Jason T. Machan

Microwave Ablation of Lung Malignancies: Effectiveness, CT Findings, and Safety in 50 Patients

PURPOSE To retrospectively evaluate effectiveness, follow-up imaging features, and safety of microwave ablation in 50 patients with intraparenchymal pulmonary malignancies. MATERIALS AND METHODS This HIPAA-compliant study was approved by the institutional review board; informed consent was waived. From November 10, 2003, to August 28, 2006, 82 masses (mean, 1.42 per patient) in 50 patients (28 men, 22 women; mean age, 70 years) were percutaneously treated in 66 microwave ablation sessions. Each tumor was ablated with computed tomographic (CT) guidance. Follow-up contrast material-enhanced CT and positron emission tomographic (PET) scans were reviewed. Mixed linear modeling and logistic regression were performed. Time-event data were analyzed (Kaplan-Meier survival estimates and log-rank statistic). All event times were the time to a patients first event (alpha level = .05, all analyses). RESULTS At follow-up (mean, 10 months), 26% (13 of 50) of patients had residual disease at the ablation site, predicted by using index size of larger than 3 cm (P = .01). Another 22% (11 of 50) of patients had recurrent disease resulting in a 1-year local control rate of 67%, with mean time to first recurrence of 16.2 months. Kaplan-Meier analysis yielded an actuarial survival of 65% at 1 year, 55% at 2 years, and 45% at 3 years from ablation. Cancer-specific mortality yielded a 1-year survival of 83%, a 2-year survival of 73%, and a 3-year survival of 61%; these values were not significantly affected by index size of larger than 3 cm or 3 cm or smaller or presence of residual disease. Cavitation (43% [35 of 82] of treated tumors) was associated with reduced cancer-specific mortality (P = .02). Immediate complications included pneumothorax (Common Terminology Criteria for Adverse Events [CTCAE] grades 1 [18 of 66 patients] and 2 [eight of 66 patients]), hemoptysis (four of 66 patients), and skin burns (CTCAE grades 2 [one of 66 patients] and 3 [one of 66 patients]). CONCLUSION Microwave ablation is effective and may be safely applied to lung tumors. (c) RSNA, 2008.

Nonalcoholic fatty liver disease in severely obese subjects.

BACKGROUND:Nonalcoholic fatty liver disease (NAFLD) has been consistently associated with obesity and insulin resistance. Nonalcoholic steatohepatitis (NASH) is a histological entity within NAFLD that can progress to cirrhosis. The exact prevalence of NASH in severe obesity is unknown. It is unclear whether differences in insulin sensitivity exist among subjects with NASH and simple fatty liver.OBJECTIVE:To evaluate the prevalence and correlates of NASH and liver fibrosis in a racially diverse cohort of severely obese subjects.DESIGN:Ninety-seven subjects were enrolled. Liver biopsies, indirect markers of insulin resistance, metabolic parameters, and liver function tests were obtained.RESULTS:Thirty-six percent of subjects had NASH and 25% had fibrosis. No cirrhosis was diagnosed on histology. Markers of hyperglycemia, insulin resistance, and the metabolic syndrome but not body mass index were associated with the presence of NASH and fibrosis. Elevated transaminase levels correlated strongly with NASH and fibrosis but 46% subjects with NASH had normal transaminases. Subjects with NASH had more severe insulin resistance when compared to those with simple fatty liver. A signal detection model incorporating AST and the presence of diabetes predicted the presence of NASH while another incorporating ALT and HbA1C predicted the presence of fibrosis.CONCLUSIONS:NAFLD is associated with the metabolic syndrome rather than excess adipose tissue in severe obesity. Insulin resistance is higher in subjects with NASH versus those with simple fatty liver. Statistical models incorporating markers of liver injury and hyperglycemia may be useful in predicting the presence of liver pathology in this population.

