A Computer Simulation Model of the Natural History and Economic Impact of Chronic Obstructive Pulmonary Disease

OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is a major health problem with high societal costs. The Global Initiative for Chronic Lung Disease (GOLD) has identified a need for health economics data for COPD. For chronic diseases, such as COPD, where the natural history of disease is lifetime, a modeling approach for economic evaluation may be more realistic than prospective, piggy-backed clinical trials or specific COPD cohort studies. Simulation models can be used to extrapolate clinical data beyond the limited time frame of clinical trials, to analyze subgroups of patients or to explore uncertainty regarding the results by using sensitivity analysis techniques. Our purpose has been to develop a flexible computer simulation model for COPD that will represent disease progression and GOLD recommendations, useful for economic evaluations of new medicines to meet the needs of various payer requirements for reimbursement and resource allocation. METHODS: This article describes a two-dimensional Markov model, which uses data from multiple sources about disease progression, exacerbation frequency and duration, mortality, costs, burden of illness, and the relationships between those variables. The model is evaluated using stochastic uncertainty analysis, it allows comparison of treatments affecting different disease mechanisms, and it uses primary data validated against published sources. RESULTS: We have evaluated two hypothetical interventions treating different features of the disease (lung function decline and acute exacerbations). These analyses show that reducing lung function decline must be a long-term strategy compared to reducing the number of exacerbations. It was necessary to have a long term like 30 years, with 10,000 patients and 20% increase in price, or 20 years with equal prices to show cost-effectiveness with statistical significance for a treatment that reduces lung function decline. CONCLUSIONS: Our study shows the value of modeling as a tool for evaluating different scenarios and for combining several sources of data, to provide estimates that would otherwise be unavailable. Clinical trials of this size and duration would be unrealistic.     

Phase II multicentre study of efficacy and feasibility of dose-intensified preoperative weekly cisplatin,epirubicin, and paclitaxel (PET) in resectable gastroesophageal cancer

Background

Perioperative chemotherapy improves the overall survival of resectable gastroesophageal adenocarcinoma (GEA) patients. However, more than 40 % of the patients are not healthy enough to complete their post-operative chemotherapy, and the progression-free survival rate is lower than 35 % at 5 years. In order to optimise neoadjuvant chemotherapy regimen, a pilot study of weekly dose-intensified cisplatin, epirubicin, and paclitaxel (PET) was conducted. The primary objective was a complete resection (R0) rate. Then, a R0 rate ≤80 % was considered as uninteresting, with an expected R0 rate of 92 %. Secondary objectives were the feasibility, safety, histological response rate (Becker score), and survival (Trial registration: NCT01830270).

Methods

Patients with >T1N0M0 GEA were included. Treatment consisted of eight preoperative cycles of weekly PET regimen at 30/50/80 mg/m² of cisplatin, epirubicin, and paclitaxel, respectively. Primary prophylaxis by granulocyte colony-stimulating factor was administered. Surgery was performed 4–6 weeks following the last cycle of chemotherapy. Using Fleming two-step design with a unilateral alpha type one error of 5 % and a statistical power of 80 %, it would be required to include 68 patients. At planned interim analysis for futility, it was required to observe at least 25 of 29 patients with R0 resection to pursue inclusion. At the second step, it was required to observe at least 61 of 68 patients with R0 resection to conclude for promising activity of the dose-intensified chemotherapy.

Results

Between May 2011 and January 2013, 29 patients were enrolled. Median age was 62 years (range 39–83 years), and seven (24 %) patients presented signet-ring cell histology. Twenty-seven (93 %) patients underwent surgery. Pathological complete responses (Becker score 1a) were observed in four patients, and nearly complete responses (Becker score 1b) for additional three patients. A R0 rate was achieved for 24 of 29 (82.7 %; 95 % CI 64–94 %) patients. No Becker score 1a/1b response was observed among patients with signet-ring cell GEA. Twenty-one (72 %) patients completed all eight cycles, and 86 % received seven or more cycles. Sixteen (56 %) patients experienced grade 3–4 neutropenia, and five patients had febrile neutropenia. Among non-haematological toxicities, mucositis and fatigue were the most frequent ones. The median-delivered relative dose intensity (DI) was 80 % for cisplatin, 75 % for epirubicin, and 79 % for paclitaxel. However, only 45 % of the patients received at least 80 % of the planned median DI for all three drugs.

