (preferably lobectomy) are options for patients with stage IIIA(N2) non-small-cell lung cancer. FUNDING: National Cancer Institute, Canadian Cancer Society, and National Cancer Institute of Canada.

Patterns and prevalence of disordered eating and weight control behaviors in women ages 25-45.

OBJECTIVE: The current study describes detailed eating behaviors, dieting behaviors, and attitudes about shape and weight in 4023 women ages 25 to 45. METHOD: The survey was delivered on-line and participants were identified using a national quota-sampling procedure. RESULTS: Disordered eating behaviors, extreme weight loss measures, and negative cognitions about shape and weight were widely endorsed by women in this age group and were not limited to White participants. Thirty-one percent of women without a history of anorexia nervosa or binge eating reported having purged to control weight, and 74.5% of women reported that their concerns about shape and weight interfered with their happiness. DISCUSSION: Unhealthy approaches to weight control and negative attitudes about shape and weight are pervasive even among women without eating disorders. The development of effective approaches to address the impact of these unhealthy behaviors and attitudes on the general well-being and functioning of women is required.

Increasing tumor volume is predictive of poor overall and progression-free survival: secondary analysis of the Radiation Therapy Oncology Group 93-11 phase I-II radiation dose-escalation study in patients with inoperable non-small-cell lung cancer.

PURPOSE: Patients with non-small-cell lung cancer (NSCLC) in the Radiation Therapy Oncology Group (RTOG) 93-11 trial received radiation doses of 70.9, 77.4, 83.8, or 90.3 Gy. The locoregional control and survival rates were similar among the various dose levels. We investigated the effect of the gross tumor volume (GTV) on the outcome. METHODS AND MATERIALS: The GTV was defined as the sum of the volumes of the primary tumor and involved lymph nodes. The tumor response, median survival time (MST), and progression-free survival (PFS) were analyzed separately for smaller (< or =45 cm(3)) vs. larger (>45 cm(3)) tumors. RESULTS: The distribution of the GTV was as follows: < or =45 cm(3) in 79 (49%) and >45 cm(3) in 82 (51%) of 161 patients. The median GTV was 47.3 cm(3). N0 status and female gender were associated with better tumor responses. Patients with smaller (< or =45 cm(3)) tumors achieved a longer MST and better PFS than did patients with larger (>45 cm(3)) tumors (29.7 vs. 13.3 months, p < 0.0001; and 15.8 vs. 8.3 months, p < 0.0001, respectively). Increasing the radiation dose had no effect on the MST or PFS. On multivariate analysis, only a smaller GTV was a significant prognostic factor for improved MST and PFS (hazard ratio [HR], 2.12, p = 0.0002; and HR, 2.0, p = 0.0002, respectively). The GTV as a continuous variable was also significantly associated with the MST and PFS (HR, 1.59, p < 0.0001; and HR, 1.39, p < 0.0001, respectively). CONCLUSIONS: Radiation dose escalation up to 90.3 Gy did not result in improved MST or PFS. The tumor responses were greater in node-negative patients and women. An increasing GTV was strongly associated with decreased MST and PFS. Future radiotherapy trials patients might need to use stratification by tumor volume.

Effect of amifostine on response rates in locally advanced non-small-cell lung cancer patients treated on randomized controlled trials: a meta-analysis.

PURPOSE: Amifostine can reduce the cytotoxic effects of chemotherapy and radiotherapy in patients with locally advanced non-small-cell lung cancer, but concerns remain regarding its possible tumor-protective effects. Studies with sufficient statistical power to address this question are lacking. METHODS AND MATERIALS: We performed a meta-analysis of all published clinical trials involving locally advanced non-small-cell lung cancer patients treated with radiotherapy with or without chemotherapy, who had been randomized to treatment with amifostine vs. no amifostine or placebo. Random effects estimates of the relative risk of overall, partial, and complete response were obtained. RESULTS: Seven randomized trials involving 601 patients were identified. Response rate data were available for six studies (552 patients). The pooled relative risk (RR) estimate was 1.07 (95% confidence interval, 0.97-1.18; p = 0.18), 1.21 (95% confidence interval, 0.83-1.78; p = 0.33), and 0.99 (95% confidence interval, 0.78-1.26; p = 0.95) for overall, complete, and partial response, respectively (a RR >1 indicates improvement in response with amifostine compared with the control arm). The results were similar after sensitivity analyses. No evidence was found of treatment effect heterogeneity across the studies. CONCLUSIONS: Amifostine has no effect on tumor response in patients with locally advanced non-small-cell lung cancer treated with radiotherapy with or without chemotherapy.

