The association of body mass index with safety and effectiveness of first-line carboplatin-based chemotherapy in patients with metastatic non-small cell lung cancer.

INTRODUCTION: Carboplatin is an anticancer drug used for treatment of various types of cancer including non-small cell lung cancer (NSCLC). Dosing is based on estimated glomerular filtration rate (GFR) using the Cockcroft-Gault formula. In overweight patients, the GFR is more likely overestimated, resulting in a potentially overdose of carboplatin affecting treatment response. This study investigated the association of body mass index (BMI) on overall survival (OS) and progression-free survival (PFS) in stage-IV NSCLC patients treated with first-line carboplatin-based chemotherapy. Secondary safety endpoints were thrombocytopenia and toxicity-related hospitalizations. MATERIALS AND METHODS: This was a retrospective multicenter cohort study. Patients were categorized according to BMI<25.0 kg/m2 (normal weight and reference), 25.0-29.9 kg/m2 (overweight) or ≥30.0 kg/m2 (obese). For survival analyses adjusted hazard ratios [aHR] were calculated using multivariate Cox regression analysis. Secondary outcomes were analyzed using multivariate logistic regression providing adjusted odd ratios [aOR]. RESULTS: Overweight patients (n=174) had a significantly better OS (aHR=0.72, 95%-CI:0.59-0.89) and PFS (aHR=0.74, 95%-CI:0.61-0.90) compared to normal weight patients (n=268). OS nor PFS were different in obese (n=51) compared to normal weight patients. However, obesity was associated with significantly higher incidences of thrombocytopenia grade ≥3 (aOR=3.47, 95%-CI:1.75-6.90). CONCLUSION: This study shows a significantly longer survival for overweight compared to normal weight patients. Obese patients have an increased risk for grade ≥3 thrombocytopenia without a difference in survival following carboplatin-based chemotherapy. The implications for clinical practice are to use the Cockcroft-Gault formula with caution in patients with BMI≥30.0 kg/m2, and to verify calculated dosing of carboplatin for appropriateness.

Dichotomous ALK-IHC Is a Better Predictor for ALK Inhibition Outcome than Traditional ALK-FISH in Advanced Non-Small Cell Lung Cancer.

Purpose: ALK rearrangement detection using FISH is the standard test to identify patients with non-small cell lung carcinoma (NSCLC) eligible for treatment with ALK inhibitors. Recently, ALK protein expression in resectable NSCLC showed predictive value. We evaluated tumor response rate and survival after crizotinib treatment of patients with advanced NSCLC with ALK activation using both dichotomous immunohistochemical (IHC) staining and FISH.Experimental Design: Patients with stage IV NSCLC treated with crizotinib were selected. Tumor response was assessed. ALK rearrangements were detected by FISH (Vysis ALK-break-apart FISH-Probe KIT) and IHC [Ventana ALK (D5F3) CDx assay]. Cohorts of patients with ALK-FISH-positive advanced NSCLC from four other hospitals were used for validation.Results: Twenty-nine consecutive patients with ALK-positive advanced NSCLC diagnosed by FISH and/or IHC on small biopsies or fine-needle aspirations (FNA) were treated with ALK inhibitors. All ALK-IHC-positive patients responded to crizotinib except three with primary resistance. No tumor response was observed in 13 ALK-FISH-positive but ALK-IHC-negative patients. This was confirmed in an external cohort of 16 patients. Receiver operator characteristic (ROC) curves for ALK-IHC and ALK-FISH compared with treatment outcome showed that dichotomous ALK-IHC outperforms ALK-FISH [tumor response area under the curve: (AUC), 0.86 vs. 0.64, P = 0.03; progression-free survival (PFS): AUC 0.86 vs. 0.36, P = 0.005; overall survival (OS): AUC, 0.78 vs. 0.41, P = 0.01, respectively].Conclusions: Dichotomous ALK-IHC is superior to ALK-FISH on small biopsies and FNA to predict tumor response and survival to crizotinib for patients with advanced NSCLC. Our data strongly suggest adapting the guidelines and using dichotomous ALK-IHC as standard companion diagnostic test to select patients with NSCLC who benefit from ALK-targeting therapy. Clin Cancer Res; 23(15); 4251-8. ©2017 AACR.

A randomized phase II study comparing paclitaxel-carboplatin-bevacizumab with or without nitroglycerin patches in patients with stage IV nonsquamous nonsmall-cell lung cancer: NVALT12 (NCT01171170)†.