Conclusions

Despite high R0 and pathological response rates, neoadjuvant PET chemotherapy did not meet the primary end-point and failed to show an acceptable relative DI. PET chemotherapy is not recommended in resectable GEA patients.     

High risk of in-breast tumor recurrence after BRCA1/2-associated breast cancer

The purpose of the study was to compare breast-conserving therapy (BCT) and mastectomy (M) in BRCA1/2 mutation carriers. Women with invasive breast cancer and a pathogenic mutation in BRCA1 or BRCA2 were included in the study (n = 162). Patients treated with BCT (n = 45) were compared with patients treated with M (n = 118). Endpoints were local recurrence as first recurrence (LR), overall survival (OS), breast cancer death, and distant recurrence. Cumulative incidence was calculated in the presence of competing risks. For calculation of hazard ratios and for multivariable analysis, cause-specific Cox proportional hazards regression was used. Compared to M, BCT was associated with an increased risk of LR in univariable analysis (HR 4.0; 95 % CI 1.6–9.8) and in multivariable analysis adjusting for tumor stage, age, and use of adjuvant chemotherapy (HR 2.9; CI 1.1–7.8). Following M, all local recurrences were seen in the first 5 years after breast cancer diagnosis. Following BCT, the rate of LR continued to be high also after the first 5 years. The cumulative incidence of LR in the BCT group was 15, 25, and 32 % after 5, 10, and 15 years, respectively. There were no significant differences between BCT and M for OS, breast cancer death, or distant recurrence. BRCA1/2 mutation carriers treated with BCT have a high risk of LR, many of which are new primary breast cancers. This must be thoroughly discussed with the patient and is an example of how rapid treatment-focused genetic testing could influence choice of treatment.     

Immunohistochemical dual staining as an adjunct in assessment of mitotic activity in melanoma

Background: The mitotic rate was introduced as a major prognostic criterion for the staging of thin (≤1.0 mm) melanoma by the 2009 American Joint Committee on Cancer Staging and Classification (seventh edition). The detection of a single mitotic figure changes the tumor stage in thin melanoma. We sought to address the value of a dual staining to facilitate the determination of the mitotic rate and to assign the mitotic activity to melanocytes. Methods: The mitotic rate of melanoma cells was determined by dual phosphohistone‐H3 (PHH3)/Melan‐A immunohistochemistry. Results were compared with PHH3 staining alone and conventional hematoxylin and eosin (H&E)‐stained slides of 15 melanomas with a tumor thickness <1.0 mm. Results: PHH3 staining clearly labeled cells in the mitotic cell cycle. The mitotic rate in the PHH3/Melan‐A dual stain was equal to that derived by H&E staining. Time required for counting mitotic figures was significantly reduced. Conclusions: The evaluation of mitotic rate with an immunohistochemical dual stain is faster (mean 63.0%) and more reliable than evaluation by routine H&E staining alone. Dual staining immunohistochemistry may be a useful additional tool to standardize the determination of mitotic rate and may be helpful in evaluation of challenging cases. Ikenberg K, Pfaltz M, Rakozy C, Kempf W. Immunohistochemical dual staining as an adjunct in assessment of mitotic activity in melanoma.     

No association of vitamin D metabolism-related polymorphisms and melanoma risk as well as melanoma prognosis: a case–control study

Melanoma is one of the most aggressive human cancers. The vitamin D system contributes to the pathogenesis and prognosis of malignancies including cutaneous melanoma. An expression of the vitamin D receptor (VDR) and an anti-proliferative effect of vitamin D in melanocytes and melanoma cells have been shown in vitro. Studies examining associations of polymorphisms in genes coding for vitamin D metabolism-related proteins (1α-hydroxylase [CYP27B1], 1,25(OH)(2)D-24hydroxylase [CYP24A1], vitamin D-binding protein [VDBP]) and cancer risk are scarce, especially with respect to melanoma. Mainly VDR polymorphisms regarding melanoma risk and prognosis were examined although other vitamin D metabolism-related genes may also be crucial. In our hospital-based case-control study including 305 melanoma patients and 370 healthy controls single nucleotide polymorphisms in the genes CYP27B1 (rs4646536), CYP24A1 (rs927650), VDBP (rs1155563, rs7041), and VDR (rs757343, rs731236, rs2107301, rs7975232) were analyzed for their association with melanoma risk and prognosis. Except VDR rs731236 and VDR rs2107301, the other six polymorphisms have not been analyzed regarding melanoma before. To further improve the prevention as well as the treatment of melanoma, it is important to identify further genetic markers for melanoma risk as well as prognosis in addition to the crude phenotypic, demographic, and environmental markers used in the clinic today. A panel of genetic risk markers could help to better identify individuals at risk for melanoma development or worse prognosis. We, however, found that none of the polymorphisms tested was associated with melanoma risk as well as prognosis in logistic and linear regression models in our study population.     