Mixed Salmonella infection: case report and review of the literature.

Mixed infection with multiple Salmonella serotypes in the same patient is an unusual finding. We present a case of enteric fever in which both Salmonella Typhi and Salmonella Paratyphi A were isolated from the blood of a patient traveling from India.

Effect of pilocarpine during radiation therapy: results of RTOG 97-09, a phase III randomized study in head and neck cancer patients.

Radiation therapy is an important curative modality in the treatment of patients with head and neck cancer. However, radiation-induced changes in the oral cavity, such as xerostomia and mucositis, are among the most debilitating treatment sequelae experienced by patients undergoing radiation therapy, and attempts at ameliorating these side effects have been poor at best. Pilocarpine has been approved for post-radiation xerostomia, and the effect of its use during radiation therapy on salivary flow, xerostomia, mucositis, and quality of life (QOL) was assessed in a phase III study conducted by the Radiation Therapy Oncology Group (RTOG 97-09). In total, 245 evaluable patients were randomized to pilocarpine or placebo. Selected patients were required to have > or = 50% of the volume of the major salivary glands receive > or = 50Gy; to agree to provide stimulated and unstimulated samples of saliva (measured in g) before treatment, at the end of treatment, and 3 and 6 months after completion of radiation therapy; and to complete the University of Washington Head and Neck Symptom Scale. Following the completion of radiation therapy, the average unstimulated salivary flow was statistically greater in the pilocarpine group, whereas no difference was noted following parotid stimulation. There was no effect on the amelioration of mucositis. The results of the QOL scales did not reveal any significant difference between the pilocarpine and placebo groups with regard to xerostomia and mucositis. The significant difference in unstimulated salivary flow supports the concomitant use of oral pilocarpine to decrease radiation-associated xerostomia. However, the absent correlation between improved salivary flow and QOL scores is of some concern (though not a new finding) and may be related to the existence of comorbidities and the lack of effect on mucositis.

Infection of surgical wounds in the maxillofacial region and free flap donor sites with methicillin-resistant Staphylococcus aureus.

We studied the acquisition of methicillin-resistant Staphylococcus aureus (MRSA) in two groups of patients who had free flap reconstructions of defects after excision of lesions in the head and neck. The first group (n=31) was given a 5-day perioperative course of antibiotic prophylaxis (long-term) and the second (n=33) a 24-h course (short-term). MRSA was the main infecting organism. Seventeen of the 64 patients (27%) developed an infection with MRSA, including seven at donor sites of free flaps. All infections were acquired after operation, and delayed healing or discharge in five patients with MRSA and four with infections with other organisms. The median length of hospital admission was greater for patients that acquired MRSA (p=0.005). There were significantly fewer patients with wounds infected by MRSA in the short-term group (4/33 compared with 13/31, p=0.01). We recommend the short-term use of an antibiotic for surgical prophylaxis and the application of cross-infection control measures on the ward.

Effect of overall treatment time on outcomes after concurrent chemoradiation for locally advanced non-small-cell lung carcinoma: analysis of the Radiation Therapy Oncology Group (RTOG) experience.

