Early assessment of minimal residual disease in AML by flow cytometry during aplasia identifies patients at increased risk of relapse.

In acute myeloid leukemia (AML), assessment of minimal residual disease (MRD) by flow cytometry (flow MRD) after induction and consolidation therapy has been shown to provide independent prognostic information. However, data on the value of earlier flow MRD assessment are lacking. Therefore, the value of flow MRD detection was determined during aplasia in 178 patients achieving complete remission after treatment according to AMLCG (AML Cooperative Group) induction protocols. Flow MRD positivity during aplasia predicted poor outcome (5-year relapse-free survival (RFS) 16% vs 43%, P<0.001) independently from age and cytogenetic risk group (hazard ratio for MRD positivity 1.71; P=0.009). Importantly, the prognosis of patients without detectable MRD was neither impacted by morphological blast count during aplasia nor by MRD status postinduction. Early flow MRD was also evaluated in the context of existing risk factors. Flow MRD was prognostic within the intermediate cytogenetic risk group (5-year RFS 15% vs 37%, P=0.016) as well as for patients with normal karyotype and NPM1 mutations (5-year RFS 13% vs 49%, P=0.02) or FLT3-ITD (3-year RFS rates 9% vs 44%, P=0.016). Early flow MRD assessment can improve current risk stratification approaches by prediction of RFS in AML and might facilitate adaptation of postremission therapy for patients at high risk of relapse.

Gustatory and olfactory function in patients with granulomatosis with polyangiitis (Wegener's).

OBJECTIVES: Recent findings suggest that autoimmune disorders predispose to a diminished capacity to taste and smell. This has been shown for patients with systemic lupus erythematosus as well as for patients with rheumatoid arthritis (RA). Granulomatosis with polyangiitis (GPA), with its particular manifestations in the upper respiratory tract, may therefore have an even higher impact on these senses. The aims of this study were to evaluate the gustatory and olfactory function in patients with GPA, to compare them to sex- and age-matched healthy controls, and to correlate these findings with their GPA disease severity. METHOD: Patients with established GPA were analysed by standardized assessments for gustatory and olfactory functions and examined for disease activity, stage of disease, and treatment. RESULTS: Forty-four GPA patients were tested for their chemosensory functions. Compared to age- and sex-matched healthy controls, GPA patients showed significantly decreased olfactory scores along with diminished scores for their gustatory functions. The diminished sense of smell in GPA patients correlated significantly with elevated C-reactive protein (CRP) values whereas the gustatory impairment correlated with the duration and extent of the disease. CONCLUSIONS: Our results indicate that olfactory and gustatory functions are significantly decreased in GPA. As the olfactory function of these patients was comparable to patients with RA, chemosensory impairment may not simply be a consequence of the involvement of the upper respiratory tract, but rather a common complication of systemic autoimmune diseases.

Tumor markers CEA and CA 19-9 correlate with radiological imaging in metastatic colorectal cancer patients receiving first-line chemotherapy.