History of Foot Ulcer Increases Mortality Among Individuals With Diabetes: Ten-year follow-up of the Nord-Tr?ndelag Health Study,Norway

OBJECTIVE

To compare mortality rates for individuals with diabetes with and without a history of foot ulcer (HFU) and with that for the nondiabetic population.

RESEARCH DESIGN AND METHODS

This population-based study included 155 diabetic individuals with an HFU, 1,339 diabetic individuals without an HFU, and 63,632 nondiabetic individuals who were all followed for 10 years with mortality as the end point.

RESULTS

During the follow-up period, a total of 49.0% of diabetic individuals with an HFU died, compared with 35.2% of diabetic individuals without an HFU and 10.5% of those without diabetes. In Cox regression analyses adjusted for age, sex, education, current smoking, and waist circumference, having an HFU was associated with more than a twofold (2.29 [95% CI 1.82–2.88]) hazard risk for mortality compared with that of the nondiabetic group. In corresponding analyses comparing diabetic individuals with and without an HFU, an HFU was associated with 47% increased mortality (1.47 [1.14–1.89]). Significant covariates were older age, male sex, and current smoking. After inclusion of A1C, insulin use, microalbuminuria, cardiovascular disease, and depression scores in the model, each was significantly related to life expectancy.

CONCLUSIONS

AN HFU increased mortality risk among community-dwelling adults and elderly individuals with diabetes. The excess risk persisted after adjustment for comorbidity and depression scores, indicating that close clinical monitoring might be warranted among individuals with an HFU, who may be particularly vulnerable to adverse outcomes.Hospital-based studies have shown that mortality rates in individuals with diabetic foot ulcers are about twice those observed in individuals with diabetes without foot ulcers (1,2). A diabetic foot ulcer reflects the presence of underlying pathological conditions, and the risk of recurrent ulcers is high (3,4). It has been suggested that the elevated mortality rate among individuals with diabetic foot ulcers is related to comorbid disease such as cardiovascular disease and nephropathy (5) or to psychological factors including depression (6). Although the mortality rate in individuals with diabetes is high, no large population-based studies have examined the impact on mortality of a history of foot ulcers (HFU) among individuals with diabetes.The purpose of this study was to compare mortality rates for individuals with diabetes reporting an HFU with those for individuals without an HFU and the nondiabetic population. These issues were investigated in the Nord-Trøndelag Health Study (HUNT 2), which includes a very large population-based sample of men and women from a well-defined geographic area. Participants with self-reported diabetes were well characterized with regard to their diabetes, and information on demographics, lifestyle, and prevalent disease including depression was available.     

Heterogeneity of Patients With Latent Autoimmune Diabetes in Adults: Linkage to Autoimmunity Is Apparent Only in Those With Perceived Need for Insulin Treatment: Results from the Nord-Tr?ndelag Health (HUNT) study

