Pharmacokinetics and Toxicity of Sodium Selenite in the Treatment of Patients with Carcinoma in a Phase I Clinical Trial: The SECAR Study

Background: Sodium selenite at high dose exerts antitumor effects and increases efficacy of cytostatic drugs in multiple preclinical malignancy models. We assessed the safety and efficacy of intravenous administered sodium selenite in cancer patients’ refractory to cytostatic drugs in a phase I trial. Patients received first line of chemotherapy following selenite treatment to investigate altered sensitivity to these drugs and preliminary assessment of any clinical benefits. Materials and Methods: Thirty-four patients with different therapy resistant tumors received iv sodium selenite daily for consecutive five days either for two weeks or four weeks. Each cohort consisted of at least three patients who received the same daily dose of selenite throughout the whole treatment. If 0/3 patients had dose-limiting toxicities (DLTs), the study proceeded to the next dose-level. If 2/3 had DLT, the dose was considered too high and if 1/3 had DLT, three more patients were included. Dose-escalation continued until the maximum tolerated dose (MTD) was reached. MTD was defined as the highest dose-level on which 0/3 or 1/6 patients experienced DLT. The primary endpoint was safety, dose-limiting toxic effects and the MTD of sodium selenite. The secondary endpoint was primary response evaluation. Results and Conclusion: MTD was defined as 10.2 mg/m², with a calculated median plasma half-life of 18.25 h. The maximum plasma concentration of selenium from a single dose of selenite increased in a nonlinear pattern. The most common adverse events were fatigue, nausea, and cramps in fingers and legs. DLTs were acute, of short duration and reversible. Biomarkers for organ functions indicated no major systemic toxicity. In conclusion, sodium selenite is safe and tolerable when administered up to 10.2 mg/m² under current protocol. Further development of the study is underway to determine if prolonged infusions might be a more effective treatment strategy.     

Efficacy and tolerability of preoperative chemoradiotherapy with S-1 alone for locally advanced rectal cancer

Preoperative chemoradiotherapy with capecitabine or 5-fluorouracil is a standard treatment for locally advanced rectal cancer (LARC). S-1, a prodrug of 5-fluorouracil, is a candidate for this chemoradiotherapy regimen in Japan; however, treatment outcomes after S-1 treatment alone are not clear. This study aimed to assess the efficacy and tolerability of preoperative chemoradiotherapy with S-1 alone for LARC. We retrospectively evaluated 54 LARC patients who underwent preoperative chemoradiotherapy with S-1 alone in our institution between 2005 and 2017. The clinical tumor stage was cT2–3 in 31 patients and cT4 in 23 patients, and lymph node metastases were clinically evident in 31 patients. S-1, at a dose of 80 mg/m²/day, was orally administered during radiotherapy. A total dose of 45–50.4 Gy was delivered in 25–28 fractions (median: 50.4 Gy). Surgical resections were scheduled 6–10 weeks after chemoradiotherapy completion. The 3- and 5-year overall survival rates were 92.4 and 72.8%, respectively, with a median follow-up time of 51 months. The 3- and 5-year local control rates were 96.2 and 85.9%, respectively. A pathological complete response was observed in 7 patients (13.0%) at the time of surgery. Ten patients (18.5%) had grade 3 acute toxicities and 5 patients (9.3%) had grade 3 late toxicities. No grade 4 or 5 toxicities were observed. Preoperative chemoradiotherapy with S-1 alone followed by total mesorectal excision resulted in a low incidence of toxicities and comparable clinical results. Therefore, S-1 alone can be a treatment option for preoperative chemoradiotherapy in LARC patients.     

Concurrent chemoradiotherapy for T3–4 and N0–1 nasopharyngeal cancer: Asian multicenter trial of the Forum for Nuclear Cooperation in Asia

