Michal G. Rose

Therapy and prevention of thrombotic thrombocytopenic purpura during pregnancy: A clinical study of 16 pregnancies

Thrombotic thrombocytopenic purpura (TTP) is a severe multisystem disorder of unknown pathogenesis, with preference to women. The mortality rate of patients with TTP was 90% until the introduction of plasma therapy that increased the survival rate to 70–80%, with minimal or no sequelae. Of the survivors, 30–60% suffer from relapses, often in association with precipitating factors such as infections, surgery, and pregnancy. Women who are either pregnant or in the postpartum period make up 10–25% of TTP patients, and once the disease occurs during a pregnancy, it tends to recur in subsequent ones. We treated five women who suffered at least one TTP episode during pregnancy. They had a total of 16 pregnancies, eight of which were complicated by TTP. They suffered seven additional TTP episodes that were not associated with pregnancy. We assessed the severity of each TTP episode with a scoring system used in our previous studies. Presented is the course of their disease and their pregnancies, and guidelines for the management and prevention of TTP during pregnancy are provided.

Improving Colorectal Cancer Screening and Care in the Veterans Affairs Healthcare System

The Veterans Health Administration (VHA) has recently launched several nationwide initiatives to improve the quality of its colorectal cancer (CRC) screening and care. The timeliness of follow-up diagnostic tests in patients who have positive noncolonoscopic CRC screening tests is one of the target areas of these initiatives. Multiple aspects of colon cancer care are being monitored, and the degree of adherence to accepted quality measures is being assessed. The purpose of this review is to describe the background leading to these initiatives and their expected impact on CRC screening and management in the VHA.

Using Nurse Navigation to Improve Timeliness of Lung Cancer Care at a Veterans Hospital

The Connecticut Veterans Affairs Healthcare System (CT-VAHCS) sought to improve the timeliness of lung cancer care by filling the new position of cancer care coordinator with an advanced practice nurse (APN) functioning as a nurse navigator. The multifaceted nature of diagnosing lung cancer and the barriers encountered by patients and families as they access the complex healthcare system contributed to substantial delays in diagnosing and treating this disease. Beginning in January 2007 when the cancer care coordinator was hired, she recorded data regarding timeliness and stage at diagnosis for all patients diagnosed with non-small cell lung cancer. CT-VAHCS created and modified several processes to improve timeliness and quality of cancer care as soon as a patients imaging suggested a new diagnosis of malignancy. The cancer care coordinator effected a measurable improvement in timeliness. In 2003, the average was 136 days from suspicion of cancer to treatment compared to 55 days in 2010, with a trend toward diagnosis of non-small cell lung cancer at an earlier stage. Oncology-certified APNs in the position of cancer care coordinator can engage multiple disciplines to generate process changes and improve timeliness of lung cancer care.

Effects of androgen deprivation on brain function in prostate cancer patients – a prospective observational cohort analysis

BackgroundDespite a lack of consensus regarding effectiveness, androgen deprivation therapy (ADT) is a common treatment for non-metastatic, low-risk prostate cancer. To examine a particular clinical concern regarding the possible impact of ADT on cognition, the current study combined neuropsychological testing with functional magnetic resonance imaging (fMRI) to assess both brain activation during cognitive performance as well as the integrity of brain connectivity.MethodsIn a prospective observational cohort analysis of men with non-metastatic prostate cancer at a Veterans Affairs medical center, patients receiving ADT were compared with patients not receiving ADT at baseline and at 6 months. Assessments included fMRI, the N-back task (for working memory), the stop-signal task (for cognitive control), and a quality of life questionnaire.ResultsAmong 36 patients enrolled (18 in each group), 30 completed study evaluations (15 in each group); 5 withdrew participation and 1 died. Results for the N-back task, stop-signal task, and quality of life were similar at 6 months vs. baseline in each group. In contrast, statistically significant associations were found between ADT use (vs. non use) and decreased medial prefrontal cortical activation during cognitive control, as well as decreased connectivity between the medial prefrontal cortex and other regions involved with cognitive control.ConclusionsAlthough ADT for 6 months did not affect selected tests of cognitive function, brain activations during cognitive control and functional brain connectivity were impaired on fMRI. The long-term clinical implications of these changes are not known and warrant future study.

