Long‐term effects of crizotinib in ALK‐positive tumors (excluding NSCLC): A phase 1b open‐label study

Crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK), MET, and ROS1, is approved for treatment of patients with ALK‐positive or ROS1‐positive advanced non‐small‐cell lung cancer (NSCLC). However, ALK rearrangements are also implicated in other malignancies, including anaplastic large‐cell lymphoma and inflammatory myofibroblastic tumors (IMTs). In this ongoing, multicenter, single‐arm, open‐label phase 1b study (PROFILE 1013; NCT01121588), patients with ALK‐positive advanced malignancies other than NSCLC were to receive a starting dose of crizotinib 250 mg twice daily. Primary endpoints were safety and objective responses based on Response Evaluation Criteria in Solid Tumors version 1.1 or National Cancer Institute International Response Criteria. Forty‐four patients were enrolled (lymphoma, n = 18; IMT, n = 9; other tumors, n = 17). The objective response rate was 53% (95% confidence interval [CI], 28–77) for lymphoma, with 8 complete responses (CRs) and 1 partial response (PR); 67% (95% CI, 30–93) for IMTs, with 1 CR and 5 PRs; and 12% (95% CI, 2–36) for other tumors, with 2 PRs in patients affected by colon carcinoma and medullary thyroid cancer, respectively. The median duration of treatment was almost 3 years for patients with lymphoma and IMTs, with 2‐year progression‐free survival of 63% and 67%, respectively. The most common treatment‐related adverse events were diarrhea (45.5%) and vision disorders (45.5%), mostly grade 1. These findings indicate strong and durable activity of crizotinib in ALK‐positive lymphomas and IMTs. The safety profile was consistent with the known safety profile of crizotinib even with long‐term treatment.     

RET‐rearranged non‐small‐cell lung cancer and therapeutic implications

First‐line tyrosine kinase inhibitors are standard of care for non‐small‐cell lung cancers (NSCLC) harbouring an epidermal growth factor receptor mutation, anaplastic lymphoma kinase fusion or c‐ros oncogene 1 rearrangement. Other targetable oncogenic drivers have been identified but testing for these is neither funded nor commonly performed in Australia. Using a case example, we discuss the importance of considering several other genomic aberrations in our population, such as rearrangements in the RET proto‐oncogene, which occur in 1–2% of lung adenocarcinoma. New oncogenic drivers and corresponding targeted agents are constantly being discovered; these will continue to refine the treatment of non‐small‐cell lung cancer in the era of precision medicine.     

No improvement in lung cancer care: the management of lung cancer in 1996 and 2002 in New South Wales

Background: Patterns‐of‐care studies emphasize significant variation in the management of lung cancer. The aim of the study was to compare the patterns of care for patients diagnosed with lung cancer in 1996 and 2002 within three health areas in New South Wales. Methods: Treatment data were collected from medical records and treating doctors for the calendar year 1996 and between 1 November 2001 and 31 December 2002. Patients were residents of either south‐western Sydney, Hunter or Northern Sydney health areas at the time of diagnosis. χ²‐tests were used to investigate changes in treatment patterns between the two time periods. An adjusted odds ratio for treatment in 2002 relative to 1996 was calculated using logistic regression. Results: Data were available for 738 and 567 cases in 1996 and 2002, respectively. Cancer‐specific therapy was given within 6 months of diagnosis to 62 and 64% of patients, respectively. Adjusting for health area, age, sex, pathology and performance status, the odds ratio (OR) of treatment in 2002 relative to 1996 was 1.03 (95% confidence interval (CI) 0.78–1.35). When stage was included, the odds of treatment in 2002 relative to 1996 for non‐small‐cell lung cancer (n = 950) was 1.21 (95%CI 0.87–1.68). After adjustment for potential confounders, patients diagnosed with small‐cell lung cancer (n = 176) were substantially less likely to receive treatment in 2002 compared with patients diagnosed in 1996 (OR = 0.11; 95%CI 0.04–0.34). Conclusion: The odds of receiving treatment in 2002 and 1996 were similar. However, patients diagnosed with small‐cell lung cancer in 2002 were significantly less likely to receive treatment. Overall, this study suggests there has been no change in lung cancer care in New South Wales. Further work is required to determine what proportion of persons with lung cancer should receive cancer‐specific treatment so that clinical practices can be judged appropriately.     