The aim of this study was to evaluate the toxicity and efficacy of radiotherapy concurrent with weekly cisplatin for T3–4 and N0–1 nasopharyngeal cancer. Between 2005 and 2010, 70 patients with nasopharyngeal cancer (T3–4 N0–1 M0, World Health Organization Type 2–3) from Vietnam, Indonesia, Malaysia and Thailand were registered. Patients were treated with 2D radiotherapy concurrent with weekly cisplatin (30 mg/m²). Neither adjuvant nor induction chemotherapy was given. Ninety-three percent of the patients completed at least four cycles of weekly cisplatin during radiotherapy. The median total doses for the primary tumor and positive lymph nodes were 70 and 66 Gy, respectively. The median overall treatment time of concurrent chemoradiotherapy was 52 days. No treatment-related deaths occurred. Grade 3–4 acute toxicities of mucositis, nausea/vomiting and leukopenia were observed in 34%, 4% and 4% of patients, respectively. With a median follow-up time of 52 months for the 40 surviving patients, the 3-year local control, locoregional tumor control, distant metastasis–free survival and overall survival rates were 80%, 75%, 74% and 80%, respectively. In conclusion, the current results illustrate that our concurrent chemoradiotherapy regimen was feasible, but disease control remained insufficient. Further research is encouraged in order to improve clinical outcomes.     

Initial experience of radiotherapy plus cetuximab for Japanese head and neck cancer patients

In Japan, cetuximab with concurrent bioradiotherapy (BRT) for squamous cell carcinoma of head and neck (SCCHN) was approved in December 2012. We herein report our initial experience of BRT, with special emphasis on acute toxicities of this combination therapy. Thirty-one non-metastatic SCCHN patients who underwent BRT using cetuximab between July 2013 and June 2014 were retrospectively evaluated. All patients received cetuximab with a loading dose of 400 mg/m² one week before the start of radiotherapy, followed by 250 mg/m² per week during radiotherapy. The median cycle of cetuximab was seven cycles and the median dose of radiotherapy was 70 Gy. Twenty-five patients (80.6%) accomplished planned radiotherapy and six cycles or more cetuximab administration. Six patients (19.4%) discontinued cetuximab. Grade 3 dermatitis, mucositis and infusion reaction occurred in 19.4%, 48.3% and 3.2%, respectively. One patient experienced Grade 3 gastrointestinal bleeding caused by diverticular hemorrhage during BRT. Grade 3 drug-induced pneumonitis occurred in two patients. The response rate was 74%, including 55% with a complete response. BRT using cetuximab for Japanese patients with SCCHN was feasible as an alternative for cisplatin-based concurrent chemoradiation, although longer follow-up is necessary to evaluate late toxicities.     

Analysis of simultaneous modulated accelerated radiotherapy (SMART) for nasopharyngeal carcinomas

The purpose of this study was to analyze the clinical outcomes of simultaneous modulated accelerated radiotherapy (SMART) in patients with nasopharyngeal carcinoma (NPC). A total of 97 patients who underwent SMART for NPC between August 2005 and November 2011 were evaluated. The prescribed dose was 69.9 Gy/30 fractions at 2.33 Gy/fraction to the primary gross tumor volume (PGTV) including the nasopharynx gross target volume and the positive neck lymph nodes, and 60 Gy/30 fraction at 2.0 Gy/fraction to the PCTV1; 54 Gy/30 fractions at 1.8 Gy/fraction was given to the PCTV2. Among 59 patients with local advanced disease, 31 patients received concurrent chemoradiotherapy (chemo-RT) with a regimen consisting of 135 mg/m² paclitaxel on Day 1 and 25 mg/m² cisplatin on Days 1–3. The median follow-up period was 42 months. The local control rate (LCR), distant metastases-free survival (DMFS) and overall survival (OS) rates were 93.3%, 90.3% and 91.6% at 3 years, and 87.6%, 87.9% and 85.7% at 5 years, respectively. There was no significant difference in outcome with respect to these three indicators for Stage III and IV disease treated with/without concurrent chemoradiotherapy (P > 0.05). Acute toxicities included Grade 3 mucositis, skin desquamation, and leucopenia, which occurred in 78 (80.4%), 8 (8.2%), and 45 (46.4%) patients, respectively. No patient had a Grade 3–4 late toxicity. SMART was associated with a favorable outcome for NPC with acceptable toxicity. The local-regional control was excellent but distant metastasis remains the main risk. The combination of SMART and chemotherapy needs to be optimized through further studies to enhance outcomes for locally advanced diseases.     