Cardiovascular Pathology in Hutchinson-Gilford Progeria: Correlation With the Vascular Pathology of Aging

Objective—Children with Hutchinson-Gilford progeria syndrome (HGPS) exhibit dramatically accelerated cardiovascular disease (CVD), causing death from myocardial infarction or stroke between the ages of 7 and 20 years. We undertook the first histological comparative evaluation between genetically confirmed HGPS and the CVD of aging. Methods and Results—We present structural and immunohistological analysis of cardiovascular tissues from 2 children with HGPS who died of myocardial infarction. Both had features classically associated with the atherosclerosis of aging, as well as arteriolosclerosis of small vessels. In addition, vessels exhibited prominent adventitial fibrosis, a previously undescribed feature of HGPS. Importantly, although progerin was detected at higher rates in the HGPS coronary arteries, it was also present in non-HGPS individuals. Between the ages of 1 month and 97 years, progerin staining increased an average of 3.34% per year (P<0.0001) in coronary arteries. Conclusion—We find concordance among many aspects of cardiovascular pathology in both HGPS and geriatric patients. HGPS generates a more prominent adventitial fibrosis than typical CVD. Vascular progerin generation in young non-HGPS individuals, which significantly increases throughout life, strongly suggests that progerin has a role in cardiovascular aging of the general population.

Decreased lubricin concentrations and markers of joint inflammation in the synovial fluid of patients with anterior cruciate ligament injury

OBJECTIVE To study the effect of anterior cruciate ligament (ACL) injury on lubricin concentrations in synovial fluid (SF) and its correlation with time postinjury, inflammatory cytokines, lubricin-degrading enzymes, and SF proteoglycan content. METHODS SF samples were obtained from both knees of 30 patients with unilateral ACL insufficiency, 32-364 days postinjury. Lubricin, inflammatory cytokines (interleukin-1beta [IL-1beta], tumor necrosis factor alpha [TNFalpha], and IL-6), and catabolic enzymes (procathepsin B and neutrophil elastase) were measured in SF from injured and contralateral (uninjured) joints, by enzyme-linked immunosorbent assay. Sulfated glycosaminoglycan (sGAG) levels in the SF were measured by Alcian blue binding assay. RESULTS SF lubricin concentrations were significantly (P < 0.001) reduced at an early stage following ACL injury when compared with those in the contralateral joint. Within 12 months, the lubricin concentration in the injured knee (slope = 0.006, SE = 0.00010, P < 0.001) approached that in the contralateral knee, which did not change with time (slope = -0.0002, SE = 0.00050, P = 0.71). TNFalpha levels showed a significant negative relationship with log2 lubricin levels. IL-1beta, TNFalpha, IL-6, procathepsin B, and neutrophil elastase concentrations in SF from injured knees were greater in samples from recently injured knees compared with those that were chronically injured. There were no detectable cytokines or enzymes in the SF of contralateral joints. Concentrations of sGAG were significantly (P = 0.0002) higher in the SF from injured knees compared with the contralateral joints. CONCLUSION The decrease in SF lubricin concentrations following ACL injury may place the joint at an increased risk of wear-induced damage as a consequence of lack of boundary lubrication, potentially leading to secondary osteoarthritis. The decrease in SF lubricin was associated with an increase in levels of inflammatory cytokines.

Diffusion-Weighted MRI of Peripheral Zone Prostate Cancer: Comparison of Tumor Apparent Diffusion Coefficient With Gleason Score and Percentage of Tumor on Core Biopsy

OBJECTIVE The objective of our study was to determine the relationship between the apparent diffusion coefficient (ADC) value on diffusion-weighted imaging (DWI) and Gleason score of prostate cancer and percentage of tumor involvement on prostate core biopsy. MATERIALS AND METHODS We performed a retrospective study of 57 patients with biopsy-proven prostate cancer who underwent endorectal MRI with DWI between July 2007 and March 2008. Regions of interest (ROIs) were drawn on ADC maps at sites of visible tumor on DW images and ADC maps. A hierarchic mixed linear model was used to compare the ADC value of prostate cancer with the Gleason score and the percentage of tumor on core biopsy. RESULTS Eighty-one sites of biopsy-proven prostate cancer were visible on DW images and ADC maps. The least-squares mean ADC for disease with a Gleason score of 6 was 0.860 x 10(-3) mm(2)/s (standard error of the mean [SEM], 0.036); Gleason score of 7, 0.702 x 10(-3) mm(2)/s (SEM, 0.030); Gleason score of 8, 0.672 x 10(-3) mm(2)/s (SEM, 0.057); and Gleason score of 9, 0.686 x 10(-3) mm(2)/s (SEM, 0.067). Differences between the mean ADC values for a prostate tumor with a Gleason score of 6 and one with a Gleason score of 7 (p = 0.0096) and for a prostate tumor with a Gleason score of 6 and one with a Gleason score of 8 (p = 0.0460) were significant. Comparison between the ADC and percentage of tumor on core biopsy showed a mean ADC decrease of 0.006 (range, 0.004-0.008 x 10(-3) mm(2)/s) for every 1% increase in tumor in the core biopsy specimen. CONCLUSION DWI may help differentiate between low-risk (Gleason score, 6) and intermediate-risk (Gleason score, 7) prostate cancer and between low-risk (Gleason score, 6) and high-risk (Gleason score > 7) prostate cancer. There is an inverse relationship between the ADC and the percentage of tumor involvement on prostate core biopsies.