Central retinal artery occlusion,an early sign of crizotinib resistance in an alk positive adenocarcinoma of lung: A rare case report

About 4% of non‐small‐cell lung carcinomas involve an EML4‐ALK tyrosine kinase fusion gene and occur almost absolutely in carcinomas arising in non‐smokers. Crizotinib, the first inhibitor of anaplastic lymphoma kinase (ALK), ROS1 and c‐Met receptor kinase, has been used in the treatment of ALK‐positive non‐small cell lung cancer. Side effects of crizotinib mostly consist of grade 1–2 gastrointestinal events (nausea, vomiting, diarrhea and constipation), grade 1–2 edema and fatigue; grade 1 visual disorders, rare cases of elevated liver enzymes and pneumonitis. We are presenting a case of adenocarcinoma of lung, who progressed on first‐line chemotherapy and received crizotinib as second line therapy for 9 months. Patient has very good partial response to crizotinib and had some side effects of crizotinib like nausea, vomiting, diarrhea, fatigue, asthenia and anorexia, asymptomatic transaminitis in the first 2 to 3 weeks of therapy and managed symptomatically. But after 9 months, he developed sudden onset left sided vision loss. On fundoscopic examination he was found to have “cherry red spot” and fundus flourescein angiography revealed central retinal artery occlusion (CRAO). After 15 days of vision loss patient developed pleural effusion, and pleural fluid cytology was positive for malignant cells. Visual symptoms are very well known in the literature as side effects of crizotinib, but CRAO is not yet been documented. As this patient is not having any prothrombotic state like diabetes, hypertension, atherosclerosis, hyperhomocysteinemia or any genetic disorders except malignancy. Hypercoagulability disorders are known to be commonly associated with a variety of cancer types including lung cancer. This appears to be a sign of early crizotinib resistance in this patient because there was no history of prior hypercoagulable state. To the best of our knowledge this is the first case report in the world literature, as CRAO presenting as a sign of crizotinib resistance in an adenocarcinoma of lung patient who was on crizotinib.     

Prevalence of hepatitis B virus infection in non‐Hodgkin lymphoma: a systematic review and meta‐analysis

Background and aim: A recent meta‐analysis has demonstrated an association between hepatitis C virus and non‐Hodgkin lymphoma (NHL). There is also evidence on the association between hepatitis B virus (HBV) and NHL. The aim of this study was to evaluate this evidence using a meta‐analytic approach. Methods: We searched the MEDLINE database from 1962 to 2008 for case–control studies that have reported the association of HBV with NHL. We calculated the odds ratio (OR) and 95% confidence intervals (CI) to assess the prevalence of HBV infection and pooled the results using three different statistical models. Results: Our search yielded 12 studies with 11 studies (3262 NHL patients, 1 523 205 controls) evaluating HBV infection in NHL and one study (3888 HBV‐infected individuals, 205 203 controls) that had investigated for NHL in HBV infection. The OR of detecting HBV infection in NHL when compared with the control population was 2.56 (95% CI, 2.24–2.92) by the fixed effects model; 2.61 (95% CI, 2.29–2.98) by the exact method and 2.67 (95% CI, 2.04–3.49) by the random effects model suggesting a high prevalence of HBV carrier state in lymphoma. There was evidence of statistical heterogeneity which disappeared after exclusion of retrospective studies on sensitivity analysis. Conclusions: The results of this study suggest a possible causal relation between HBV infection and NHL which needs to be confirmed by experimental and epidemiological studies. In countries where prevalence of HBV infection is 1% or more, it may be prudent to screen patients with NHL for occult HBV infection.     