Neoadjuvant capecitabine,bevacizumab and radiotherapy for locally advanced rectal cancer: results of a single-institute Phase I study

The aim of this Phase I clinical trial was to assess the feasibility and safety of capecitabine-based preoperative chemoradiotherapy (CRT) combined with bevacizumab and to determine the optimal capecitabine dose for Japanese patients with locally advanced rectal cancer. Patients with cT3/T4 rectal cancer were eligible. Bevacizumab was administered at 5 mg/kg intravenously on Days 1, 15 and 29. Capecitabine was administered on weekdays concurrently with pelvic radiotherapy at a daily dose of 1.8 Gy, totally to 50.4 Gy. Capecitabine was initiated at 825 mg/m² twice daily at Dose Level 1, with a planned escalation to 900 mg/m² twice daily at Dose Level 2. Within 6.1–10.3 (median, 9.4) weeks after the completion of the CRT, surgery was performed. Three patients were enrolled at each dose level. Regarding the CRT-related acute toxicities, all of the adverse events were limited to Grade 1. There was no Grade 2 or greater toxicity. No patient needed attenuation or interruption of bevacizumab, capecitabine or radiation. All of the patients received the scheduled dose of CRT. All of the patients underwent R0 resection. Two (33.3%) of the six patients had a pathological complete response, and five (83.3%) patients experienced downstaging. In total, three patients (50%) developed postoperative complications. One patient developed an intrapelvic abscess and healed with incisional drainage. The other two patients healed following conservative treatment. This regimen was safely performed as preoperative CRT for Japanese patients with locally advanced rectal cancer. The recommended capecitabine dose is 900 mg/m² twice daily.     

Diet-Related Phototoxic Reactions in Psoriatic Patients Undergoing Phototherapy: Results from a Multicenter Prospective Study

Vegans and vegetarians often consume foods containing photosensitizers capable of triggering phytophotodermatitis. The potential effect of vegan and vegetarian diets on the response of psoriatic patients undergoing phototherapy is not well characterized. We assessed clinical outcomes of vegan, vegetarian and omnivore adult psoriatic patients undergoing band ultraviolet B phototherapy (NB-UVB). In this multicenter prospective observational study, we enrolled 119 adult, psoriatic patients, of whom 40 were omnivores, 41 were vegetarians and 38 were vegans, with phototherapy indication. After determining the minimum erythemal dose (MED), we performed NB-UVB sessions for 8 weeks. The first irradiation dosage was 70.00% of the MED, then increased by 20.00% (no erythema) or by 10.00% (presence of erythema) until a maximum single dose of 3 J/cm² was reached and constantly maintained. All the enrolled patients completed the 8 weeks of therapy. Severe erythema was present in 16 (42.11%) vegans, 7 (17.07%) vegetarians and 4 (10.00%) omnivores (p < 0.01). MED was lowest among vegans (21.18 ± 4.85 J/m²), followed by vegetarians (28.90 ± 6.66 J/m²) and omnivores (33.63 ± 4.53 J/m², p < 0.01). Patients with severe erythema were more likely to have a high furocumarin intake (OR 5.67, 95% CI 3.74–8.61, p < 0.01). Vegans consumed the highest amount of furocumarin-rich foods. A model examining erythema, adjusted for gender, age, skin type, MED, phototherapy type, number of phototherapies and furocumarin intake, confirmed that vegans had a lower number of treatments. Vegans had more frequent severe erythema from NB-UVB, even after adjustment of the phototherapy protocol for their lower MED. Assessing diet information and adapting the protocol for vegan patients may be prudent.     

Impact of concurrent chemotherapy on definitive radiotherapy for women with FIGO IIIb cervical cancer

The purpose of this retrospective study is to investigate the impact of concurrent chemotherapy on definitive radiotherapy for the International Federation of Gynecology and Obstetrics (FIGO) IIIb cervical cancer. Between 2000 and 2009, 131 women with FIGO IIIb cervical cancer were treated by definitive radiotherapy (i.e. whole pelvic external beam radiotherapy for 40–60 Gy in 20–30 fractions with or without center shielding and concomitant high-dose rate intracavitary brachytherapy with 192-iridium remote after loading system for 6 Gy to point A of the Manchester method). The concurrent chemotherapy regimen was cisplatin (40 mg/m²/week). After a median follow-up period of 44.0 months (range 4.2–114.9 months) and 62.1 months for live patients, the five-year overall survival (OS), loco-regional control (LRC) and distant metastasis-free survival (DMFS) rates were 52.4, 80.1 and 59.9%, respectively. Univariate and multivariate analyses revealed that lack of concurrent chemotherapy was the most significant factor leading to poor prognosis for OS (HR = 2.53; 95% CI 1.44–4.47; P = 0.001) and DMFS (HR = 2.53; 95% CI 1.39–4.61; P = 0.002), but not for LRC (HR = 1.57; 95% CI 0.64–3.88; P = 0.322). The cumulative incidence rates of late rectal complications after definitive radiotherapy were not significantly different with or without concurrent chemotherapy (any grade at five years 23.9 vs 21.7%; P = 0.669). In conclusion, concurrent chemotherapy is valuable in definitive radiotherapy for Japanese women with FIGO IIIb cervical cancer.     