OBJECTIVE—Subjects with the diagnosis of latent autoimmune diabetes in adults (LADA) are more prone to need insulin treatment than those with type 2 diabetes. However, not all patients with LADA develop the need for insulin treatment, indicating the heterogeneity of LADA. We investigated this heterogeneity by comparing phenotypes of LADA with and without perceived need for insulin treatment (data obtained at times when diagnosis of LADA was not investigated) and also compared LADA and type 2 diabetes phenotypes.RESEARCH DESIGN AND METHODS—We used data from the all population–based Nord-Trøndelag Health study (n = 64,931), performed in 1995–1997. Data were assembled for individuals with LADA (n = 106) and type 2 diabetes (n = 943).RESULTS—In the comparison of individuals with LADA both with and without the need for insulin, insulin-treated subjects had higher titers of GAD antibodies (P < 0.001) and lower fasting C-peptide levels (P < 0.001). GAD antibodies and C-peptide correlated negatively (r = −0.40; P = 0.009). In the comparison of individuals with LADA and type 2 diabetes, all without the need for insulin, markers of metabolic syndrome were equally prevalent and pronounced. Age, C-peptide, and glucose levels were also similar. In the comparison of insulin-treated individuals with LADA and type 2 diabetes, more patients with LADA received insulin (40 vs. 22%, P < 0.001) and C-peptide levels were lower (P < 0.001). Patients with LADA were leaner but were still overweight (mean BMI 28.7 vs. 30.9 kg/m² in type 2 diabetes, P < 0.001). In the comparison of type 2 diabetic patients with and without insulin, insulin-treated subjects were more obese and had higher A1C and lower C-peptide levels (P < 0.001).CONCLUSIONS—Our conclusions are that 1) the need for insulin treatment in LADA is linked to the degree of autoimmunity and β-cell failure, 2) subjects with LADA and type 2 diabetes without the need for insulin treatment are phenotypically similar, and 3) insulin treatment in type 2 diabetic patients is associated with both insulin resistance and β-cell insufficiency.Autoimmunity is the major cause of type 1 diabetes. Autoimmunity is also assumed to be the major cause of latent autoimmune diabetes in adults (LADA) because this category of diabetes shares biochemical markers of β-cell–directed autoimmunity with “classic” type 1 diabetes. In clinical practice, autoimmunity in classic type 1 diabetes as well as in LADA is usually documented by antibodies against GAD.LADA is considered a “mild” form of type 1 diabetes. Mild indicates the fact that patients with LADA do not by clinical judgment need insulin from the time of diagnosis. However, within the first few years after the diagnosis of diabetes a need for insulin treatment develops in many patients with LADA. This distinguishes patients with LADA from those with nonautoimmune type 2 diabetes in whom a need for insulin treatment develops later than in those with LADA (1). An early need for insulin treatment in patients with LADA points to ongoing autoimmune-mediated destruction of β-cells in these patients.Risk factors for type 2 diabetes, such as age, obesity, and lack of physical activity, are associated with the development of LADA (2). In fact, odds ratios in terms of risk for diabetes for these factors of insulin resistance were the same for LADA and type 2 diabetes. This raises the question of the relative importance of autoimmunity vis-à-vis insulin resistance for the etiology of LADA and whether etiology differs among patients with LADA. Support for etiological heterogeneity comes from the large UK Prospective Diabetes Study (UKPDS), in which only a minority of patients with the diagnosis of LADA, when defined solely as GAD antibody positivity, developed the need for insulin treatment during 6 years of follow-up (1). The heterogeneity of LADA is also evident when one compares phenotypes of patients with LADA in different studies (3–6).Heterogeneity of patients with LADA could be further elucidated by comparing phenotypes of insulin-treated patients with LADA with those not treated with insulin. However, several conditions have to be met for such comparisons to be valid. First, groups of diabetic subjects to be compared must be drawn from the same geographically defined population. A population-based study is necessary to avoid the possible biases incurred by studying referral patients or patients selected for inclusion in clinical intervention studies. Second, the perceived need for insulin treatment has to be unbiased by LADA classification, because it has been shown that insulin treatment is initiated earlier when prior knowledge of autoimmunity, measured as GAD antibodies, is available (7). Third, valid comparison groups of insulin-treated and non–insulin-treated type 2 diabetic patients from the same population must be at hand.We had the opportunity to study patients with LADA and type 2 diabetes fulfilling the above-mentioned conditions, who were identified and characterized in the Nord-Trøndelag (HUNT) study. The HUNT study was performed between 1995 and 1997. The study was open to all adult subjects (∼90,000) living in a geographically defined area and had a high attendance rate (70%). To our knowledge, the patients with LADA and type 2 diabetes defined in the HUNT study did not participate in any study at the time of diagnosis and initiation of treatment, thereby minimizing any deviation from standard clinical practice and obviating increased attentiveness for signs of insufficient metabolic control and insulin requirement. Further, autoantibodies, such as GAD antibodies, were not measured by doctors (general practitioners) responsible for treatment in the region as part of the diabetes workup before and at the time of assembling data in 1995–1997. Thus, patients with autoimmune diabetes not requiring insulin at time of diagnosis were regarded and treated as type 2 diabetic patients. This assumption provided a unique opportunity to use the need for insulin as clinically perceived as a parameter for subclassifying patients with LADA and to compare phenotypes of insulin-treated and non–insulin-treated patients with LADA with respective groups of type 2 diabetic patients. Specifically, we wished to assess the influence of autoimmunity and β-cell insufficiency vis-à-vis insulin resistance factors for the perceived need for insulin treatment in patients with LADA.