Polymorphisms of drug‐metabolizing genes and risk of non‐Hodgkin lymphoma

Drug metabolizing genes are involved in the detoxification of chemical carcinogens. Polymorphisms in drug‐metabolizing genes affect the risk of some forms of cancer. We analyzed six polymorphisms to evaluate their association with risk for non‐Hodgkin lymphoma (NHL), and to examine whether smoking modifies these associations in population‐based study in Korea (713 cases and 1,700 controls). The GSTP1 rs1695 AG and the combined AG/GG genotypes were associated with decreased risk of NHL (odds ratio (OR)_AG = 0.67, 95% confidence interval (CI) = 0.55–0.82; OR_AG/GG = 0.66, 95% CI = 0.54–0.80) and DLBCL (OR_AG = 0.63, 95% CI = 0.49–0.82; OR_AG/GG = 0.64, 95% CI = 0.50–0.82). For T‐cell lymphoma, only the combined AG/GG genotype was associated with decreased risk (OR_AG/GG = 0.65, 95% CI = 0.44–0.96). The CYP1A1 rs1048943 AG genotype and the combined AG/GG genotypes were associated with increased risk of NHL (OR_AG = 1.28, 95% CI = 1.07–1.54; OR_AG/GG = 1.26, 95% CI = 1.06–1.51) and DLBCL (OR_AG = 1.32, 95% CI = 1.04–1.66; OR_AG/GG = 1.30, 95% CI = 1.03–1.63), but not T‐cell lymphoma. Smoking does not modify the association between these polymorphisms and NHL risk. Our data provide evidence that the GSTP1 rs1695 and the CYP1A1 rs1048943 genotypes affect the risk of NHL in Korea. Am. J. Hematol. 2009. © 2009 Wiley‐Liss, Inc.     

Hepatitis B virus and risk of non‐Hodgkin lymphoma: An updated meta‐analysis of 58 studies

Previous studies have focused on the relationship between hepatitis B virus (HBV) infection and non‐Hodgkin lymphoma (NHL). However, the results remain inconsistent and somehow conflicting in different subgroups. The aim of this study was to combine the findings of independent studies to comprehensively assess the association between HBV and NHL using a meta‐analysis. Relevant studies were identified through structured keyword searches in PubMed, EMBASE and the China National Knowledge Infrastructure (CNKI) database, and 58 studies with a total of 53 714 NHL cases and 1 778 591 controls were finally included. Pooled estimates indicated a significantly increased NHL risk in HBV‐infected individuals (summary odds ratio [sOR]: 2.50; 95% confidence interval [CI]: 2.20‐2.83) regardless of the study design (case–control studies: sOR: 2.47; 95% CI: 2.16‐2.82; cohort studies: sOR: 2.64; 95% CI: 1.78‐3.91). Considerable heterogeneity was observed across studies that was primarily attributed to the NHL subtypes (meta‐regression: P < .05). Overall, B‐cell NHL (sOR: 2.46; 95% CI: 1.97‐3.07) presented a stronger association with HBV infection than T‐cell NHL (sOR: 1.67; 95% CI: 1.34‐2.10). Within the B‐cell NHL subtypes, HBV infection was significantly associated with diffuse large B‐cell lymphoma (DLBCL, sOR: 2.06; 95% CI: 1.48‐2.88) and follicular lymphoma (FL, sOR: 1.54; 95% CI: 1.11‐2.12), but not with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) and Burkitt lymphoma. The results of this meta‐analysis support a positive link between HBV infection and NHL development. Further investigations for the mechanisms underlying HBV‐induced NHL are warranted.     

Complementary and alternative medicine use among long‐term lymphoma survivors: A pilot study

No published survey has specifically addressed the beliefs, knowledge, and usage of complementary and alternative medicine (CAM) in long‐term (5–20 years) lymphoma survivors alone. In this pilot project, 95 subjects were randomly selected from a population of 2,475 long‐term lymphoma survivors and mailed a questionnaire. The median time from lymphoma diagnosis to completion of the questionnaire was 11 years (range 6–20). Overall, 68% (95% CI: 54–80%) of the long‐term lymphoma survivors reported that they have used CAM, a rate higher than the estimated usage rate reported for the general population The most commonly used modalities were chiropractic (39%, 95% CI: 27–53%) and massage therapy (21%, 95% CI: 12–34%). Less than 10% used meditation (5%, 95% CI: 1–15%) and relaxation (7%, 95% CI: 2–17%). In terms of common herbal usage, 5% (95% CI: 1–15%) had used St. John's Wort and 7% (95% CI: 2–17%) had used shark cartilage. Although none of the patients reported that CAM usage was directed specifically towards treating their lymphoma, 4% (95% CI: 0–12%) of patients reported that CAM could cure cancer, and 14% (95% CI: 6–26%) reported that CAM could increase their feeling of control over their health. This pilot study suggests that long‐term lymphoma survivors appear to use CAM at a rate higher than the general population. The use of potential agents of risk by the survivors and the lack of access to potentially beneficial modalities highlights the need for further study of CAM in this population. Am. J. Hematol., 2009. © 2009 Wiley‐Liss, Inc.     