PURPOSE: To determine whether overall treatment time affects outcomes after definitive concurrent chemoradiotherapy for locally advanced non-small-cell lung carcinoma (NSCLC). METHODS AND MATERIALS: Data were analyzed from 3 prospective Radiation Therapy Oncology Group trials (RTOG 91-06, 92-04, and 94-10) in which immediate concurrent chemoradiation (cisplatin-based) was the primary therapy for good-performance status Stage III (and selected inoperable Stage II) NSCLC. "Short" overall treatment time (per protocol) was defined as completing treatment within 5 days of plan; other patients were considered to have had "prolonged" treatment time (protocol violation); treatment time was also analyzed as a continuous variable in a multivariate model. Actuarial analysis was performed for overall survival, progression-free survival, freedom from local-regional progression, and toxicity. RESULTS: A total of 474 patients were analyzed. Median follow-up for surviving patients was 6.1 years. Treatment time was delivered per protocol in 387 (82%), whereas 87 patients (18%) had a prolonged treatment time. Long treatment time was significantly associated with severe acute esophagitis. Median survival was slightly better in patients completing treatment on time (19.5 months vs. 14.8 months), but this did not reach statistical significance (p = 0.15) in the univariate analysis. However, in the multivariate analysis of treatment time as a continuous variable, prolonged treatment time was significantly associated with poorer survival (p = 0.02), indicating a 2% increase in the risk of death for each day of prolongation in therapy. Histology (squamous fared worse) and performance status were also significant in the multivariate model. CONCLUSIONS: This retrospective analysis demonstrates a correlation between prolonged overall radiotherapy treatment time and survival in patients with locally advanced NSCLC, even when concurrent chemotherapy is used. Further study of novel radiation-chemotherapy dose/fractionation regimens is warranted.

Phase I study of thoracic radiation dose escalation with concurrent chemotherapy for patients with limited small-cell lung cancer: Report of Radiation Therapy Oncology Group (RTOG) protocol 97-12.

PURPOSE: The purpose of RTOG 97-12 was to determine the maximum tolerated dose (MTD) of thoracic radiation therapy (RT) with concurrent chemotherapy for patients with limited-stage small-cell lung cancer. PATIENTS AND METHODS: Sixty-four patients received four cycles of cisplatin (60 mg/m(2) i.v.) and etoposide (120 mg/m(2) i.v. Days 1-3) (PE), with concurrent thoracic RT starting on Day 1. Thoracic RT was given during the first two cycles with 1.8 Gy/fraction daily to the clinical target volume, followed by thoracic RT to the gross tumor volume b.i.d. for the last 3, 5, 7, 9, or 11 treatment days (total dose 50.4, 54.0, 57.6, 61.2, or 64.8 Gy, respectively). The MTD was based on the dose that produced Grades 3-4 nonhematologic toxicity (mainly esophagitis and pneumonitis) in greater than 50% of patients. RESULTS: After the first 8 patients were enrolled in Arm 1, administration of etoposide was changed from 120 mg/m(2) i.v. on Days 2 and 3 of each cycle to 240 mg/m(2) p.o. for patient convenience as outpatients. Total thoracic RT doses from 50.4 Gy to 61.2 Gy over 5 weeks given with PE were well tolerated. Three of the first 5 patients in the 64.8 Gy arm developed Grade 3 acute esophagitis; the MTD was determined to be 61.2 Gy. Fifty-four (87%) of the 62 evaluable patients achieved a complete (68%) or partial (19%) tumor response. The 18-month survival was 25% for patients receiving 50.4 Gy and 82% for those receiving 61.2 Gy. CONCLUSIONS: The MTD for this accelerated thoracic RT regimen with concurrent PE was 61.2 Gy over 5 weeks.

Can urine dipstick testing for urinary tract infection at point of care reduce laboratory workload?

AIM: The University Hospitals of Leicester NHS Trust microbiology laboratory receives 150 000 urine samples each year, approximately 80% of which prove to be culture negative. The aim of this study was to reduce the proportion of culture negative urines arriving in the laboratory, by producing local evidence based guidelines for the use of urine dipstick testing at point of care within the trust's three acute hospitals. METHODS: One thousand and seventy six unborated urine samples were dipstick tested at the point of care using an automatic strip reader. Quantitative results for the four infection associated markers-leucocyte esterase, nitrite, blood, and protein-were compared with the results of conventional laboratory microscopy and culture. RESULTS: The performance of different marker combinations was calculated against the routine laboratory methods. One hundred and seventy five (16.3%) samples were negative for all four markers. Of these dipstick negative samples, only three (1.7% of all true positives) were positive by culture. The absence of all four infection associated markers was found to have a greater than 98% negative predictive value and a sensitivity and specificity of 98.3% and 19.2%, respectively. CONCLUSIONS: A urinary dipstick testing algorithm for infection associated markers was derived for use in hospital patients to screen out negative urines. Two years after distributing the algorithm and promoting access to reagent strips and strip readers, a reduction in the urine workload has been seen against an otherwise increasing laboratory specimen load.

Catastrophic Head-Neck Dissociation of a Modular Cementless Femoral Component.