In patients with metastatic colorectal cancer (mCRC), radiological imaging represents the current standard to evaluate the efficacy of chemotherapy. However, with growing knowledge about tumor biology, other diagnostic tools become of interest which can supplement radiology. The aim of the present study was to examine the correlation of tumor and serum markers with radiological imaging in patients with mCRC receiving first-line therapy. Patients were included if tumor (carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA 19-9)) and serum marker (lactatdehydrogenase (LDH), γ-glutamyltransferase (γGT), alkaline phosphatase (AP), C-reactive protein (CRP), leucocyte count (WBC), hemoglobin (Hb)) levels were available at baseline and at least two times during treatment. The decline and increase of tumor and serum markers over time were approximated for each patient by estimating slopes depending on the radiological assessment. A linear mixed effects multiple regression model for each subject was used to evaluate the intra-class correlation of these slopes modeling tumor and serum marker changes with radiological imaging. Data of 124 patients (41 female, 83 male; median age 62.9 years, range 27-85) who received first-line chemotherapy for mCRC from 11/2007 to 04/2010 were analyzed retrospectively. CEA level slopes (n = 49; slopes = 102) differed between radiologically determined progressive disease (PD) and partial response (PR) (p = 0.005) and between PD and stable disease (SD) (p = 0.042). CA 19-9 level slopes (n = 57; slopes = 127) also showed a significant difference between PD and PR (p = 0.002) and PD and SD (p = 0.058). Furthermore, CRP slopes (n = 62; slopes = 134) differed significantly between PD and PR (p = 0.009). For LDH, ALP, γGT, Hb, and WBC, no correlations were observed. The results indicate the correlation of the tumor markers CEA, CA 19-9, and the serum marker CRP with radiological imaging in patients with mCRC receiving first-line chemotherapy. Further data analyses would be helpful to develop a predictive model for tumor response based on an early tumor marker increase or decrease.

Radioembolization with Yttrium-90 microspheres (SIRT) in pancreatic cancer patients with liver metastases: efficacy, safety and prognostic factors.

OBJECTIVE: To analyze the clinical efficacy of (90)Y radioembolization in liver metastases from pancreatic cancer, to describe treatment toxicities and to identify biomarkers as predictors of outcome. METHODS: Data from 19 pancreatic cancer patients (9 females/10 males) who had received (90)Y radioembolization for metastatic liver disease between 06/2004 and 01/2011 were analyzed retrospectively. RESULTS: The median age at (90)Y radioembolization was 63 years (range 43-77). In 16 patients, previous palliative gemcitabine-based chemotherapy was given for metastatic disease. Objective response in the liver after (90)Y radioembolization was 47%. Median local progression-free survival in the liver was 3.4 months (range 0.9-45.0). Median overall survival (OS) was 9.0 months (range 0.9-53.0) and 1-year survival was 24%. Cox regression models for baseline biomarkers at (90)Y radioembolization revealed correlations of increased carbohydrate antigen 19-9 (p = 0.02) and C-reactive protein (p = 0.03) with shorter OS. Short-term adverse events (nausea, vomiting, fatigue, fever and abdominal pain) did not exceed grade 3. As long-term adverse events, liver abscesses, gastroduodenal ulceration, cholestasis and cholangitis, ascites and spleen infarction were observed. CONCLUSION: (90)Y radioembolization is able to induce an encouraging local response rate of liver metastases of pancreatic cancer patients. Most short-term toxicities are manageable; however, patients should be followed up carefully for severe long-term toxicities.

Prognostic factors for 60-day mortality in first-line treatment of metastatic colorectal cancer (mCRC): individual patient analysis of four randomised, controlled trials by the AIO colorectal cancer study group.

BACKGROUND: The 60 day mortality is an established parameter for chemotherapy-related safety in randomised trials for metastatic colorectal cancer (mCRC). Prognostic factors associated with 60-day mortality would be helpful to identify high-risk patients in advance. PATIENTS AND METHODS: Individual baseline patient data from four randomised, controlled trials from the Arbeitsgemeinschaft Internistische Onkologie (AIO) study group were retrospectively analysed. Chemotherapy consisted of fluoropyrimidine (5-FU/capecitabine), irinotecan, oxaliplatin with or without bevacizumab or cetuximab. Prognostic factors were identified by univariate and multivariate logistic regression models in two cohorts: one limited to ECOG PS 0 and 1 and one including ECOG PS 2 patients. RESULTS: A total of 1377 patients were evaluated. The analysis of ECOG PS 0, 1 and 2 patients consisted of 898 patients where a total of 33 deaths within the first 60 days of treatment (3.7%) occurred. In multivariate analysis, 60-day mortality was significantly associated with ECOG PS 2 and high leucocyte count (white blood cell, WBC). Odds ratio was 6.28 for WBC and 12.92 for ECOG PS 2. Exclusion of ECOG PS 2 patients but inclusion of one trial limited to ECOG PS 0 and 1 patients resulted in 1302 assessable patients and 44 early deaths (3.4%). In both cohorts, around 50% of deaths were disease related. WBC was confirmed as a significant risk factor for early death (OR 7.60). A combined score using ECOG PS 2 and WBC ≥8.000/µl is able to identify high-risk patients with a sensitivity of 18% and specificity of 98%. CONCLUSIONS: In this large retrospective analysis of individual patient data, around 50% of early deaths were disease related. Elevated WBC was found strongly associated with increased 60-day mortality in first-line treatment of mCRC. The proposed AIO-60-Day-Mortality score serves as an additional trial exclusion criterion.