Effect of Fecal Microbiota Transplantation on Recurrence in Multiply Recurrent Clostridium difficile Infection: A Randomized Trial

Clostridium difficile infection (CDI) is the most common health careassociated infection in U.S. hospitals, with approximately 453000 infections and 29000 deaths in 2011 (1). Antibiotics are frequently ineffective (2, 3), with recurrence rates of 15% to 35% after a first episode and up to 65% after treatment of a second recurrence (4, 5). Recurrences are clinically challenging and are typically treated with prolonged courses of antibiotics, which maintain and exacerbate intestinal dysbiosis (6). Fecal microbiota transplantation (FMT) restores the normal composition of gut microbiota and is recommended when antibiotics fail to clear the infection (3). However, the evidence for FMT rests largely on case series and several open-label clinical trials that have suggested cure rates of 81% to 100% in recurrent CDI (712). To date, there has not been an adequately controlled and blinded trial of FMT for CDI treatment. Furthermore, the optimal method for administering FMT has not been determined. Evidence suggests that colonoscopic delivery has advantages in terms of efficacy (9), safety (13), and patient acceptance and tolerability (14) compared with administration via the nasoenteric route. We therefore performed a double-blind, randomized, controlled study of colonoscopic FMT for treatment of recurrent CDI. Cure rates and adverse events (AEs) were compared between donor FMT and autologous FMT (given as a placebo) in patients who had at least 3 CDI recurrences. Methods Design Overview This prospective, dual-center, double-blind, randomized, controlled trial compared FMT using donor stool or the patients own stool administered by colonoscopy. Patients treated with autologous FMT whose CDI relapsed during the 8-week follow-up were offered FMT using donor stool. Those who underwent donor FMT and had relapse were offered repeated FMT using stool from a different donor. Patients were enrolled between 15 November 2012 and 10 March 2015 at 2 academic hospitals: Montefiore Medical Center in the Bronx, New York (NY), and The Miriam Hospital in Providence, Rhode Island (RI). Microbiome analyses on donor and patient fecal specimens were performed at the University of Minnesota in Minneapolis. The institutional review board at each center approved the study protocol (Supplement). A data and safety monitoring board monitored the trial using halting rules for serious, unexpected, and related adverse safety outcomes, and all authors performed data analysis. Supplement. Supplemental Information Study Population The study population comprised adult outpatients who had 3 or more documented CDI recurrences (defined as 3 unformed stools over 24 hours for 2 consecutive days and either a positive stool test result for C difficile or pseudomembranes on colonoscopy) and who did not maintain cure after a course of tapered or pulsed vancomycin or were unable to taper or discontinue vancomycin (or an alternative antibiotic with activity against CDI) without recurrent diarrhea requiring anti-CDI treatment. All patients had completed at least 10 days of vancomycin therapy for the most recent CDI and continued therapy until 2 to 3 days before the procedure. Major exclusion criteria included age 75 years or older; inflammatory bowel disease, irritable bowel syndrome (IBS), or chronic diarrheal disorder; any immunocompromised state or immunodeficiency; anaphylactic food allergy; previous FMT; untreated, in situ colorectal cancer; and inability to undergo colonoscopy. Donor Identification and Screening Patients were permitted to identify a donor or choose to be treated with stool from healthy volunteers who were recruited at each site. All prospective donors underwent a medical interview and physical examination and were excluded if they had a known communicable disease, features of the metabolic syndrome, a diarrheal disorder, an autoimmune or atopic disease, a tumor, a neurologic disorder, or chronic pain syndrome or if they had used antibiotics for any indication within 3 months. Potential donors also completed a modified AABB full-length donor history questionnaire, and those with risk factors for infectious agents were excluded (Supplement). Testing for HIV-1 and HIV-2 was performed within 2 weeks before donation for FMT. Other serologic and stool testing was performed within 1 month before FMT and included testing for hepatitis A, B, and C viruses; testing for Treponema pallidum; polymerase chain reaction (PCR) testing for detection of C difficile toxin; culture for enteric pathogens (Escherichia coli, Salmonella, Shigella, Yersinia, Campylobacter, Listeria monocytogenes, Vibrio parahaemolyticus, and V cholerae); testing for fecal Giardia and Cryptosporidium antigens; acid-fast stain for detection of Cyclospora and Isospora; ova and parasite testing; and enzyme immunoassay for detection of Rotavirus. Patients also had baseline testing for HIV-1 and HIV-2; hepatitis A, B, and