Efficacy and safety of nedaplatin-based concurrent chemoradiotherapy for FIGO Stage IB2–IVA cervical cancer and its clinical prognostic factors

Cisplatin-based concurrent chemoradiotherapy (CCRT) is a standard treatment for cervical cancer, but nedaplatin-based CCRT is not routinely administered. We evaluated the efficacy and safety of nedaplatin-based CCRT (35 mg/m² weekly) and analyzed prognostic factors for survival among 52 patients with International Federation of Gynecology and Obstetrics (FIGO) Stage IB2–IVA cervical cancer treated from 1999 to 2009. Patients were treated with a combination of external beam radiotherapy of 40–56 Gy (in 20–28 fractions) and 13.6–28.8 Gy (in 2–4 fractions) of high-dose-rate (HDR) intracavitary brachytherapy or 18 Gy (in 3 fractions) of HDR interstitial brachytherapy. Overall survival (OS), progression-free survival (PFS), and local control (LC) were estimated using the Kaplan–Meier method. The Cox proportional hazard model was used for multivariate analysis. Acute and late toxicities were evaluated using the Common Terminology Criteria for Adverse Events version 4.0. The median follow-up period was 52 months. The median patient age was 63 years. The 5-year OS, PFS and LC rates were 78%, 57% and 73%, respectively. Multivariate analysis showed that histologic type, maximum tumor diameter, and pretreatment hemoglobin level were independent risk factors for PFS. Regarding adverse effects, 24 patients (46%) had acute Grade 3–4 leukopenia and 5 (10%) had late Grade 3 gastrointestinal toxicities. No patient experienced renal toxicity. Nedaplatin-based CCRT for FIGO Stage IB2–IVA cervical cancer was efficacious and safe, with no renal toxicity. Histologic type, maximum tumor diameter, and pretreatment hemoglobin level were statistically significant prognostic factors for PFS.     

Effect of different treatment plans on irradiated small-bowel volume in gynecologic patients undergoing whole-pelvic irradiation

To evaluate the effect of different treatment plans for whole-pelvic irradiation on small-bowel volumes (SBVs) in patients with gynecologic malignancies, 40 patients were enrolled in this study. Computed tomography (CT) simulations were performed, and the small bowel of each patient was outlined manually. Treatment plans with equal-weighted (EW) and non-equal-weighted (NEW) (70% in bilateral directions) techniques of four-field and intensity-modulated radiation therapy (IMRT) were performed. The V10–V100 represented the volume (cm³) at different levels of the prescribed doses (10–100%). The V10–V100 was compared among the different treatment planning techniques, and patients who were suitable for IMRT or NEW were identified. IMRT and NEW significantly reduced the V50–V100 and V40–V60 levels compared with EW, respectively. NEW caused a significant reduction in the V30–V60 levels in patients with a BMI ≥26 kg/m². Patients with IMRT demonstrated lower V70–V100 levels compared with those with NEW. In patients with a BMI ≥26 kg/m² or an age ≥55 years, lower V20–V50 levels were noted using NEW compared with IMRT. Treatment planning with larger weighting in the bilateral directions in four-field radiotherapy reduces the low-dose SBV in patients with gynecologic malignancies, especially in those with a high BMI or the elderly. IMRT effectively reduces high-dose SBV, especially in patients with a low BMI.     