Evaluation of prognostic factors in liver-limited metastatic colorectal cancer: a preplanned analysis of the FIRE-1 trial.

BACKGROUND: Liver-limited disease (LLD) denotes a specific subgroup of metastatic colorectal cancer (mCRC) patients. PATIENTS AND METHODS: A total of 479 patients with unresectable mCRC from an irinotecan-based randomised phase III trial were evaluated. Patients with LLD and non-LLD and hepatic resection were differentiated. Based on baseline patient characteristic, prognostic factors for hepatic resection were evaluated. Furthermore, prognostic factors for median overall survival (OS) were estimated via Cox regression in LLD patients. RESULTS: Secondary liver resection was performed in 38 out of 479 patients (resection rate: 7.9%). Prognostic factors for hepatic resection were LLD, lactate dehydrogenase (LDH), node-negative primary, alkaline phosphatase (AP) and Karnofsky performance status (PS). Median OS was significantly increased after hepatic resection (48 months), whereas OS in LLD (17 months) and non-LLD (19 months) was comparable in non-resected patients. With the inapplicability of Koehne's risk classification in LLD patients, a new score based on only the independent prognostic factors LDH and white blood cell (WBC) provided markedly improved information on the outcome. CONCLUSION: Patients undergoing hepatic resection showed favourable long-term survival, whereas non-resected LLD patients and non-LLD patients did not differ with regard to progression-free survival and OS. The LDH levels and WBC count were confirmed as prognostic factors and provide a useful and simple score for OS-related risk stratification also in LLD.

KRAS allel-specific activity of sunitinib in an isogenic disease model of colorectal cancer.

PURPOSE: To investigate the impact of different KRAS mutations on treatment with the tyrosine kinase inhibitor sunitinib in SW48 colorectal cancer cell line variants. MATERIALS AND METHODS: Isogenic SW48 KRAS wt, G12A, G12C, G12D, G12R, G12S, G12 V, and G13D cells were evaluated for ERK phosphorylation with and without EGF stimulation. In addition, the respective cell lines were tested for the effect of sunitinib on ERK/ELK phosphorylation, cell cycle, and cytotoxicity. RESULTS: Compared to KRAS wt cells, all KRAS mutant variants were associated with resistance to sunitinib treatment. In the MTT chemosensitivity assay, the grade of resistance was less pronounced in G13D and highest in G12A, G12C, and G12S mutant cells. The reduction in ERK phosphorylation due to treatment with sunitinib was highest in G12V (89 %) mutant cells and lowest in G12A (24 %) mutant cells. ELK phosphorylation was less decreased in all KRAS mutant variants compared to KRAS wt cells following sunitinib treatment. The grade of resistance appears to correlate with the individual KRAS-dependent intrinsic activation of ERK. CONCLUSION: Our isogenic cell culture model suggests that KRAS mutations in SW48 colorectal cancer cells are linked to resistance to the multityrosine kinase inhibitor sunitinib. KRAS G13D mutant SW48 cells represented the KRAS subspecies with the lowest grade of resistance. Future studies will have to clarify whether KRAS can be used to guide sunitinib treatment or-in general-a treatment with a multityrosine kinase inhibitor in mCRC.