C viruses; and T pallidum. Randomization and Interventions Donors took an osmotic laxative (magnesium hydroxide) the evening before and provided fresh stool the day of FMT. All donor specimens were transported on ice and processed within 6 hours of collection. Patients were given a standard bowel purge (sodium sulfate, potassium sulfate, and magnesium sulfate oral solution) the evening before the procedure. For patient convenience, sodium sulfate, potassium sulfate, and magnesium sulfate oral solution was substituted for the polyethylene glycol (PEG) bowel purge described in the study protocol. After initiating the preparation, patients were required to collect the first stool passed (for possible use in autologous FMT), transfer it to a clean container, and keep it either refrigerated or on ice. Within 1 hour before the scheduled FMT procedure, the nonblinded research assistant took possession of the stool specimens from both the donor and the patient. Patients were equally allocated to the donor and autologous FMT groups via block randomization by C difficile positivity at baseline, with stratification by study site. The protocol specified a dose of 100 g of stool diluted in 500 mL of nonbacteriostatic 0.9% normal saline immediately before the procedure, but the study relied on fresh stool, which has unpredictable weight and volume, and most provided specimens were less than 100 g. Because patients had discontinued use of vancomycin, had completed bowel lavage, and had been randomly assigned, we elected to use the lesser amount of fecal material. In those circumstances, available stool was weighed and suspended in a proportionately reduced volume of saline. A mean stool dose of 64 g (SD, 25 g; range, 20 to 100 g) was infused for donor FMT. Colonoscopies were performed within the endoscopy units of the study centers. Endoscopic findings and the depth of insertion were recorded. The study physician administered 300 mL of the fecal suspension through the instruments working channel into the furthest point reached (terminal ileum or cecum). After FMT, patients were transferred to the recovery area and encouraged to retain the stool for at least 1 hour. If they were unable to do so, the time of the first postprocedure bowel movement was recorded. Follow-up Patients were instructed to contact the clinical team if they had recurrence of diarrhea and were provided with a thermometer for daily oral temperature readings and a diary card to record solicited AEs for 7 days and unsolicited AEs for 30 days after transplantation. They were contacted by telephone 2 and 7 days after FMT and then biweekly for 8 weeks and questioned about stool form and frequency. All patients were seen in the clinic for follow-up 2 and 8 weeks after treatment, where they were assessed for infectious and gastrointestinal symptoms and underwent physical examination. They submitted stool specimens at baseline and at each post-FMT visit for C difficile PCR testing and microbiome analysis. All patients were contacted by telephone by a study representative 6 months after the last treatment to record any serious AEs (SAEs), new medical conditions or diagnoses, or changes in medical conditions or medications since the last study contact. End Points The primary efficacy end point was the rate of clinical cure in the intention-to-treat (ITT) population 8 weeks after FMT or at the time of early withdrawal. Clinical cure was defined as lack of CDI recurrence with maintenance of resolution (that is, <3 unformed stools per day) for 8 weeks without requirement for further antibiotics (metronidazole, vancomycin, or fidaxomicin). Because nucleic acid testing does not distinguish colonized patients from those with symptomatic disease (15), it cannot test for cure (2, 16); therefore, patients meeting the definition of clinical cure were considered to be cured regardless of the results of follow-up PCR testing of stool for C difficile. Safety end points were evaluated by review of SAEs, AEs, new medical conditions or diagnoses, or changes in medical conditions at the 6-month follow-up. Analysis of Fecal Microbiota Fecal microbiota was analyzed from patients at least 5 days before and 2 and 8 weeks after FMT, as well as from donor samples. DNA extraction, 16S ribosomal RNA gene amplification, and sequencing were performed by the University of Minnesota Genomics Center. Processing details are described in the Supplement, and data are archived in the Sequence Read Archive at the National Center for Biotechnology Information under BioProject accession number SRP066964. Taxonomic assignments were made against the Ribosomal Database Project using mothur software, version 1.34.0 (17). Alpha and beta diversity of bacterial communities were evaluated using the same software. Shannon indices and abundance-based coverage estimate parameters were calculated to assess alpha diversity. Differences in beta diversity and abundances of genera were performed using analysis of similarity and KruskalWallis analysis, respectively (18). Statis