Dementia medications and risk of falls, syncope, and related adverse events: meta-analysis of randomized controlled trials

OBJECTIVES: To evaluate the effect of cholinesterase inhibitors (ChEIs) and memantine on the risk of falls, syncope, and related events, defined as fracture and accidental injury. DESIGN: Meta‐analysis of randomized controlled trials that were identified from MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (no language restriction, through July 2009), and manual search. SETTING: Community and nursing homes. PARTICIPANTS: Participants in fifty‐four placebo‐controlled randomized trials and extension studies of ChEIs and memantine that reported falls, syncope, and related events in cognitively impaired older adults. MEASUREMENTS: Falls, syncope, fracture, and accidental injury. RESULTS: ChEI use was associated with greater risk of syncope (odds ratio (OR)=1.53, 95% confidence interval (CI)=1.02–2.30) than placebo but not with other events (falls: OR=0.88, 95% CI=0.74–1.04; fracture: OR=1.39, 95% CI=0.75–2.56; accidental injury: OR=1.13, 95% CI=0.87–1.45). Memantine use was associated with fewer fractures (OR=0.21, 95% CI=0.05–0.85) but not with other events (falls: OR=0.92, 95% CI=0.72–1.18; syncope: OR=1.04, 95% CI=0.35–3.04; accidental injury: OR=0.80, 95% CI=0.56–1.12). There was no differential effect according to type and severity of cognitive impairment, residential status, or length of follow‐up, although because of underreporting and small number of events, a potential benefit or risk cannot be excluded. CONCLUSION: ChEIs may increase the risk of syncope, with no effects on falls, fracture, or accidental injury in cognitively impaired older adults. Memantine may have a favorable effect on fracture, with no effects on other events. More research is needed to confirm the reduction in fractures observed for memantine.     

Replication of results of genome-wide association studies on lung cancer susceptibility loci in a Korean population

Background and objective: Genome‐wide association studies (GWAS) have identified the three chromosomal regions, 5p15, 6p21 and 15q25, as being associated with lung cancer risk in European populations. This study was performed to confirm these associations in Korean patients with lung cancer. Methods: The genotypes at rs2736100, rs402710, rs401681 and rs31489 at 5p15, rs9295740 at 6p22, which is in extensive linkage disequilibrium with the 6p21 region, as well as rs2036534 and rs6495309 at 15q25, were determined in 1094 patients with lung cancer and 1100 healthy control subjects, who were frequency matched for age and gender. Results: The single‐nucleotide polymorphisms (SNP) at 5p15 (rs2736100, adjusted odds ratio [aOR] 1.32, 95% confidence interval [CI] 1.03–1.67, P = 0.025; rs402710, aOR 0.82, 95% CI 0.69–0.98, P = 0.025; rs401681, aOR 0.82, 95% CI 0.69–0.98, P = 0.026) and at 15q25 (rs2036534, aOR 0.75, 95% CI 0.61–0.93, P = 0.01; rs6495309, aOR 0.81, 95% CI 0.65–1.00, P = 0.052) were significantly associated with lung cancer risk. The magnitude of the effect was similar to that reported in previous studies, and the association was in the same direction. The effect of SNP in the 5p15 region on the risk of lung cancer was significant only for adenocarcinoma. The two SNP in the 15q25 region were significantly associated with lung cancer risk in ever‐smokers and in patients with squamous‐cell carcinoma. However, there was no association between the SNP at 6p22 and lung cancer risk. Conclusions: The association between SNP in the 5p15 and 15q25 regions and the risk of lung cancer was confirmed in a Korean population.     