Phase II randomised proof-of-concept study of the urokinase inhibitor upamostat (WX-671) in combination with gemcitabine compared with gemcitabine alone in patients with non-resectable, locally advanced pancreatic cancer.

BACKGROUND: To evaluate the efficacy and tolerability of the urokinase plasminogen activator (uPA) inhibitor upamostat in combination with gemcitabine in locally advanced pancreatic adenocarcinoma (LAPC). METHODS: Within a prospective multicenter study, LAPC patients were randomly assigned to receive 1000 mg m(-2) of gemcitabine IV weekly either alone (arm A) or in combination with 200 mg (arm B) or 400 mg (arm C) oral upamostat daily. Efficacy endpoints of this proof-of-concept study included response rate, time to first metastasis, progression-free and overall survival (OS). RESULTS: Of the 95 enroled patients, 85 were evaluable for response and 93 for safety. Median OS was 12.5 months (95% CI 8.2-18.2) in arm C, 9.7 months (95% CI 8.4-17.1) in arm B and 9.9 months (95% CI 7.4-12.1) in arm A; corresponding 1-year survival rates were 50.6%, 40.7% and 33.9%, respectively. More patients achieved a partial remission (confirmed responses by RECIST) with upamostat combination therapy (arm C: 12.9%; arm B: 7.1%; arm A: 3.8%). Overall, only 12 patients progressed by developing detectable distant metastasis (arm A: 4, arm B: 6, arm C: 2). The most common adverse events considered to be related to upamostat were asthenia, fever and nausea. CONCLUSION: In this proof-of-concept study targeting the uPA system in LAPC, the addition of upamostat to gemcitabine was tolerated well; similar survival results were observed for the three treatment arms.

Actinic keratosis in the en-face and slice imaging mode of high-definition optical coherence tomography and comparison with histology.

BACKGROUND: Optical coherence tomography (OCT) allows real-time, in vivo examination of nonmelanoma skin cancer. An innovative high-definition (HD)-OCT with a horizontal (en-face) and vertical (slice) imaging mode offers additional information in the diagnosis of actinic keratosis (AK) and may potentially replace invasive diagnostic biopsies. OBJECTIVES: To define the characteristic morphological features of AK by using HD-OCT in the two imaging modes compared with histopathology as gold standard. METHODS: In total, 20 AKs were examined by HD-OCT in the en-face and slice imaging modes and characteristic features were described and evaluated in comparison with the histopathological findings. Furthermore, the HD-OCT images of a subgroup of AKs were compared with those of the clinically normal adjacent skin. RESULTS: The preoperative in vivo diagnostics showed the following features in the en-face imaging mode of HD-OCT: disruption of stratum corneum, architectural disarray, cellular/nuclear polymorphism in the stratum granulosum/stratum spinosum, and bright irregular bundles in the superficial dermis. In the vertical slice imaging mode the following characteristics were found: irregular entrance signal, destruction of layering, white streaks and dots, and grey areas. In contrast, the clinically healthy adjacent skin showed mainly a regular epidermal 'honeycomb' pattern in the en-face mode and distinct layering of the skin in the slice mode. CONCLUSIONS: HD-OCT with both the en-face and slice imaging modes offers additional information in the diagnosis of AK compared with conventional OCT and might enhance the possibility of the noninvasive diagnosis of AK prior to treatment procedures and possibly in the monitoring of noninvasive treatment strategies.

Thermal grill-evoked sensations of heat correlate with cold pain threshold and are enhanced by menthol and cinnamaldehyde.