Time trends in glioblastoma multiforme survival: the role of temozolomide

BACKGROUND In 2005, maximum safe surgical resection, followed by radiotherapy with concomitant temozolomide (TMZ), followed by adjuvant TMZ became the standard of care for glioblastoma (GBM). Furthermore, a modest, but meaningful, population-based survival improvement for GBM patients occurred in the US between 1999 (when TMZ was first introduced) and 2008. We hypothesized that TMZ usage explained this GBM survival improvement. METHODS We used national Veterans Health Administration (VHA) databases to construct a cohort of GBM patients, with detailed treatment information, diagnosed 1997-2008 (n = 1645). We compared survival across 3 periods of diagnosis (1997-2000, 2001-2004, and 2005-2008) using Kaplan-Meier curves. We used proportional hazards models to calculate period hazard rate ratios (HRs) and 95% confidence intervals (CIs), adjusted for demographic, clinical, and treatment covariates. RESULTS Survival increased over calendar time (stratified log-rank P < .0001). After adjusting for age and Charlson comorbidity score, for cases diagnosed in 2005-2008 versus 1997-2000, the HR was 0.72 (95% CI, 0.64-0.82; p-trend < .0001). Sequentially adding non-TMZ treatment variables (ie, surgery, radiotherapy, non-TMZ chemotherapy) to the model did not change this result. However, adding TMZ to the model containing age, Charlson comorbidity score, and all non-TMZ treatments eliminated the period effect entirely (HR = 1.01; 95% CI, 0.86-1.19; p-trend = 0.84). CONCLUSIONS The observed survival improvement among GBM patients diagnosed in the VHA system between 1997 and 2008 was completely explained by TMZ. Similar studies in other populations are warranted to test the generalizability of our finding to other patient cohorts and health care settings.

The Effect of a Lung Cancer Care Coordination Program on Timeliness of Care

BACKGROUND Timeliness of care improves patient satisfaction and might improve outcomes. The CCCP was established in November 2007 to improve timeliness of care of NSCLC at the Veterans Affairs Connecticut Healthcare System (VACHS). PATIENTS AND METHODS We performed a retrospective cohort analysis of patients diagnosed with NSCLC at VACHS between 2005 and 2010. We compared timeliness of care and stage at diagnosis before and after the implementation of the CCCP. RESULTS Data from 352 patients were analyzed: 163 with initial abnormal imaging between January 1, 2005 and October 31, 2007, and 189 with imaging conducted between November 1, 2007 and December 31, 2010. Variables associated with a longer interval between the initial abnormal image and the initiation of therapy were: (1) earlier stage (mean of 130 days for stages I/II vs. 87 days for stages III/IV; P < .0001); (2) lack of cancer-related symptoms (145 vs. 60 days; P < .0001); (3) presence of more than 1 medical comorbidity (123 vs. 82; P = .0002); and (4) depression (126 vs. 98 days; P = .029). The percent of patients diagnosed at stages I/II increased from 32% to 48% (P = .006) after establishment of the CCCP. In a multivariate model adjusting for stage, histology, reason for imaging, and presence of primary care provider, implementation of the CCCP resulted in a mean reduction of 25 days between first abnormal image and the initiation of treatment (126 to 101 days; P = .015). CONCLUSION A centralized, multidisciplinary, hospital-based CCCP can improve timeliness of NSCLC care, and help ensure that early stage lung cancers are diagnosed and treated.

A Distinct Entity in the Spectrum of the Cd30+ Cutaneous Lymphoproliferative Diseases: Oligolesional Nodules With Pseudoepitheliomatous Hyperplasia Followed by Spontaneous Resolution

Pseudoepitheliomatous hyperplasia (PEH) in biopsies of CD30+ anaplastic large-cell lymphoma (ALCL) is present infrequently and is of unknown prognostic value and significance. Our goal was to review the clinicopathologic features of cases of ALCL with PEH, study their course, and review the literature on the subject. Biopsy specimens of all cases of CD30+ lymphoproliferative disorders (59) were retrieved from the files of Yale Dermatopathology Laboratory over a 17-year period and reviewed. We identified 4 cases of ALCL (7%) exhibiting prominent PEH. All 4 patients presented with 1 or 2 nodules. In 2 patients, the lesions spontaneously regressed within a few months after initial diagnosis. One patient chose to have an excision in which only a small number of CD30+ cells were present. We were unable to obtain follow-up for the fourth patient. In the spectrum of CD30+ lymphoproliferative disorders, cases of ALCL with PEH are infrequent. In addition to the 4 cases described here, in our review of the literature we found 35 cases of ALCL with PEH. Most of these patients present with 1 or a few lesions. In the majority of these cases, the lesions started showing evidence of clinical spontaneous regression and even complete resolution within a few months of initial diagnosis. The clinicopathologic correlation between ALCL and PEH has not been emphasized. Because most of these cases follow a relatively benign clinical course, we recommend a more conservative approach in the clinical management of these patients.