Signs of intoxication and server intervention among 18-39-year-olds drinking at licensed premises in New South Wales,Australia

Aims To estimate the extent of responsible service of alcohol (RSA) practice to young adults showing signs of alcohol intoxication on licensed premises in New South Wales. Design Telephone‐based cross‐sectional survey. Setting New South Wales, Australia. Participants A total of 1090 people aged 18–39 years old. Findings Seventy‐five per cent of males and 64% of females reported that they had consumed at levels for acute alcohol‐related harm during the previous 12 months, with 34% of males and 24% of females reporting doing so weekly; 54% (95% CI: 51–58%) of both males and females who had consumed at acute‐risk levels, reported that this last drinking occasion occurred at a licensed premises. Of these, 56% (95% CI: 51–61%) reported that they had exhibited at least one sign of overt alcohol intoxication, while 19% (95% CI: 15–23%) reported showing three or more signs of intoxication. Among those reporting at least one sign of intoxication, only 10% (95% CI: 7–15%) reported that the licensed premises staff had provided at least one of seven different responsible service initiatives, while 55% (95% CI: 48–61%) reported that they were continued to be served alcohol. While these results suggest that intoxicated patrons are not being refused service as often as they should, there was evidence for some degree of responsible service provision with around half of the ‘non‐intoxicated’ patrons reporting that they had seen licensed premises staff intervene in some way with other ‘intoxicated’ patrons. Conclusions While the majority of 18–39‐year‐olds report showing signs of intoxication while drinking at licensed premises in NSW, only a small minority report experiencing RSA initiatives from bar staff in response to these signs.     

Hepatitis C virus risk behaviors within the partnerships of young injecting drug users

Aims Young injection drug users (IDU) are at high risk for hepatitis C virus (HCV). We sought to determine whether perceiving one's injecting partner to be HCV positive was associated with decreased odds of engaging in receptive needle/syringe sharing (RNS) or ancillary equipment sharing (AES) with that partner. Design Cross sectional study. Setting 2003 to 2007 in San Francisco. Participants 212 young (under age 30) IDU who were HCV antibody negative reported on 492 injecting partnerships. Measurements Self‐reported RNS and AES within injecting partnerships. Findings RNS and AES (in the absence of RNS) occurred in 23% and 64% of injecting partnerships in the prior month. The odds of engaging in RNS were significantly lower for relationships in which the participant reported that his/her partner was HCV positive (odds ratio [OR] 0.49; 95% confidence interval [CI] 0.25–0.95). This association was attenuated when adjusted for reusing one's own needle/syringe (adjusted OR 0.57; 95% CI 0.28–1.15). The odds of engaging in AES were lower for participants who did not know the HCV status of their partner, only among non‐sexual partnerships (OR 0.47; 95% CI 0.29–0.76). Conclusions Because perceiving one's partner to be HCV positive was associated with decreased RNS, increased HCV testing and partner disclosure may be warranted. AES was common and was decreased only among non‐sexual partnerships in which the HCV status of the partner was not known. This suggests that interventions to reduce AES in young IDU must be widespread.     

Colorectal endoscopic submucosal dissection: Systematic review of mid‐term clinical outcomes

With a drive towards minimally invasive surgery, endoscopic submucosal dissection (ESD) is now gaining popularity. In a number of East Asian countries, ESD is now the treatment of choice for early non‐metastatic gastric cancer, but the outcomes of ESD for colorectal lesions are unclear. The present review summarizes the mid‐term outcomes of colorectal ESD including complication and recurrence rates. A systematic literature search was done in May 2014, identifying 20 publications reporting the outcomes of colorectal ESD which were included in this review. En‐bloc resection rates, complete (R0) resection rates, endoscopic clearance rates, complication and recurrences rates were analyzed. Statistical pooling was done to calculate weighted means using random effects modeling. Twenty studies reporting the outcomes of 3060 colorectal ESD procedures were reported. Overall weighted en‐bloc resection rate was 89% (95% CI: 83–94%), R0 resection rate 76% (95% CI: 69–83%), endoscopic clearance rate 94% (95% CI: 90–97%) and recurrence rate 1% (95% CI: 0.5–2%). Studies that followed up patients for over 1 year were found to have an en‐bloc resection rate of 91% (95% CI: 86–96%), R0 resection rate of 81% (95% CI: 75–88%), endoscopic clearance rate 93% (95% CI: 90–97%) and recurrence rate of 0.8% (95% CI: 0.4–1%). Colorectal ESD can be carried out effectively and safely with a 1% recurrence rate. Further studies with longer follow‐up periods are required to determine whether colorectal ESD is a viable alternative to conventional surgical therapy.     

Association of widespread body pain with an increased risk of cancer and reduced cancer survival: A prospective,population‐based study

Objective

To determine whether reported widespread body pain is related to an increased incidence of cancer and/or reduced survival from cancer, since our previous population surveys have demonstrated a relationship between widespread body pain and a subsequent 2‐fold increase in mortality from cancer over an 8‐year period.