Protective effect and the therapeutic index of indralin in juvenile rhesus monkeys

The radioprotective effect of indralin in rhesus monkeys was examined over 60 d following gamma irradiation. Male and female rhesus macaques (Macaca mulatta) 2–3-years-old and weighing 2.1–3.5 kg were used. Animals were exposed to total-body gamma irradiation from ⁶⁰Co at a dose of 6.8 Gy (lethal dose, 100% lethality over 30 days). Indralin (40–120 mg kg^–1) was administered intramuscularly 5 min prior to radiation exposure. Indralin taken at a dose of 120 mg kg^–1 protected five out of six monkeys (compared with the radiation control group, in which all 10 animals died). The average effective dose of indralin in the monkeys exposed to gamma irradiation for 30 min was equal to 77.3 (63.3–94.3) mg kg^–1, and the maximum tolerated dose of indralin administered to monkeys was 800 mg kg^–1. Indralin reduced radiation-induced injuries in macaques, thus resulting in a less severe course of acute radiation syndrome. Delayed and less pronounced manifestation of the haemorrhagic syndrome of the disease, and milder forms of both leukopenia and anaemia were also noted. The therapeutic index for indralin, expressed as the ratio of the maximum tolerated dose to the average effective dose_, was equal to 10. Therefore, indralin has a significant radioprotective effect against radiation and has a high therapeutic index in rhesus monkeys.     

Inflammation in Relation to Sarcopenia and Sarcopenic Obesity among Older Adults Living with Chronic Comorbidities: Results from the National Health and Nutrition Examination Survey 1999–2006

Loss of muscle mass and waning in muscle strength are common in older adults, and inflammation may play a key role in pathogenesis. This study aimed to examine associations of C-reactive protein (CRP) and systemic immune-inflammation index (SII) with sarcopenia and sarcopenic obesity in older adults with chronic comorbidities. Cross-sectional data from the National Health and Nutrition Examination Survey (1999–2006) were obtained for participants aged ≥60 years. Sarcopenia was defined by a lean mass and body height (males < 7.26 kg/m², females < 5.45 kg/m²). Sarcopenic obesity was defined by the concurrent presence of sarcopenia and obesity (defined by relative fat mass). Logistic regression was used to assess the associations of CRP and SII with sarcopenia and sarcopenic obesity. The dose–response relationship was examined via restricted cubic splines. Of the participants (n = 2483), 23.1% (n = 574) and 7.7% (n = 190) had sarcopenia and sarcopenic obesity, respectively. The multivariable logistic regression models suggested a positive association of SII with sarcopenia and sarcopenic obesity, but a positive statistically significant association was not consistently observed for CRP. Dose–response curves suggested similar association patterns for these biomarkers. In clinical practice, measures to prevent sarcopenia and sarcopenic obesity are needed for older vulnerable people with high systemic inflammation.     

Adaptive dose finding for phase I clinical trials of drugs used for chemotherapy of cancer

Phase I clinical trials of cancer chemotherapy drugs are intended to determine the maximum tolerable dose (MTD). Thestandard method employed is a rule-based dose-escalation scheme in which escalation depends on the number of patients at a dose level that have dose-limiting toxicity (DLT). The MTD is thus defined in terms of the rules and a series of dose levels selected for sampling. For some trials it is desirable to have a more precise definition of the MTD, and to determine the MTD more accurately than possible with the rule-based schemes. Continuous reassessment methods (CRMs) define the MTD to be the dose at which a fixed fraction of patients experience DLT, and thus appear suited to these trials. It is shown, however, that these methods can have failure modes that in fact make them unattractive. An alternative data-driven dose-finding method is described that combines the robustness of the rule-based methods and with features of CRMs. The method has two stages. In the first stage, doses are escalated by a factor of 1.5. In the second stage, which begins at the first instance of DLT, a two-parameter logistic dose-response model estimates the MTD from the DLT experience of all patients. The model is initialized by setting the dose (d10) at which 10 per cent of patients would experience DLT to half the dose at which the first DLT was observed, and the dose (d90) at which 90 per cent would experience DLT to ten times d10. Weights are assigned such that the information at d10 and d90 is equivalent to that of one patient at each of the two doses. Cohorts of three patients are treated in both stages, and the dose for a new cohort in the second stage is the estimated MTD. The only prior information required to specify the design completely is the dose which will be given to the first cohort. Two stopping rules are investigated; among the requirements for these are that at least three (or four) DLTs be observed and at least nine patients be treated in the second stage. Simulations show that a coefficient of variation of approximately 0.4 on a target DLT probability of 0.3 is obtained over a wide variation in dose-response characteristics of the study drug. The performance of the new method is compared to that of rule-based methods.     