Multicenter Pilot Treatment Trial for Psychogenic Nonepileptic Seizures A Randomized Clinical Trial

IMPORTANCE There is a paucity of controlled treatment trials for the treatment of conversion disorder, seizures type, also known as psychogenic nonepileptic seizures (PNES). Psychogenic nonepileptic seizures, the most common conversion disorder, are as disabling as epilepsy and are not adequately addressed or treated by mental health clinicians. OBJECTIVE To evaluate different PNES treatments compared with standard medical care (treatment as usual). DESIGN, SETTING, AND PARTICIPANTS Pilot randomized clinical trial at 3 academic medical centers with mental health clinicians trained to administer psychotherapy or psychopharmacology to outpatients with PNES. Thirty-eight participants were randomized in a blocked schedule among 3 sites to 1 of 4 treatment arms and were followed up for 16 weeks between September 2008 and February 2012; 34 were included in the analysis. INTERVENTIONS Medication (flexible-dose sertraline hydrochloride) only, cognitive behavioral therapy informed psychotherapy (CBT-ip) only, CBT-ip with medication (sertraline), or treatment as usual. MAIN OUTCOMES AND MEASURES Seizure frequency was the primary outcome; psychosocial and functioning measures, including psychiatric symptoms, social interactions, quality of life, and global functioning, were secondary outcomes. Data were collected prospectively, weekly, and with baseline, week 2, midpoint (week 8), and exit (week 16) batteries. Within-group analyses for each arm were performed on primary (seizure frequency) and secondary outcomes from treatment-blinded raters using an intention-to-treat analysis. RESULTS The psychotherapy (CBT-ip) arm showed a 51.4% seizure reduction (P = .01) and significant improvement from baseline in secondary measures including depression, anxiety, quality of life, and global functioning (P < .001). The combined arm (CBT-ip with sertraline) showed 59.3% seizure reduction (P = .008) and significant improvements in some secondary measures, including global functioning (P = .007). The sertraline-only arm did not show a reduction in seizures (P = .08). The treatment as usual group showed no significant seizure reduction or improvement in secondary outcome measures (P = .19). CONCLUSIONS AND RELEVANCE This pilot randomized clinical trial for PNES revealed significant seizure reduction and improved comorbid symptoms and global functioning with CBT-ip for PNES without and with sertraline. There were no improvements in the sertraline-only or treatment-as-usual arms. This study supports the use of manualized psychotherapy for PNES and successful training of mental health clinicians in the treatment. Future studies could assess larger-scale intervention dissemination. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00835627.

Amyloid efflux transporter expression at the blood-brain barrier declines in normal aging.

Reduced clearance of amyloid &bgr; peptides (A&bgr;) across the blood-brain barrier contributes to amyloid accumulation in Alzheimer disease. Amyloid &bgr; efflux transport is via the endothelial low-density lipoprotein receptor-related protein 1 (LRP-1) and P-glycoprotein (P-gp), whereas A&bgr; influx transport is via the receptor for advanced glycation end products. Because age is the major risk factor for developing Alzheimer disease, we measured LRP-1 and P-gp expression and associated transporter expression with A&bgr; accumulation in aging rats. Quantitative LRP-1 and P-gp microvessel expression was measured by immunohistochemistry (IHC); LRP-1 and P-gp expression were assessed in microvessel isolates by Western blotting. There was an age-dependent loss of capillary LRP-1 across all ages (3-36 months) by IHC (linear trend p = 0.0004) and between 3 and 20 months by Western blotting (linear trend p < 0.0001). There was a late (30-36 months) P-gp expression loss by IHC (p < 0.05) and Western blotting (p = 0.0112). Loss ofLRP-1 correlated with A&bgr;42 accumulation (p = 0.0121) and verynearly with A&bgr;40 (p = 0.0599) across all ages. Expression of LRP-1correlated negatively with the expression of receptor for advanced glycation end products (p < 0.0004). These data indicate that alterations in LRP-1 and P-gp expression seem to contribute progressively to A&bgr; accumulation in aging.