Methods

A total of 6,565 subjects in Northwest England participated in 2 health surveys during 1991–1992. The subjects were classified according to their reported pain status (no pain, regional pain, and widespread pain), and were subsequently followed up prospectively until December 31, 1999. During followup, information was collected on incidence of cancer and survival rates among those developing cancer. Associations between the original pain status and development of cancer and cancer survival were expressed as the incidence rate ratio (IRR) and mortality rate ratio (MRR), respectively. All analyses were adjusted for age, sex, and study location, the latter being a proxy measure of socioeconomic status.

Results

Among the study population, 6,331 had never been diagnosed with cancer at the time of participation in the survey. Of these subjects, 956 (15%) were classified as having widespread pain, 3,061 (48%) as having regional pain, and 2,314 (37%) as having no pain. There were a total of 395 first malignancies recorded during followup. In comparison with subjects reporting no pain, those with regional pain (IRR 1.19, 95% confidence interval [95% CI] 0.94–1.50) and widespread pain (IRR 1.61, 95% CI 1.21–2.13) experienced an excess incidence of cancer during the followup period. The increased incidence among subjects previously reporting widespread pain was related, most strongly, to breast cancer (IRR 3.67, 95% CI 1.39–9.68), but there were also cancers of the prostate (IRR 3.46, 95% CI 1.25–9.59), large bowel (IRR 2.35, 95% CI 0.96–5.77), and lung (IRR 2.04, 95% CI 0.96–4.34). Subjects reporting widespread pain who subsequently developed cancer, in comparison with those previously reporting no pain, had an increased risk of death (MRR 1.82, 95% CI 1.18–2.80). This decreased survival was highest among subjects with cancers of the breast and prostate, although the effects on site‐specific survival were nonsignificant.

Conclusion

This study has demonstrated that widespread pain reported in population surveys is associated with a substantial subsequent increased incidence of cancer and reduced cancer survival. At present there are no satisfactory biologic explanations for this observation, although several possible leads have been identified.

     

Use of thiopurines in the treatment of inflammatory bowel disease is associated with an increased risk of non-melanoma skin cancer in an at-risk population: a cohort study

Background and Aim: The thiopurines azathioprine and 6‐mercaptopurine are effective in the management of patients with inflammatory bowel disease (IBD) in whom aminosalicylates, antibiotics and corticosteroids have failed to induce or maintain remission. Long‐term use of these agents has been linked to a greatly increased risk of non‐melanoma skin cancer and lymphatic cancer in organ transplant recipients. There is some evidence to suggest that IBD patients receiving thiopurines might be at increased risk of cancer. Our aim was to determine the incidence of cancer in a cohort of patients with IBD managed in our clinic, and to relate this to thiopurine exposure. Methods: We conducted a retrospective study based on the clinical and pathology records of patients attending a specialist IBD clinic at Groote Schuur Hospital, Cape Town, South Africa between 1960 and 2007. Results: We analyzed the records of 1084 patients. A total of 123 subjects (11.5%) had received thiopurine therapy. Cancer was identified in 51 patients (4.7%), including colorectal cancer (15 patients), melanoma (two patients), non‐melanoma skin cancer (seven patients) and non‐Hodgkin's lymphoma (five patients). A diagnosis of non‐melanoma skin cancer was significantly associated with thiopurine exposure (odds ratio 5.0, 95% confidence interval 1.1–22.8). Six of seven non‐melanoma skin cancers occurred in Caucasian patients, with a highly significant association with thiopurine use (odds ratio 12.4, 95% confidence interval 2.3–67.4). Conclusions: Patients with IBD who receive thiopurines are at increased risk of non‐melanoma skin cancer. The risk is highest in Caucasian patients, and is negligible in other groups.     