BACKGROUND: Nitroglycerin (NTG) increases tumor blood flow and oxygenation by inhibiting hypoxia-inducible-factor (HIF)-1. A randomized phase II study has shown improved outcome when NTG patches were added to vinorelbine/cisplatin in patients with advanced nonsmall-cell lung cancer (NSCLC). In addition, there is evidence that the combination of bevacizumab and HIF-1 inhibitors increases antitumor activity. PATIENTS AND METHODS: In this randomized phase II trial, chemo-naive patients with stage IV nonsquamous NSCLC were randomized to four cycles of carboplatin (area under the curve 6)-paclitaxel (200 mg/m(2))-bevacizumab 15 mg/kg on day 1 every 3 weeks with or without NTG patches 15 mg (day -2 to +2) followed by bevacizumab with or without NTG until progression. Response was assessed every two cycles. Primary end point was progression-free survival (PFS). The study was powered (80%) to detect a decrease in the hazard of tumor progression of 33% at α = 0.05 with a two-sided log-rank test when 222 patients were enrolled and followed until 195 events were observed. RESULTS: Between 1 January 2011 and 1 January 2013, a total of 223 patients were randomized; 112 control arm and 111 experimental arm; response rate was 54% in control arm and 38% in experimental arm. Median [95% confidence interval (CI)] PFS in control arm was 6.8 months (5.6-7.3) and 5.1 months (4.2-5.8) in experimental arm, hazard ratio (HR) 1.27 (95% CI 0.96-1.67). Overall survival (OS) was 11.6 months (8.8-13.6) in control arm and 9.4 months (7.8-11.3) in experimental arm, HR 1.02 (95% CI 0.71-1.46). In the experimental arm, no additional toxicity was observed except headache (6% versus 52% in patients treated with NTG). CONCLUSION: Adding NTG to first-line carboplatin-paclitaxel-bevacizumab did not improve PFS and OS in patients with stage IV nonsquamous NSCLC.

Current status of research on osteoporosis in COPD: a systematic review.

Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of osteoporosis. However, the prevalence, correlates and effectiveness of treatment of osteoporosis in COPD patients remain unclear. We performed a systematic review of the literature to answer three questions. 1) What is the prevalence of osteoporosis in COPD? 2) What are identified correlates of osteoporosis in COPD? 3) What are the effects of treatment of osteoporosis in COPD? A computerised literature search in MEDLINE/PubMed and the Cochrane database was carried out. In addition, reference lists were searched by hand and authors were contacted if necessary. The prevalence of osteoporosis and osteopenia varied 9-69% and 27-67%, respectively. Prevalence of osteoporosis was generally higher than in healthy subjects and some other chronic lung diseases. Correlates of osteoporosis in COPD are mainly measures of body composition, disease severity and the use of corticosteroids, although causality has not been proven. Effects of treatment of osteoporosis have not been investigated in samples consisting of COPD patients only. Longitudinal follow-up to assess determinants of osteoporosis in COPD and randomised placebo-controlled trials on the effects of treatment of osteoporosis in patients with COPD only are warranted.

[Acute abdominal pain and fever in a young woman as the first symptoms of lymphangioleiomyomatosis]. / Acute buikpijn en koorts bij een jonge vrouw als eerste verschijnselen van lymfangioleiomyomatose.

A previously healthy 28-year-old woman presented to the emergency clinic with acute severe abdominal pain and high fever. A diagnostic laparoscopy was performed, during which a large retroperitoneal tumour was found. A CT-scan of the abdomen and thorax confirmed the presence of a retroperitoneal mass but also revealed multiple renal angiomyolipomas and extensive cystic lesions in all lung fields. Based on these findings, the diagnosis lymphangioleiomyomatosis (LAM) was suspected, and later confirmed by histological examination of a biopsy specimen. The acute abdomen and fever appeared to have been caused by a Streptococcus agalactiae infection of the retroperitoneal lymphangiomyoma, which was treated with intravenous antibiotics. LAM is a very rare disease affecting mostly women of childbearing age and presenting almost exclusively with pulmonary symptoms. This is the first description of LAM presenting with an acute surgical abdomen and fever due to infection of a lymphangiomyoma.

Negligible influence of comorbidity on prognosis of patients with small cell lung cancer: a population-based study in the Netherlands.

Management of small cell lung cancer (SCLC) among elderly is complex because of decreased organ functions and interactions with comorbidity. Since elderly patients are often excluded from clinical trials, little is known about the way they are treated and outcome. We evaluated the prognostic effects of rising age and comorbidity in unselected Dutch SCLC patients (Eindhoven Cancer Registry). Elderly patients received chemotherapy less often and the dose was also reduced more often. Cardiovascular diseases, hypertension or diabetes lowered the proportion receiving combined chemotherapy and radiotherapy among patients with limited disease. About 80% of the patients receiving chemotherapy suffered from a side effect, which was not related to age. After adjustment for age, gender, stage and treatment modality, comorbidity had a negligible prognostic effect. Chemotherapy (in combination with radiotherapy) seemed to improve survival, however, toxicity and quality of life in these patients should be evaluated thoroughly in future randomized studies.

