Current status of National Institutes of Health funding for thoracic surgeons in the United States: Beacon of hope or candle in the wind?

OBJECTIVE: Increasing forces threaten the viability of thoracic surgeon-initiated research, a core component of our academic mission. National Institutes of Health funding is a benchmark of research productivity and innovation. This study examined the current status of National Institutes of Health funding for thoracic surgeons. METHODS: Thoracic surgeon principal investigators on National Institutes of Health-funded grants during June 2010, June 2015, and June 2020 were identified using National Institutes of Health iSearchGrants (version 2.4). American Association of Medical Colleges data were used to identify all surgeons in the United States. Types and total costs of National Institutes of Health-funded grants were compared relative to other surgical specialties. RESULTS: A total of 61 of 4681 (1.3%), 63 of 4484 (1.4%), and 60 of 4497 (1.3%) thoracic surgeons were principal investigators on 79, 76, and 87 National Institutes of Health-funded grants in 2010, 2015, and 2020, respectively; these rates were higher than those for most other surgical specialties (P ≤ .0001). Total National Institutes of Health costs for Thoracic Surgeon-initiated grants increased 57% from 2010 to 2020, outpacing the 33% increase in total National Institutes of Health budget. Numbers and types of grants varied among cardiovascular, transplant, and oncology subgroups. Although the majority of grants and costs were cardiovascular related, increased National Institutes of Health expenditures primarily were due to funding for transplant and oncology grants. Per-capita costs were highest for transplant-related grants during both years. Percentages of R01-to-total costs were constant at 55%. Rates and levels of funding for female versus male thoracic surgeons were comparable. Awards to 5 surgeons accounted for 33% of National Institutes of Health costs for thoracic surgeon principal investigators in 2020; a similar phenomenon was observed for 2010 and 2015. CONCLUSIONS: Long-term structural changes must be implemented to more effectively nurture the next generation of thoracic surgeon scientists.

Blinatumomab Nonresponse and High-Disease Burden Are Associated With Inferior Outcomes After CD19-CAR for B-ALL.

PURPOSE: CD19-targeted chimeric antigen receptor T cells (CD19-CAR) and blinatumomab effectively induce remission in relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) but are also associated with CD19 antigen modulation. There are limited data regarding the impact of prior blinatumomab exposure on subsequent CD19-CAR outcomes. PATIENTS AND METHODS: We conducted a multicenter, retrospective review of children and young adults with relapsed or refractory ALL who received CD19-CAR between 2012 and 2019. Primary objectives addressed 6-month relapse-free survival (RFS) and event-free survival (EFS), stratified by blinatumomab use. Secondary objectives included comparison of longer-term survival outcomes, complete remission rates, CD19 modulation, and identification of factors associated with EFS. RESULTS: Of 420 patients (median age, 12.7 years; interquartile range, 7.1-17.5) treated with commercial tisagenlecleucel or one of three investigational CD19-CAR constructs, 77 (18.3%) received prior blinatumomab. Blinatumomab-exposed patients more frequently harbored KMT2A rearrangements and underwent a prior stem-cell transplant than blinatumomab-naïve patients. Among patients evaluable for CD19-CAR response (n = 412), blinatumomab nonresponders had lower complete remission rates to CD19-CAR (20 of 31, 64.5%) than blinatumomab responders (39 of 42, 92.9%) or blinatumomab-naive patients (317 of 339, 93.5%), P < .0001. Following CD19-CAR, blinatumomab nonresponders had worse 6-month EFS (27.3%; 95% CI, 13.6 to 43.0) compared with blinatumomab responders (66.9%; 95% CI, 50.6 to 78.9; P < .0001) or blinatumomab-naïve patients (72.6%; 95% CI, 67.5 to 77; P < .0001) and worse RFS. High-disease burden independently associated with inferior EFS. CD19-dim or partial expression (preinfusion) was more frequently seen in blinatumomab-exposed patients (13.3% v 6.5%; P = .06) and associated with lower EFS and RFS. CONCLUSION: With the largest series to date in pediatric CD19-CAR, and, to our knowledge, the first to study the impact of sequential CD19 targeting, we demonstrate that blinatumomab nonresponse and high-disease burden were independently associated with worse RFS and EFS, identifying important indicators of long-term outcomes following CD19-CAR.

Evaluation of Factors Associated With Successful Matriculation to Colon and Rectal Surgery Fellowship.