Prevalence and self-reported health consequences of vaginal practices in KwaZulu-Natal, South Africa: findings from a household survey

Objectives To investigate population‐level prevalence of vaginal practices, their frequency and self‐reported health consequences in KwaZulu‐Natal, South Africa. Methods A household survey using multi‐stage cluster sampling was conducted in 2007. Women aged 18–60 (n = 867) were interviewed on demographics, sexual behaviours and vaginal practices, focusing on intravaginal practices. Design‐based analysis used multivariate logistic regression to identify factors associated with intravaginal or any practice. Results Most women currently perform vaginal practices (90.2%), with 34.8% reporting two and 16.3%≥3 practices. Internal cleansing, the commonest practice (63.3% of women), is undertaken frequently (61.6% cleansing twice daily; 20.0% using ≥2 products). Fewer report application (10.1%), insertion (11.6%) or ingestion (14.3%) practices. Hygiene is a common motivation, even for the 23.2% of women reporting intravaginal practices around the time of sex. Prevalence of any practice was lower among women with tertiary education than those without primary education (AOR = 0.26, 95% CI = 0.08–0.85), nearly twice as common in sexually active women (95% CI = 1.05–3.56) and increased as overall health status declined. Adjusted odds of intravaginal practices were 1.8‐fold higher in women reporting unprotected sex (95% CI = 1.11–2.90). Few reported health problems with current practices (0.6%); though, 12.6% had ever‐experienced adverse effects. Conclusions Vaginal practices are common in KwaZulu‐Natal. Although self‐reported health problems with current practices are rare, high lifetime risk of adverse events and potential for asymptomatic but clinically important damage make continued research important.     

Risk of malignancy in children with juvenile idiopathic arthritis not treated with biologic agents

Objective

To estimate the relative risk of incident cancer diagnosis among patients with juvenile idiopathic arthritis (JIA) compared to patients without JIA.

Methods

A cohort of biologics‐naive patients diagnosed with JIA between 1998 and 2007 and a matched cohort of comparators without JIA were assembled from the PharMetrics Patient‐Centric Database. The primary outcome was any incident malignancy, excluding nonmelanoma skin cancer and carcinoma in situ. Claims profiles of patients with any cancer‐related diagnosis codes were reviewed to determine outcomes. Incidence rates and 95% confidence intervals (95% CIs) of cancer were calculated and compared between cohorts using Cox proportional hazards regression. Standardized incidence ratios (SIRs) for each cohort compared to the general population were calculated using reference rates from the US Surveillance, Epidemiology, and End‐Results (SEER) program.

Results

The JIA and non‐JIA cohorts included 3,605 and 37,689 patients, respectively, with a mean age of 11 years. The incidence rates of cancer were 67.0 (95% CI 1.3–132.5) cases/100,000 person‐years (PY) for JIA and 23.2 (95% CI 12.2–34.2) cases/100,000 PY for non‐JIA. The risk of cancer associated with biologics‐naive JIA was elevated (hazard ratio 2.8, 95% CI 0.9–8.3). The JIA cohort had a significantly elevated SIR of 4.0 (95% CI 2.6–6.0); the non‐JIA cohort SIR was not significantly above SEER rates (SIR 1.4, 95% CI 0.6–2.6).

Conclusion

We found a nearly 3‐fold increased risk of cancer in biologics‐naive JIA patients, which approached significance despite the small number of outcomes. This finding suggests an elevated underlying risk of cancer in this disease population.     

Smokeless tobacco use related to military deployment, cigarettes and mental health symptoms in a large, prospective cohort study among US service members

Aims To characterize smokeless tobacco initiation and persistence in relation to deployment, combat, occupation, smoking and mental health symptoms. Design Prospective cohort, utilizing self‐reported survey data from the Millennium Cohort Study. Setting US military service members in all branches including active duty, reserve and National Guard. Participants Population‐based sample of 45 272 participants completing both baseline (July 2001–June 2003; n = 77 047) and follow‐up (June 2004–January 2006; n = 55 021) questionnaires (follow‐up response rate = 71.4%). Measurements Self‐reported smokeless tobacco initiation and persistence. Findings Over the study period, 72.4% did not deploy, 13.7% deployed without combat exposures and 13.9% deployed with combat exposures, while 1.9% were smokeless tobacco initiators and 8.9% were persistent users. The odds of initiation were greater for deployers with combat exposure [odds ratio (OR), 1.76; 95% confidence interval (CI), 1.49–2.09], deployers without combat exposure (OR, 1.31; 95% CI, 1.07–1.60) and those who deployed multiple times (OR, 1.67; 95% CI, 1.31–2.14), as well as in smoking recidivists/initiators (OR, 4.65; 95% CI, 3.82–5.66) and those reporting post‐traumatic stress disorder symptoms (OR, 1.54; CI, 1.15–2.07). A similar pattern for higher odds of persistent use was observed for deployment and combat exposure, but not for smoking and mental health symptoms. Military occupation was not significantly associated with initiation or persistence. Conclusions Deployment and combat exposure in the US military are associated with increased risk of smokeless tobacco initiation and persistence while smoking and symptoms of post‐traumatic stress disorder increase the odds for initiation. Research is needed on aspects of military service amenable to the reduction or prevention of tobacco consumption.     