Pilot pharmacologic randomized controlled trial for psychogenic nonepileptic seizures

Objective: There have been few treatment trials for psychogenic nonepileptic seizures (PNES). Some psychotherapies have been shown to improve PNES and comorbid symptom outcomes. We evaluated a pharmacologic intervention to test the hypothesis that sertraline would reduce PNES. Methods: We conducted a pilot, double-blind, randomized, placebo-controlled trial in an academic medical hospital with epilepsy center outpatients. Subjects aged 18 to 65 years diagnosed with video-EEG–confirmed PNES were treated with flexible-dose sertraline or placebo over 12 weeks. Seizure calendars and symptom scales were charted prospectively. Secondary outcome measures included psychiatric symptom scales and psychosocial variables. Results: Thirty-eight subjects enrolled, and 26 (68%) completed the trial. Thirty-three subjects with nonzero nonepileptic seizure rates at baseline were included in intent-to-treat analysis of the primary outcome. Subjects assigned to the sertraline arm experienced a 45% reduction in seizure rates from baseline to final visit (p = 0.03) vs an 8% increase in placebo (p = 0.78). Secondary outcome scales revealed no significant between-group differences in change scores from baseline to final visit, after adjustment for differences at baseline. Conclusions: PNES were reduced in patients treated with a serotonin selective reuptake inhibitor, whereas those treated with placebo slightly increased. This study provides feasibility data for a larger-scale study. Level of evidence: This study provides Class II evidence that flexible-dose sertraline up to a maximum dose of 200 mg is associated with a nonsignificant reduction in PNES rate compared with a placebo control arm (risk ratio 0.51, 95% confidence interval 0.25–1.05, p = 0.29), adjusting for differences at baseline.

Disease Progression in Hutchinson-Gilford Progeria Syndrome: Impact on Growth and Development

OBJECTIVES. Hutchinson-Gilford progeria syndrome is a rare and uniformly fatal segmental “premature aging” disease that affects a variety of organ systems. We sought to more clearly define the bone and weight abnormalities in patients with progeria as potential outcome parameters for prospective clinical trials. PATIENTS AND METHODS. We collected and analyzed longitudinal medical information, both retrospectively and prospectively, from a total of 41 children with Hutchinson-Gilford progeria syndrome spanning 14 countries, from the Progeria Research Foundation Medical and Research Database at the Brown University Center for Gerontology. RESULTS. In addition to a number of previously well-defined phenotypic findings in children with progeria, this study identified abnormalities in the eruption of secondary incisors lingually and palatally in the mandible and maxilla, respectively. Although bony structures appeared normal in early infancy, clavicular resorption, coxa valga, avascular necrosis of the femoral head, modeling abnormalities of long bones with slender diaphyses, flared metaphyses, and overgrown epiphyses developed. Long bones showed normal cortical thickness centrally and progressive focal demineralization peripherally. The most striking finding identified in the retrospective data set of 35 children was an average weight increase of only 0.44 kg/year, beginning at ∼24 months of age and persisting through life, with remarkable intrapatient linearity. This rate is >2 SD below normal weight gain for any corresponding age and sharply contrasts with the parabolic growth pattern for normal age- and gender-matched children. This finding was also confirmed prospectively. CONCLUSIONS. Our analysis shows evidence of a newly identified abnormal growth pattern for children with Hutchinson-Gilford progeria syndrome. The skeletal and dental findings are suggestive of a developmental dysplasia rather than a classical aging process. The presence of decreased and linear weight gain, maintained in all of the patients after the age of 2 years, provides the ideal parameter on which altered disease status can be assessed in clinical trials.