BACKGROUND: As an increasing number of general surgery residents apply for fellowship positions, it is important to identify factors associated with successful matriculation. For applicants to colon and rectal surgery, there are currently no objective data available to distinguish which applicant attributes lead to successful matriculation. OBJECTIVE: The purpose of this study was to identify objective factors that differentiate colon and rectal surgery fellowship applicants who successfully matriculate with those who apply but do not matriculate. DESIGN: This was a retrospective analysis of colon and rectal surgery applicant characteristics. SETTINGS: Deidentified applicant data provided by the Association of American Medical Colleges from 2015 to 2017 were included. MAIN OUTCOME MEASURES: Applicant demographics, medical school and residency factors, number of program applications, number of publications, and journal impact factors were analyzed to determine associations with successful matriculation. RESULTS: Most applicants (n = 371) and subsequent matriculants (n = 248) were white (61%, 62%), male (65%, 63%), US citizens (80%, 88%) who graduated from US allopathic medical schools (66%, 75%). Statistically significant associations included graduation from US allopathic medical schools (p < 0.0001), US citizenship (p < 0.0001), and number of program applications (p = 0.0004). Other factors analyzed included American Osteopathic Association membership (p = 0.57), university-based residency (p = 0.51), and residency association with a colon and rectal surgery training program (p = 0.89). Number of publications and journal impact factors were not statistically different between cohorts (p = 0.067, p = 0.150). LIMITATIONS: American Board of Surgery In-Training Examination scores, rank list, and subjective characteristics, such as strength of interview and letters of recommendation, were not available using our data source. CONCLUSIONS: Successful matriculation to a colon and rectal surgery fellowship program was found to be associated with US citizenship, graduation from a US allopathic medical school, and greater number of program applications. The remaining objective metrics analyzed were not associated with successful matriculation. Subjective and objective factors that were unable to be measured by this study are likely to play a determining role. See Video Abstract at http://links.lww.com/DCR/B415. EVALUACIN DE FACTORES VINCULADOS EN LA INMATRICULACIN EXITOSA PARA BECAS DE CIRUGA COLORRECTAL: ANTECEDENTES:A medida que un número cada vez mayor de residentes de Cirugía General solicitan una beca, es importante identificar los factores vinculados con una inmatriculación exitosa. Para los candidatos a una beca en Cirugía Colorrectal, hoy en día no existen datos objetivos disponibles para distinguir qué atributos del solicitante conducen a una inmatriculación exitosa.OBJETIVO:Identificar objetivamente los factores que diferencian un candidato a una beca en Cirugía Colorrectal que se inmatricula con éxito de aquel que aplica pero no llega a inmatricularse.DISEÑO:Análisis retrospectivo de las características de los solicitantes de beca para Cirugía Colorrecatl.AJUSTES:Datos de los solicitantes no identificados, proporcionados por la Asociación de Colegios Médicos Estadounidenses de 2015 a 2017.PRINCIPALES MEDIDAS DE RESULTADO:Se analizaron los factores demográficos del solicitante, las facultades de medicina y los factores de la residencia, el número de solicitudes de programas, el número y el factor de impacto de las publicaciones realizadas para determinar la asociación con una inmatriculación exitosa.RESULTADOS:La mayoría de los solicitantes (n = 371) que posteriormente fueron inmatriculados exitosamente (n = 248) eran blancos (61%, 62%, respectivamente), hombres (65%, 63%), ciudadanos estadounidenses (80%, 88%) que se graduaron de Facultades de medicina alopática en los EE. UU. (66%, 75%). Las asociaciones estadísticamente significativas incluyeron la graduación de las escuelas de medicina alopática de los EE. UU. (P <0,0001), la ciudadanía de los EE. UU. (P <0,0001) y el número de solicitudes de programas (p = 0,0004). Otros factores analizados incluyeron: membresía AOA (p = 0,57), la residencia universitaria (p = 0,51) y asociación de la residencia con un programa de formación en Cirugía Colorrectal (p = 0,89). El número de publicaciones y los factores de impacto de las revistas no fueron estadísticamente diferentes entre las cohortes (p = 0,067, p = 0,15, respectivamente).LIMITACIONES:El Score ABSITE, la posición en lista de clasificación y las características subjetivas como el de una buena entrevista y las cartas de recomendación no se encontraban disponibles en la fuente de datos.CONCLUSIONES:Se encontró que la inmatriculación exitosa a un programa de becas de Cirugía Colorreectal estaba asociada con la ciudadanía estadounidense, la graduación en una Facultad de medicina alopática en los EE. UU, y al mayor número de solicitudes de programas. El analisis de las medidas objetivas restantes no se asociaron con una inmatriculación exitosa. Es probable que los factores subjetivos y objetivos que no pudieron ser medidos por este estudio jueguen un papel determinante. Consulte Video Resumen en http://links.lww.com/DCR/B415. (Traducción-Dr Xavier Delgadillo).