BACKGROUND: Thunberg's thermal grill produces a sensation of strong heat upon skin contact with spatially interlaced innocuous warm and cool stimuli. METHODS: To examine the classes of peripheral axons that might contribute to this illusion, the effects of topical l-menthol, an activator of TRPM8, and cinnamaldehyde, a TRPA1 agonist, on the magnitude of thermal sensations were examined during grill stimulation in healthy volunteers. RESULTS: Under control conditions, cutaneous grill stimulation (interlaced 20/40 °C) evoked a sensation of heat, and for individual subjects, the magnitude of this heat sensation was positively correlated with cold pain threshold (CPT). Menthol increased the CPT and enhanced the magnitude of grill-evoked heat. Cinnamaldehyde intensified warm sensations, reduced heat pain threshold and also enhanced grill-evoked heat. CONCLUSIONS: Both TRPM8-expressing and TRPA1-expressing afferent axons can affect grill-evoked thermal sensations. The enhancement of grill-evoked sensations of temperature with menthol and cinnamaldehyde may provide an additional clinically relevant means of testing altered thermal sensitivity, which is often affected in neuropathic patient groups.

EGFR pathway biomarkers in erlotinib-treated patients with advanced pancreatic cancer: translational results from the randomised, crossover phase 3 trial AIO-PK0104.

BACKGROUND: We aimed to identify molecular epidermal growth factor receptor (EGFR) tissue biomarkers in pancreatic cancer (PC) patients treated with the anti-EGFR agent erlotinib within the phase 3 randomised AIO-PK0104 study. METHODS: AIO-PK0104 was a multicenter trial comparing gemcitabine/erlotinib followed by capecitabine with capecitabine/erlotinib followed by gemcitabine in advanced PC; primary study end point was the time-to-treatment failure after first- and second-line therapy (TTF2). Translational analyses were performed for KRAS exon 2 mutations, EGFR expression, PTEN expression, the EGFR intron 1 and exon 13 R497K polymorphism (PM). Biomarker data were correlated with TTF, overall survival (OS) and skin rash. RESULTS: Archival tumour tissue was available from 208 (74%) of the randomised patients. The KRAS mutations were found in 70% (121 out of 173) of patients and exclusively occurred in codon 12. The EGFR overexpression was detected in 89 out of 181 patients (49%) by immunohistochemistry (IHC), and 77 out of 166 patients (46%) had an EGFR gene amplification by fluorescence in-situ hybridisation (FISH); 30 out of 171 patients (18%) had a loss of PTEN expression, which was associated with an inferior TTF1 (first-line therapy; HR 0.61, P=0.02) and TTF2 (HR 0.66, P=0.04). The KRAS wild-type status was associated with improved OS (HR 1.68, P=0.005); no significant OS correlation was found for EGFR-IHC (HR 0.96), EGFR-FISH (HR 1.22), PTEN-IHC (HR 0.77), intron 1 (HR 0.91) or exon 13 R497K PM (HR 0.83). None of the six biomarkers correlated with the occurrence of skin rash. CONCLUSION: The KRAS wild-type was associated with an improved OS in erlotinib-treated PC patients in this phase 3 study; it remains to be defined whether this association is prognostic or predictive.

Capecitabine-associated hand-foot-skin reaction is an independent clinical predictor of improved survival in patients with colorectal cancer.