Segmental spinal anaesthesia for cholecystectomy in a patient with severe lung disease.

Occasionally patients awaiting heart or lung transplant because of terminal disease require other types of surgery, but present significant challenges to the anaesthetist because of impaired organ function. Regional anaesthesia may have much to offer such patients and we here report one who underwent successfully a laparoscopic cholecystectomy under segmental subarachnoid (spinal) anaesthesia performed at the low thoracic level. The anatomical and physiological consequences of such a technique are discussed.

Methotrexate effects in patients with rheumatoid arthritis with cardiovascular comorbidity.

Methotrexate, an antirheumatic drug that may increase serum homocysteine, significantly increases mortality in patients with rheumatoid arthritis and cardiovascular comorbidity.

[Management of treatment refusal by a psychiatric patient with a life-threatening infectious form of pulmonary tuberculosis]. / Beleid bij een psychiatrische patiënt met een levensbedreigende en besmettelijke vorm van longtuberculose die behandeling weigert.

A Somalian man aged 26 was admitted to a general hospital because of haemophthisis. A severe infectious and life threatening pulmonary tuberculosis was diagnosed. Thereafter, the patient denied having any disease, refused any therapy or diagnostic procedure and wanted to leave the hospital. He was isolated by virtue of the Wet Bestrijding Infectieziekten ('WBI': Bill on Management of Infectious Diseases). Permission for treatment without consent was arranged by virtue of the Wet op de Geneeskundige Behandelingsovereenkomst ('WGBO': Decree on the Medical Contract). The use of measures like fixation and involuntary administration of medication could also be arranged by virtue of the WGBO. The Wet Bijzondere Opnemingen Psychiatrische Ziekenhuizen ('Wet BOPZ': Bill on Compulsory Admission to Psychiatric Hospitals), which exclusively concerns involuntary treatment exclusively of psychiatrics patients, was of no value in this case. Analysis of the different aspects of these three laws led to the conclusion that in case of a somatic disease, whether or not complicated by a psychiatric diagnosis, a treatment without consent must be arranged by virtue of the WGBO.

Combination cyclosporine and (hydroxy)chloroquine in rheumatoid arthritis.

Antimalarials are attractive candidates for combination therapy. In vitro experiments have revealed a synergistic mode of action of cyclosporine and chloroquine which could not, however, be confirmed in a clinical trial.

Chloroquine therapy in patients with recent-onset rheumatoid arthritis: the clinical response can be predicted by the low level of acute-phase reaction at baseline.

If rheumatoid arthritis (RA) patients with a mild disease course could be identified early in the phase of the disease, therapy with less aggressive and probably less toxic antirheumatic drugs seems to be rational. The aim of this study was to investigate which factors at baseline could predict a clinical response (American College of Rheumatology preliminary response criteria) after treatment with chloroquine for 16 weeks. Two hundred and three early RA patients with active disease were treated with oral chloroquine sulphate (Nivaquine) at a daily dose of 300 mg during the first 4 weeks, 200 mg during the second 4 weeks and 100 mg thereafter. One hundred and eighty-three patients (90%) completed the study and 20 patients prematurely discontinued treatment. Of all the patients, 43 patients (21%) met the response criteria. A low level of C-reactive protein (CRP) was the only independent predictor for clinical response [relative risk: 0.97 (95% confidence interval: 0.95-0.98)]. It was concluded that a clinical response to chloroquine therapy in early RA patients can be predicted by a low CRP level at baseline.

Cyclosporin A therapy in rheumatoid arthritis: only strict application of the guidelines for safe use can prevent irreversible renal function loss.