18F-FDG PET Assessment of Malignant Pleural Mesothelioma: Total Lesion Volume and Total Lesion Glycolysis-The Central Role of Volume.

Cancer survival is related to tumor volume. 18F-FDG PET measurement of tumor volume holds promise but is not yet a clinical tool. Measurements come in 2 forms: the first is total lesion volume (TLV) based on the number of voxels in the tumor, and the second is total lesion glycolysis (TLG), which is the TLV multiplied by the average SUL (i.e., SUV normalized for lean mass) of the tumor (SULaverage). In this study, we measured tumor volume in patients with malignant pleural mesothelioma (MPM). Methods: A threshold-based program in Interactive Data Language was developed to measure tumor volume in 18F-FDG PET images. Nineteen patients with MPM were studied before and after 2 cycles (6 wk) of chemoimmunotherapy. Measurements included TLV, TLG, the sum of the SULs in the tumor (SULtotal, a measure of total 18F-FDG uptake), and SULaverageResults: Baseline TLV ranged from 11 to 2,610 cm3 TLG ranged from 32 to 8,552 cm3 g/mL and correlated strongly with TLV. Although tumor volumes ranged over 3 orders of magnitude, SULaverage stayed within a narrow range of 2.4-5.3 units. Thus, TLV was the major component of TLG, whereas SULaverage was a minor component and was essentially constant. Further evaluation of SULaverage showed that in this cohort its 2 components, SULtotal and TLV, changed in parallel and were strongly correlated (r = 0.99, P < 0.01). Thus, whether the tumors were large or small, 18F-FDG uptake as measured by SULtotal was proportional to the TLV. Conclusion: TLG equals TLV multiplied by SULaverage, essentially TLV multiplied by a constant. Thus TLG, commonly considered a measure of metabolic activity in tumors, is also in this cohort a measure of tumor volume. The constancy of SULaverage is due to the fact that 18F-FDG uptake is proportional to tumor volume. Thus, in this study, 18F-FDG uptake was also a measure of volume.

Qualities and characteristics of applicants associated with successful matriculation to pediatric surgery fellowship training.

BACKGROUND: Pediatric surgery (PS) is among the most competitive fellowship opportunities for general surgery residents. Prior investigations into factors associated with successful matriculation to PS have relied on surveys, which have inherent biases. STUDY DESIGN: Data were extracted from the Electronic Residency Application System for applicants from 2012 to 2017 and analyzed after stratification by matriculation status. RESULTS: Data were gathered on a total of 444 applicants, of which 238 matriculated. The applicant pool was predominantly Caucasian (63.5%), largely graduated from US allopathic school (81%) and had a slight male predominance (54%), although the number of female applicants increased significantly over the study period. Attendance at a US allopathic medical school (OR=4.55, p <0.001), university-based general surgery training (OR=3.02, p <0.001) and training at institutions that offer PS fellowships (OR=3.36, p<0.001) were associated with matriculation. Matriculants had a higher quantity of peer reviewed publications (median 11 vs. 6, p <0.001) and published in high impact factor journals (p<0.001). A total of 65 applicants reapplied at least once, of whom 32% successfully matriculated. CONCLUSIONS: PS applicants' medical school, residency, and research data points correlated with successful matriculation. These data may help guide general surgery residents and medical students aspiring to become pediatric surgeons. TYPE OF STUDY: Prognosis study (retrospective) LEVEL OF EVIDENCE: Level II.

Survey of Surgical Oncology Fellowship Graduates 2005-2016: Insight into Initial Practice.

BACKGROUND: Despite burgeoning interest in Complex General Surgical Oncology (CGSO) fellowship training, little is reported about postgraduate employment. The goal of this study was to characterize CGSO graduates' first employment and to identify factors that influenced this decision. METHODS: The National Cancer Institute (NCI) and Society of Surgical Oncology developed and distributed an electronic survey to CGSO fellows who graduated from 2005 to 2016. RESULTS: The survey response rate was 47% (237/509). Fifty-seven percent of respondents were first employed as faculty surgeons at a university-based/affiliated hospital, with 15% returning to their residency institution. The distribution of respondents' current employment across the United States mirrored the locations of their hometowns. Eighty-five percent of respondents care for patients across at least three disease types, most commonly hepatopancreatobiliary (81%), esophagus/gastric (75%), and sarcoma (74%). Twenty-seven percent of respondents spend the majority of their time in one area of surgical oncology; melanoma, breast, and head/neck were the most common. Two-thirds of respondents (67%) reported that they performed either clinical or basic science research as part of their current position. Multiple factors influenced the decision of first faculty position. CONCLUSIONS: Most CGSO graduates are employed at academic medical centers across the country in proximity to NCI-designated centers, treat a variety of disease types, and spend a percentage of their time dedicated to clinical research.