Mean esophageal radiation dose is predictive of the grade of acute esophagitis in lung cancer patients treated with concurrent radiotherapy and chemotherapy

The intention of this research was to define the predictive factors for acute esophagitis (AE) in lung cancer patients treated with concurrent chemotherapy and three-dimensional conformal radiotherapy. The data for 72 lung cancer patients treated with concurrent chemoradiotherapy between 2008 and 2010 were prospectively evaluated. Mean lung dose, mean dose of esophagus, volume of esophagus irradiated and percentage of esophagus volume treated were analysed according to esophagitis grades. The mean esophageal dose was associated with an increased risk of esophageal toxicity (Kruskal-Wallis test, P < 0.001). However, the mean lung dose and the volume of esophagus irradiated were not associated with an increased risk of esophageal toxicity (Kruskal-Wallis test, P = 0.50 and P = 0.41, respectively). The mean radiation dose received by the esophagus was found to be highly correlated with the duration of Grade 2 esophagitis (Spearman test, r = 0.82, P < 0.001). The mean dose of esophagus ≥28 Gy showed statistical significance with respect to AE Grade 2 or worse (receiver operating characteristic curve analysis, 95% CI, 0.929–1.014). In conclusion, the mean esophageal dose was significantly associated with a risk of esophageal toxicity in patients with lung cancer treated with concurrent radiotherapy and chemotherapy.     

A Specific High-Protein Weight Loss Program Does Not Impair Renal Function in Patients Who Are Overweight/Obese

Although high-protein diets appear to be the most efficient way to lose weight, concerns may arise about their innocuity on renal function. The objective of this study is to assess the impact of a weight loss program on renal function. A multicentric cohort-based study was performed using the RNPC© French national weight loss program. Patients with at least two creatinine measurements at the beginning of the program and at the end of the weight loss phase between 1 January 2016 and 1 July 2021 were included. Renal function was assessed by Modification of Diet in Renal Disease (MDRD) equation-based estimated glomerular filtration rate (eGFR). From 4394 patients with two creatinine measurements included, 1579 (35.9%) had normal eGFR (MDRD 90–120 mL/min/1.73 m²), 210 (4.8%) had hyperfiltration (MDRD > 120 mL/min/1.73 m²), 2383 (54.2%) had chronic kidney disease (CKD) grade 2 (MDRD 60–90 mL/min/1.73 m²), and 221 (5.0%) had CKD grade 3 (MDRD 30–60 mL/min/1.73 m²). Multivariable analyses showed no eGFR change for patients in initial CKD grade 2, normal eGFR and hyperfiltration, and a significant increase in CKD grade 3. The RNPC© program avoids renal function impairment during the two first phases, regardless of the initial eGFR.     

Silicosis prevalence and exposure-response relations in South African goldminers

Aims: To measure the prevalence of silicosis among black migrant contract workers on a South African goldmine and to investigate exposure-response relations with silica dust.

Methods: In a cross sectional study, 520 black goldminers (aged >37 years) were interviewed and had chest radiographs taken. Silicosis was defined as International Labour Organisation Classification radiological profusion of 1/1 or greater.

Results: Mean length of service was 21.8 years (range 6.3–34.5). The mean intensity of respirable dust exposure was 0.37 mg/m³ (range 0–0.70) and of quartz 0.053 mg/m³ (range 0–0.095). The prevalence of silicosis was 18.3–19.9% depending on reader. Significant trends were found between the prevalence of silicosis and length of service, mean intensity of exposure, and cumulative exposure.

Conclusion: Results confirm a large burden of silicosis among older black workers in the South African goldmining industry, which is likely to worsen as such miners spend longer periods in continuous employment in dusty jobs. An urgent need for improved dust control in the industry is indicated. If the assumption of stability of average dust concentrations on this mine over the working life of this group of workers is correct, these workers developed silicosis while exposed to a quartz concentration below the recommended occupational exposure limit (OEL) of 0.1 mg/m³. This accords with a mounting body of evidence that an OEL of 0.1 mg/m³ is not protective against silicosis.

     

Association of Body Mass Index and Mortality in Japanese Diabetic Men and Women Based on Self-Reports: The Japan Collaborative Cohort (JACC) Study

Background

The association between body mass index (BMI) and mortality among Asian diabetic people, especially with respect to the obesity paradox (ie, higher BMI is associated with lower mortality risk), remains unresolved.