Lymphoma in rheumatoid arthritis: The effect of methotrexate and anti–tumor necrosis factor therapy in 18,572 patients

Objective

The risk of lymphoma is increased in patients with rheumatoid arthritis (RA), and spontaneous reporting suggests that methotrexate (MTX) and anti–tumor necrosis factor (anti‐TNF) therapy might be associated independently with an increased risk of lymphoma. However, data from clinical trials and clinical practice do not provide sufficient evidence concerning these issues because of small sample sizes and selected study populations. The objective of this study was to determine the rate of and standardized incidence ratio (SIR) for lymphoma in patients with RA and in RA patient subsets by treatment group. Additionally, we sought to determine predictors of lymphoma in RA.

Methods

We prospectively studied 18,572 patients with RA who were enrolled in the National Data Bank for Rheumatic Diseases (NDB). Patients were surveyed biannually, and potential lymphoma cases received detailed followup. The SEER (Survey, Epidemiology, and End Results) cancer data resource was used to derive the expected number of cases of lymphoma in a cohort that was comparable in age and sex with the RA cohort.

Results

The overall SIR for lymphoma was 1.9 (95% confidence interval [95% CI] 1.3–2.7). The SIR for biologic use was 2.9 (95% CI 1.7–4.9) and for the use of infliximab (with or without etanercept) was 2.6 (95% CI 1.4–4.5). For etanercept, with or without infliximab, the SIR was 3.8 (95% CI 1.9–7.5). The SIR for MTX was 1.7 (95% CI 0.9–3.2), and was 1.0 (95% CI 0.4–2.5) for those not receiving MTX or biologics. Lymphoma was associated with increasing age, male sex, and education.

Conclusion

Lymphomas are increased in RA. Although the SIR is greatest for anti‐TNF therapies, differences between therapies are slight, and confidence intervals for treatment groups overlap. The increased lymphoma rates observed with anti‐TNF therapy may reflect channeling bias, whereby patients with the highest risk of lymphoma preferentially receive anti‐TNF therapy. Current data are insufficient to establish a causal relationship between RA treatments and the development of lymphoma.

     

Use of drug‐eluting stents for chronic total occlusions: A systematic review and meta‐analysis

Aim: To perform a systematic review and meta‐analysis of studies reporting outcomes after drug‐eluting stent (DES) implantation in chronic total occlusions (CTOs). Methods: A review of publications and online databases in January 2010 retrieved 17 published studies that reported outcomes after DES implantation in CTOs: eight uncontrolled studies, seven nonrandomized comparative studies with bare‐metal stents (BMS), one post‐hoc analysis of a randomized trial, and one randomized trial. Data were pooled using random‐effects meta‐analysis models. Results: All published studies evaluated sirolimus‐ or paclitaxel‐eluting stents. All studies reporting comparative angiographic outcomes revealed less binary angiographic restenosis with DES implantation compared to BMS (odds ratio: 0.15, 95% CI: 0.08, 0.26). Over a mean follow‐up period of 18.9 ± 16.5 months, the cumulative incidence of death, myocardial infarction, or stent thrombosis was similar between DES and BMS in all studies. Target lesion revascularization (odds ratio: 0.13, 95% CI: 0.06, 0.26) and target vessel revascularization (odds ratio 0.18, 95% CI: 0.11, 0.31) at 6–12 months were consistently lower among DES‐treated patients. Similar patterns of safety and efficacy event rates were also observed in studies reporting >12 month outcomes. Conclusions: Compared with BMS, treatment of chronic total coronary occlusions with DES is associated with significant reductions in angiographic and clinical restenosis with similar safety. The consistency and magnitude of treatment effect across both individual trials and the pooled analysis establish DES as the preferred therapy for percutaneous revascularization of CTOs. © 2010 Wiley‐Liss, Inc.