BACKGROUND: Hand-foot-skin reaction (HFSR) is an adverse event frequently observed during treatment with capecitabine (cape). In the present analysis, we sought to evaluate the potential association of HFSR and survival in German patients with metastatic colorectal cancer and locally advanced rectal cancer treated with cape in clinical trials. METHODS: Patients of the Arbeitsgemeinschaft für Internistische Onkologie (AIO) KRK-0104 and the Mannheim rectal cancer trial were evaluated. HFSR was graded according to NCI-CTC criteria in both trials. Time to first occurrence of HFSR was described per cycle and HFSR developing during cycles 1 and 2 was defined as 'early HFSR'. Baseline characteristics between the patient groups with or without HFSR were compared using Mann-Whitney-U, Fisher's exact or χ(2)-test, as appropriate. Haematological and non-haematological toxicities observed in both groups were compared using Fisher's exact test. Progression-free (PFS) or disease-free (DFS) as well as overall survival (OS) data from both trials were pooled and the HFSR group was compared with the non-HFSR using Kaplan-Meier analysis. RESULTS: A total of 374 patients were included, of whom 29.3% developed any HFSR. Of these, 51% had early HFSR. Baseline characteristics were comparable between both HFSR groups concerning age, gender, ECOG performance status and UICC stage. On multivariate analysis none of these factors had influence on the occurrence of HFSR. The percentage of all-grade (and grade 3-4) haematological toxicities did not differ between both the groups. By contrast, patients exhibiting HFSR had a significantly higher rate of all-grade (but not grade 3-4) diarrhoea, stomatitis/mucositis and fatigue (P<0.01, respectively). Patients with HFSR had improved PFS/DFS (29.0 vs 11.4 months; P=0.015, HR 0.69) and OS (75.8 vs 41.0 months; P=0.001, HR=0.56). Within the HFSR group, PFS/DFS and OS were comparable between patients with early vs late HFSR. INTERPRETATION: The present analysis provides evidence for the association of HFSR and survival in patients with colorectal cancer. Baseline characteristics, with the exception of UICC stage, older age and ECOG performance status, and the time of occurrence of HFSR had no impact on survival. Patients with HFSR had a higher probability of developing any-grade gastrointestinal toxicity and fatigue while no correlation with haematological toxicity was found.

Osteopontin expression in plasma of melanoma patients and in melanocytic tumours.

BACKGROUND: While the serological tumour marker S100 is well established for the detection of metastatic melanoma, the extracellular matrix protein osteopontin (OPN) seems to be a promising novel marker for invasive melanoma. OBJECTIVES: We analysed the potential of OPN as a serological tumour marker for metastatic melanoma and evaluated its combination with S100 and lactate dehydrogenase (LDH) levels to increase the reliability of these biomarkers for the detection of metastatic disease. METHODS: We examined OPN in the peripheral blood of 110 melanoma patients using enzyme-linked immunosorbent assay and combined it with S100 and LDH levels. In addition, the protein expression of OPN was analysed in tissue sections of melanocytic nevi and melanomas of different progression stages by immunohistochemistry. RESULTS: The independent comparison of S100 and OPN levels in metastatic vs. non-metastatic patients revealed a P-value <0.001 respectively. The predictiveness of OPN, S100 and LDH was 0.85, 0.89 and 0.69 as measured by the area under the receiver operating curve (AUC) respectively, while the combination of the two biomarkers OPN and S100 showed an AUC of 0.97. The optimal cut-off of the combination of OPN and S100 yielded a specificity of 85.9% and a sensitivity of 95.5%. By immunohistochemistry, OPN protein expression was detected in 29% (7/24) of melanocytic nevi, 67% (30/45) of primary melanomas and 39% (7/18) of metastatic melanomas. CONCLUSIONS: Together, OPN seems to be a promising novel biomarker for the detection of metastatic disease in melanoma patients, showing elevated plasma levels in metastatic disease and increased protein expression in melanocytic lesions. The combination of OPN with the well-established tumour marker S100 might increase the prediction of metastases.

The influence of KRAS and BRAF mutations on the efficacy of cetuximab-based first-line therapy of metastatic colorectal cancer: an analysis of the AIO KRK-0104-trial.