OBJECTIVES: To investigate (1) whether the increase in serum creatinine observed during cyclosporin A (CsA) therapy was reversible in a group of patients with rheumatoid arthritis (RA) treated before the current guidelines for safe use in RA were developed and (2) whether the application of these guidelines prevents serum creatinine increases in the long term. PATIENTS AND METHODS: Eighty-three RA patients who had started low-dose CsA therapy between September 1990 and October 1992, and who were treated according to guidelines that allowed a 50% rise in serum creatinine, were tested for serum creatinine levels in December 1995 if they had discontinued CsA for at least 3 months. Predictors for irreversibility of renal function were determined by using multiple regression analysis. RESULTS: The mean level of serum creatinine gradually increased from 69+/-14 (mean+/-S.D.) micromol/l when starting CsA therapy to 88+/-23 micromol/l (28% above baseline) at the moment of CsA discontinuation, and had decreased to 80+/-17 micromol/l (16% above baseline) at follow-up, 35+/-14 months after drug discontinuation. During CsA therapy, the mean level of serum creatinine had increased to 82+/-19 micromol/l (26% above baseline) at 6 months and to 87+/-22 micromol/1 (39% above baseline) at 42 months. The mean CsA dose had decreased from 3.1+/-0.9 mg/kg/day at 6 months to 1.9+/-0.8 mg/kg/day at 42 months. The absolute number of months that serum creatinine levels were > 30% above baseline was an independent predictor for a persistent increase of the serum creatinine after CsA discontinuation. More than 2 months with a serum creatinine increase of > or = 30% resulted in a higher percentage irreversible increase than for less than 2 months with a > or = 30% increase: 27 and 6%, respectively (P < 0.0001). CONCLUSION: Long-term low-dose CsA administration in RA patients was associated with an increase in serum creatinine which was partially irreversible after drug discontinuation. The increase in serum creatinine was completely reversible in the patient group that was treated according to the current guidelines for safe use of CsA.

No increased risk of malignancies and mortality in cyclosporin A-treated patients with rheumatoid arthritis.

OBJECTIVE: To evaluate the cyclosporin A (CSA)-attributed risk of developing malignancies in general and malignant lymphoproliferative diseases (LPDs) and skin cancers in particular, as well as the CSA-attributed incidence of mortality in patients with rheumatoid arthritis (RA). METHODS: In a retrospective, controlled cohort study, the incidence of malignancies and mortality was evaluated in 208 CSA-treated patients with RA compared with 415 matched control patients with RA between 1984 and 1995. Patients were followed up for a median of 5.0 years (range 1.4-12.0). RESULTS: Forty-eight cases of malignancy (8 in the CSA group and 40 in the control group; relative risk [RR] 0.40, 95% confidence interval [95% CI] 0.19-0.84) were identified, of which 8 were malignant LPDs (2 CSA versus 6 control; RR 0.67, 95% CI 0.14-3.27) and 14 were skin cancers (2 CSA versus 12 control; RR 0.33, 95% CI 0.08-1.47). Seventy-three patients died (16 CSA versus 57 control; RR 0.56, 95% CI 0.33-0.95) due primarily to cardiovascular diseases (4 CSA versus 22 control; RR 0.36, 95% CI 0.13-1.04) or a malignancy (3 CSA versus 8 control; RR 0.67, 95% CI 0.18-2.43). Proportional hazards regression analysis with correction for potential confounding factors did not significantly change the results. CONCLUSION: The study findings suggest that CSA treatment in RA patients does not increase the risk of malignancies in general or the risk of malignant LPDs or skin cancers in particular. Moreover, the incidence of mortality in CSA-treated RA patients was comparable to that in matched control RA patients.

Combination therapy in recent onset rheumatoid arthritis: a randomized double blind trial of the addition of low dose cyclosporine to patients treated with low dose chloroquine.

OBJECTIVE: To investigate whether there is interaction between chloroquine and cyclosporine (CyA) at the level of efficacy and toxicity in patients with recent onset rheumatoid arthritis (RA). METHODS: Eighty-eight patients with recent onset RA, who had shown a suboptimal clinical response on low dose chloroquine monotherapy, were randomly assigned to additional treatment with placebo, CyA 1.25 mg/kg/day, or CyA 2.50 mg/kg/day (fixed doses) for another 24 weeks. The tender joint count was the primary outcome assessment of efficacy and the serum creatinine of toxicity. The 1995 preliminary ACR response criteria for improvement were applied to evaluate individual clinical responses. RESULTS: Two patients in the placebo group (n = 29), 7 patients in the CyA 1.25 mg group (n = 29), and 8 patients in the CyA 2.50 mg group (n = 30) (p = 0.06) discontinued study medication prematurely for inefficacy or adverse events. The intention-to-treat analysis revealed that the tender joint count decreased 2.2 +/- 6.1 (mean +/- SD) joints in the placebo group, 2.2 +/- 6.6 joints in the CyA 1.25 mg group, and 5.0 +/- 5.8 joints in the CyA 2.50 mg group (p = 0.04). The 1995 preliminary ACR response criteria for clinical improvement were met by 8 (28%) patients in the placebo group, 10 (34%) patients in the CyA 1.25 mg group, and 15 (50%) patients in the CyA 2.50 mg group (p = 0.07). The serum creatinine increased 2 +/- 7 micromol/l in the placebo group, decreased 1 +/- 8 micromol/l in the CyA 1.25 mg group, and increased 10 +/- 15 micromol/l in the CyA 2.50 mg group (p < 0.001). CONCLUSION: The addition of low dose CyA is moderately effective in patients with early RA already treated with low dose chloroquine, but results in statistically significant renal function loss.