Quick efficacy seeking trial (QuEST1): a novel combination immunotherapy study designed for rapid clinical signal assessment metastatic castration-resistant prostate cancer.

Advances in immunotherapy utilizing immune checkpoint inhibitors (ICIs) have transformed the treatment landscapes of several malignancies in recent years. Oncologists are now tasked with extending these benefits to a greater number of patients and tumor types. Metastatic castration-resistant prostate cancer (mCRPC) infrequently responds to ICIs, while the cellular vaccine approved for mCRPC, sipuleucel-T, provides a 4-month survival benefit but does not produce clinical responses as monotherapy. However, many novel and generally well-tolerated immune oncology agents with potential for immune synergy and/or additive effects are undergoing clinical development. This availability presents opportunities to develop adaptive-design combination clinical trials aimed to generate, expand, and facilitate antitumor immune responses. Here we describe a currently accruing phase I/II trial (NCT03493945) testing a brachyury-targeted antitumor vaccine, TGF-ß TRAP/anti-PD-L1 antibody, an IL-15 agonist, and an IDO1 inhibitor in mCRPC. TRIAL REGISTRATION: This trial ( NCT03493945 ) was registered in National Clinical Trials on April 11th 2018.

An Examination of Applicants and Factors Associated with Matriculation to Complex General Surgical Oncology Fellowship Training Programs.

BACKGROUND: The demand for training in complex general surgical oncology (CGSO) fellowships currently exceeds the number of positions offered; however, there are scarce data defining the applicant pool or characteristics associated with successful matriculation. Our study described the applicant population and to determine factors associated with acceptance into the fellowship. STUDY DESIGN: Data were extracted from the Electronic Residency Application System for applicants in 2015 and 2016 and stratified based on matriculation status. Applicant demographics, including medical education, residency, and research achievements, were analyzed. Academic productivity was quantified using the number of peer-reviewed publications as well as the journal with the highest impact factor in which an applicant's work was published. RESULTS: Data were gathered on a total of 283 applicants, of which 105 matriculated. The overall population was primarily male (63.2%), Caucasian (40.6%), educated at a U.S. allopathic medical school (53.4%), and trained at a university-based General Surgery residency (55.5%). Education at a U.S. allopathic school (OR = 5.63, p < 0.0001), university-based classification of the applicant's surgical residency (OR = 4.20, p < 0.0001), and a residency affiliation with a CGSO fellowship (OR = 2.61, p = 0.004) or National Cancer Institute designated Comprehensive Cancer Center (OR = 3.16, p < 0.001) were found to be associated with matriculation. Matriculants published a higher number of manuscripts than nonmatriculants (median of 10 vs. 4.5, p < 0.0001) and more frequently achieved publication in journals with higher impact factors (p < 0.0001). CONCLUSIONS: This study represents the first objective description of the CGSO fellowship applicant pool. Applicants' medical school, residency, and research data points correlated with successful matriculation.

Metabolomic and BH3 profiling of esophageal cancers: novel assessment methods for precision therapy.