Our study investigated the impact of specific KRAS mutations and BRAF mutation on progression-free survival (PFS) and overall survival (OS) in patients with metastatic colorectal cancer (mCRC) treated within the AIO KRK-0104-trial as first-line therapy. In total, 146 (of 185) patients were included in this analysis. Seventy-nine patients presented with KRAS/BRAF wild-type (wt), 41 patients with a KRAS codon 12 and nine patients with a KRAS codon 13 mutation. Seventeen patients presented a BRAF-mutated tumor. The patients of our study were treated with CAPIRI/CAPOX plus cetuximab. Major differences regarding PFS and OS were observed depending on the mutation of the tumor. PFS was 8 months in patients with wt-tumors, 5.8 months with codon 12-mutated, 9.9 months with codon 13-mutated and 4.2 months with BRAF-mutated tumors. OS was 23.5 months in patients with wt-tumors, 18.9 months with codon 12-mutated, 26.2 months with codon 13-mutated and 13.0 months with BRAF-mutated tumors. Although the conventional separation of patients with KRAS wild-type versus KRAS mutant tumors did not have a significant impact on outcome parameters in the AIO KRK 0104-trial, this analysis demonstrates that markedly differing results are obtained when subtypes of KRAS and BRAF mutation are taken into account.

Influence of antiretroviral therapy on immunogenicity of simultaneous vaccinations against influenza, pneumococcal disease and hepatitis A and B in human immunodeficiency virus positive individuals.

OBJECTIVES: Immune response to many vaccinations is impaired in human immunodeficiency virus (HIV) positive patients. METHODS: A total of n = 131 HIV positive patients were vaccinated against influenza, pneumococcal disease, hepatitis A and B, with n = 82 patients (62.6%) receiving 2 or more simultaneous vaccinations. Safety and immunogenicity of simultaneous vaccinations were assessed. Current antiretroviral therapy (ART) regimens were evaluated as potential predictors for antibody response. RESULTS: Immune response rates were 45% (influenza), 68% (pneumococcus), 63.6% (hepatitis A) and 62.5% (hepatitis B). Adverse reactions after vaccination were documented in 2 of 131 patients (1.5%). No statistically significant difference between pre- and post-vaccination CD4+ T-cell counts (CD4) and HIV plasma load was observed. 85% of patients received ART containing nucleotide reverse transcriptase inhibitors, non-nucleotide reverse transcriptase inhibitors and/or protease inhibitors (PI). Higher ratio of CD4 to CD8 and intake of PI were statistically significant, independent predictors for antibody response after influenza vaccination (OR 1.9 and 2.8, p = 0.01 and 0.04, respectively). CONCLUSIONS: Simultaneous vaccinations in HIV positive patients were safe and well tolerated. The positive effect of PI on antibody response after influenza vaccination should be confirmed in larger studies.

Estimating adjusted risk difference (RD) and number needed to treat (NNT) measures in the Cox regression model.

In medical research, risk difference (RD) and number needed to treat (NNT) measures for survival times have been mainly proposed without consideration of covariates. In this paper, we develop adjusted RD and NNT measures for use in observational studies with survival time outcomes within the framework of the Cox proportional hazards regression model taking the distribution of confounders into account. We consider the typical situation of a cohort study in which the effect of an exposure on a survival time outcome is investigated and important covariates have to be taken into account. The exposure effect described by means of the RD and NNT measures in dependence on whether the effect of allocating an exposure to unexposed persons (number needed to be exposed) or that of removing an exposure from exposed persons (exposure impact number) is considered. Estimation of these adjusted RD and NNT measures is performed by using the average RD approach recently developed for logistic regression. To determine standard errors and confidence intervals for these estimators we use two approaches, the delta method with respect to the regression coefficients of the Cox model and bootstrapping and compare each other. The performance of these estimators is assessed by performing Monte Carlo simulations demonstrating clear advantages of the bootstrap method. The proposed method for point and interval estimation of adjusted RD and NNT measures in the Cox model is illustrated by means of data of the Düsseldorf Obesity Mortality Study (DOMS).

Seasonal variation of Pneumocystis jirovecii infection: analysis of underlying climatic factors.

Pneumocystis jirovecii causes severe pneumonia (PCP) in immunocompromised patients. Seasonal changes of PCP incidence may be associated with climate changes. In this first study using multiple linear regression statistics to assess monthly climatic data and Pneumocystis, PCP incidence was positively correlated with mean temperature, but not with rainfall or wind strength.