Methods

We followed a cohort of 3851 self-reported Japanese diabetics (2115 men and 1736 women) in the Japan Collaborative Cohort Study from 1988–1990 through 2009. Individuals were aged 40 to 79 years and free from a history of cardiovascular disease, cancer, renal disease, or tuberculosis. BMI was grouped into the following four categories: <20.0, 20.0–22.9, 23.0–24.9, and ≥25.0 kg/m².

Results

During 54 707 person-years of follow-up, 1457 deaths from all causes, 445 from cardiovascular disease, 421 from cancer, 43 from renal disease, and 148 from infectious disease were documented. Mortality from all causes, cardiovascular disease, cancer, and renal disease showed L-shaped associations with BMI. Compared to diabetics with BMI of 20.0–22.9 kg/m², those with BMIs of 23.0–24.9 kg/m² and ≥25.0 kg/m² had lower risks of mortality from infectious disease (ie, obesity paradox). The multivariable HRs for mortality from infectious disease were 0.50 (95% confidence interval, 0.31–0.81) and 0.51 (95% confidence interval, 0.32–0.82) among participants with BMIs of 23.0–24.9 kg/m² and ≥25.0 kg/m², respectively. Similar results were observed after stratification by smoking status and age and exclusion of early deaths.

Conclusions

We observed L-shaped associations between BMI and mortality from all causes, cardiovascular disease, cancer, and renal disease, while the association between BMI and mortality from infectious disease manifested the obesity paradox.Key words: diabetes, body mass index, mortality, infection, obesity paradox     

Curcumin and Gemcitabine in Patients With Advanced Pancreatic Cancer

Curcumin has a potent antiproliferative activity and can also potentiate the antitumor effect of gemcitabine. This study was undertaken to evaluate the activity and feasibility of gemcitabine in combination with curcumin in patients with advanced pancreatic cancer. Seventeen patients were enrolled in the study and received 8,000 mg of curcumin by mouth daily, concurrently with gemcitabine 1,000 mg/m² IV weekly × 3 of 4 wk; 5 patients (29%) discontinued curcumin after a few days to 2 wk due to intractable abdominal fullness or pain, and the dose of curcumin was reduced to 4,000 mg/day because of abdominal complaints in 2 other patients. One of 11 evaluable patients (9%) had partial response, 4 (36%) had stable disease, and 6 (55%) had tumor progression. Time to tumor progression was 1–12 mo (median 2½), and overall survival was 1–24 mo (median 5). Low compliance for curcumin at a dose of 8,000 mg/day, when taken together with systemic gemcitabine, may prevent the use of high doses of oral curcumin needed to achieve systemic effect. Further studies should be conducted to evaluate the ability of other formulations of curcumin to enhance the effect of chemotherapy in cancer patients.     

The London Underground: dust and hazards to health

Aims: To assess hazards associated with exposure to dust in the London Underground railway and to provide an informed opinion on the risks to workers and the travelling public of exposure to tunnel dust.

Methods: Concentrations of dust, as mass (PM_2.5) and particle number, were measured at different underground stations and in train cabs; its size and composition were analysed; likely maximal exposures of staff and passengers were estimated; and in vitro toxicological testing of sample dusts in comparison with other dusts was performed.

Results: Concentrations on station platforms were 270–480 µg/m³ PM_2.5 and 14 000–29 000 particles/cm³. Cab concentrations over a shift averaged 130–200 µg/m³ and 17 000–23 000 particles/cm³. The dust comprised by mass approximately 67% iron oxide, 1–2% quartz, and traces of other metals, the residue being volatile matter. The finest particles are drawn underground from the surface while the coarser dust is generated by interaction of brakes, wheels, and rails. Taking account of durations of exposure, drivers and station staff would have maximum exposures of about 200 µg/m³ over eight hours; the occupational exposure standard for welding fume, as iron oxide, is 5 mg/m³ over an eight hour shift. Toxicology showed the dust to have cytotoxic and inflammatory potential at high doses, consistent with its composition largely of iron oxide.

Discussion: It is unjustifiable to compare PM_2.5 exposure underground with that on the surface, since the adverse effects of iron oxide and combustion generated particles differ. Concentrations of ultrafine particles are lower and of coarser (PM_2.5) particles higher underground than on the surface. The concentrations underground are well below allowable workplace concentrations for iron oxide and unlikely to represent a significant cumulative risk to the health of workers or commuters.