CASE: We report two cases of modular head-neck junction failure involving the Stryker Accolade TMZF stem leading to sudden dissociation of the femoral head from the stem. Both patients presented with mechanical symptoms in the hip followed by pain and hip dysfunction. Disassembly of the head and deformation of the male taper were seen on preoperative radiographs. Intraoperatively, both patients had substantial metallosis with a markedly damaged taper requiring stem revision. CONCLUSION: We recommend regular clinical and radiographic surveillance of patients with the Stryker Accolade TMZF stem, especially those patients with pain and/or mechanical symptoms.

A randomized, controlled, safety study using imiquimod for the topical treatment of anogenital warts in HIV-infected patients. Imiquimod Study Group.

OBJECTIVE: To assess the safety of imiquimod, an immune response modifier, in the topical treatment of external anogenital warts in HIV-infected patients. SETTING: Clinical sites in the United Kingdom (eight) and the United States (five). DESIGN: A prospective, randomized, double-blind, vehicle-controlled study of imiquimod 5% cream or vehicle applied for 8+/-2 h three times per week for a maximum of 16 weeks in HIV-seropositive males (n = 97) and females (n = 3) aged 18 years or more with clinically diagnosed external anogenital warts, CD4 T lymphocyte count of > or = 100 x 10(6) cells/l and Karnofsky score > or = 70. MAIN OUTCOME MEASURES: Safety was assessed through the incidence and severity of local skin reactions and other adverse events, and through clinical laboratory tests. Wart clearance was documented by two-dimensional measurements of warts and by photography. RESULTS: Among the patients treated with imiquimod (n = 65) and vehicle (n = 35), the most common local skin reaction was erythema, (41.9 and 26.7%, respectively) and the incidence of patients reporting at least one adverse event was 69.2 and 65.7%, respectively. No clinically meaningful differences or changes in laboratory values were observed between treatment groups, nor were drug-related adverse effects observed in regard to HIV disease. While there was no significant difference between treatment groups in the number of patients who totally cleared their baseline warts (imiquimod 11% versus vehicle 6%, P = 0.488), more imiquimod-treated patients experienced a > or = 50% reduction in baseline wart area (38% versus 14%, P = 0.013). CONCLUSION: Most local skin reactions were mild and no adverse effects on HIV disease were observed. Topically applied imiquimod 5% cream reduced wart area and may have clinical utility in treating external anogenital warts in some HIV-infected patients.

Characterization of oxytocin, vasopressin, and neurophysin from the bovine corpus luteum.

Acid extracts of corpora lutea collected from nonpregnant cows were found to contain oxytocin, arginine vasopressin, and neurophysin. The inhibition curves of the oxytocin and vasopressin extracts showed parallelism with the appropriate standard preparations in specific RIAs and eluted at the same position as the standards using high performance liquid chromatography (HPLC). The neurophysin extract showed parallelism in a bovine neurophysin I RIA and had a similar elution position to the standard on both Sephadex G-50 and HPLC. However, its immunoreactive profile on HPLC differed slightly from that obtained with hypophyseal bovine neurophysin I. In nonpregnant cows the oxytocin content (about 1 microgram g-1 wet wt of tissue) was three orders of magnitude greater than the vasopressin content. Levels of luteal oxytocin were considerably lower in pregnant animals. These results show that the bovine ovary is a rich source of neurohypophysial peptides and suggest that oxytocin biosynthesis may occur within the corpus luteum.

Biosynthesis of oxytocin in the corpus luteum.

In this report we demonstrate that ovine and bovine luteal cells synthesise oxytocin by way of a precursor protein similar to that found in the hypothalamus. Isolated ovine or bovine luteal cells were incubated for up to 12 h with [35S]cysteine. Neurophysin-Sepharose column separation and HPLC of cell extracts demonstrated the presence of [35S]oxytocin. Incorporation of [35S]cysteine was confirmed by performic acid oxidation. Immunoprecipitation of cell extract with anti-rat oxytocin-neurophysin followed by SDS-PAGE yielded 2 radioactive bands of 14 kDa and 11-12 kDa. Immunoprecipitation with anti-oxytocin yielded 1 band at 14 kDa. On SDS-PAGE the 14 kDa band had a similar mobility to rat-hypothalamic oxytocin precursor.