Effects of Androgen Deprivation on Cerebral Morphometry in Prostate Cancer Patients – An Exploratory Study

Background Androgen deprivation therapy (ADT) is a common treatment for non-metastatic, low-risk prostate cancer, but a potential side effect of ADT is impaired brain functioning. Previous work with functional magnetic resonance imaging (MRI) demonstrated altered prefrontal cortical activations in cognitive control, with undetectable changes in behavioral performance. Given the utility of brain imaging in identifying the potentially deleterious effects of ADT on brain functions, the current study examined the effects of ADT on cerebral structures using high resolution MRI and voxel-based morphometry (VBM). Methods High resolution T1 weighted image of the whole brain were acquired at baseline and six months after ADT for 12 prostate cancer patients and 12 demographically matched non-exposed control participants imaged at the same time points. Brain images were segmented into gray matter, white matter and cerebral ventricles using the VBM toolbox as implemented in Statistical Parametric Mapping 8. Results Compared to baseline scan, prostate cancer patients undergoing ADT showed decreased gray matter volume in frontopolar cortex, dorsolateral prefrontal cortex and primary motor cortex, whereas the non-exposed control participants did not show such changes. In addition, the decrease in gray matter volume of the primary motor cortex showed a significant correlation with longer reaction time to target detection in a working memory task. Conclusions ADT can affect cerebral gray matter volumes in prostate cancer patients. If replicated, these results may facilitate future studies of cognitive function and quality of life in men receiving ADT, and can also help clinicians weigh the benefits and risks of hormonal therapy in the treatment of prostate cancer.

Use of paclitaxel in patients with pre-existing cardiomyopathy: A review of our experience

Cardiac toxicity is frequently the indication for discontinuation of an anthracycline in patients with tumors which remain anthracycline‐sensitive. During the 1990s, the most frequently used second‐line agents at the Yale Cancer Center (YCC) were the taxanes. The goal of this retrospective analysis was to determine the effect of paclitaxel on cardiac function in patients with cardiomyopathy. YCC outpatient clinic pharmacy order forms were used to identify all patients who had received paclitaxel between December 1995 and November 1997. The clinic records of those patients with a left ventricular ejection fraction (LVEF) of ≤50% were reviewed to determine the temporal relation between the decreased LVEF and paclitaxel therapy. In addition, clinic records were examined for evidence of prior doxorubicin therapy and history of prior cardiac disease. Between December 1995 and November 1997, 225 patients were treated with paclitaxel in the YCC outpatient clinic. Nine patients had LVEF ≤50% (mean 37%) prior to initiation of paclitaxel therapy. Six of these patients had equilibrium radionuclide angiocardiographic (ERNA) scans following completion of paclitaxel. In these 6 patients, the mean change in LVEF was +6% (range –3% to +29%). Four patients had improved LVEF following paclitaxel (mean 11%, range 2% to 29%), while 2 patients experienced a decrease in LVEF following paclitaxel treatment (mean 2.5%). The 3 patients who did not have ERNA scans following paclitaxel therapy had no clinical evidence of congestive heart failure. Our experience confirms the results of prior studies that paclitaxel can be safely administered in patients with underlying cardiac dysfunction.

Prostate Cancer, Comorbidity, and Participation in Randomized Controlled Trials of Therapy

Background Randomized controlled trials (RCTs) evaluate the potential benefits of chemotherapy regimens and guide clinical care for patients with cancer. Inclusion criteria for RCTs are usually stringent and may exclude many patients seen in clinical practice. Our objective was to determine the proportion of men with castrate-resistant prostate cancer (CRPC) in a clinical setting that would have been excluded from major phase 3 RCTs. Methods We reviewed eligibility criteria from 24 phase 3 clinical trials evaluating chemotherapy for CRPC active from January, 2004, through April, 2008. We created a common list of criteria used in at least 3 studies and separately considered the criteria from a prominent RCT (TAX 327). We applied these criteria to a population of patients with CRPC treated during 2004 to 2006 at the Veterans Affairs Connecticut Healthcare System. Results Among 106 patients with CRPC, 99 (93%) had complete medical records, and 45 (45%) of the 99 would have been excluded from RCTs. Common reasons for exclusion were abnormal laboratory values, other malignancies, and other serious medical conditions including cardiac disease. Conclusions Almost half of the CRPC patients examined in a clinical setting would have been ineligible for phase 3 RCTs, highlighting that such trials may not be applicable to general oncology practice.