BACKGROUND: Esophageal cancers accounted for nearly 16,000 deaths in 2016. The number of patients with esophageal cancers increases every year. Neoadjuvant chemoradiotherapy (nCRT) prior to esophagectomy is a standard treatment for esophageal cancers. The patients who have no residual tumor (pathological complete response (pCR)) at surgery are the most likely to experience long term survival. Accurately determining which patients will have a pCR will improve prognostic information for patients and families, confirm lack of response to nCRT, or avoid surgery if no residual tumor is present. Imaging, endoscopy, and liquid biomarkers have all failed to detect pCR without performing an esophagectomy. METHODS: In this study, we are enrolling patients with esophageal adenocarcinoma and squamous cell carcinoma. Patients will undergo standard evaluation including CT scans, laboratory tests, endoscopy with biopsies, and evaluation by a thoracic surgeon. Tissue biopsy is required for enrollment that will be sent for BH3 profiling and metabolomics. Patients will be treated with standard nCRT followed by surgery. Patients with metastatic disease are not eligible. Surgery at the National Cancer Institute will be minimally-invasive robotic surgery. Patients will remain on study indefinitely with regular clinic visits and imaging tests. DISCUSSION: The mitochondria are critically involved in the intrinsic pathway apoptosis. Bcl-2 homology domain 3 (BH3) profiling is a technique to measure a cell's susceptibility to apoptosis. BH3 profiling measures the relative interactions of proteins that induce or block apoptosis. The collective balance of these proteins determines whether a cell is near the threshold to undergo apoptosis. If the cell is near this threshold, then the tumor may be more likely to die when treated with nCRT. The mitochondria secrete metabolites that may be detectable as biomarkers. Metabolomics is a global assessment of all metabolite changes that has been performed for detection, monitoring, prognosis, and treatment response in cancers. Stratification of patients based on whether pCR occurs or not may elucidate metabolomic signatures that may be associated with response. We are asking whether BH3 profiling or a metabolomic signature will correlate with tumor death after nCRT for esophageal cancer. TRIAL REGISTRATION: NCT03223662 ; Clinicaltrials.gov. July 21, 2017.

Phase II study of satraplatin and prednisone in patients with metastatic castration-resistant prostate cancer: a pharmacogenetic assessment of outcome and toxicity.

BACKGROUND: We assessed the effect of excision repair cross-complementing group 1 (ERCC1) and x-ray cross-complementing group 1 (XRCC1) gene polymorphisms on treatment outcomes with satraplatin and prednisone in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel-based therapy. PATIENTS AND METHODS: Twenty-four patients were enrolled in this single arm study. The primary objective was to determine if the presence of ERCC1 Asn118Asn (N118N, 500C>T, rs11615) and XRCC1 Arg399Gln (R399Q, 1301G>A, rs25487) genetic variants might be associated with an impact on progression-free survival (PFS); secondary objectives included overall response, survival, and toxicity. RESULTS: After population stratification by race, white patients carrying heterozygous or variant genotypes at the ERCC1 C>T locus had a >3-fold longer median PFS (5.8 vs. 1.8 months; 2P = .18, adjusted) and 5-fold longer median overall survival (OS) (15.7 vs. 3.2 months; 2P = .010, adjusted) than did patients carrying only wild-type alleles. For the XRCC1 G>A variant, without regard to race, patients carrying the wild-type GG alleles had a longer PFS (9.3 months) than those carrying GA or AA alleles (2.7 months; 2P = .02). Similarly, those carrying GG alleles did not reach median OS, whereas those carrying GA or AA alleles had a median OS of 9.6 months (2P = .12, adjusted). Multivariable analysis by using Cox proportional hazards modeling demonstrated that only XRCC1 was associated with PFS. CONCLUSIONS: To our knowledge, this is the first prospective study to date in patients with metastatic castration-resistant prostate cancer that describes predictive germline polymorphisms of ERCC1 and XRCC1 for assessing the clinical activity of satraplatin.

Survey of nursing integration of genomics into nursing practice.

PURPOSE: Translating clinically valid genomic discoveries into practice is hinged not only on technologic advances, but also on nurses-the largest global contingent of health providers-acquiring requisite competencies to apply these discoveries in clinical care. The study aim was to assess practicing nurse attitudes, practices, receptivity, confidence, and competency of integrating genomics into nursing practice. DESIGN: A convenience sample of practicing nurses was recruited to complete an online survey that assessed domains from Roger's Diffusion of Innovations Theory and used family history utilization as the basis for competency assessment. METHODS: Results were tabulated and analyzed using descriptive statistical techniques. FINDINGS: Two-hundred-thirty-nine licensed registered nurses, 22 to 72 years of age, with a median of 20 years in practice, responded, for an overall response rate of 28%. Most were White (83%), female (92%), and held baccalaureate degrees (56%). Seventy-one percent considered genetics to be very important to nursing practice; however, 81% rated their understanding of the genetics of common diseases as poor or fair. Per-question response rates varied widely. Instrument assessment indicated that modifications were necessary to decrease respondent burden. CONCLUSIONS: Respondents' perceived genomic competency was inadequate, family history was not routinely utilized in care delivery, and the extent of family history varied widely. However, most nurses indicated interest in pursuing continuing genomic education. CLINICAL RELEVANCE: Findings from this study can lead to the development of targeted education that will facilitate optimal workforce preparation for the ongoing influx of genetics and genomics information, technologies, and targeted therapies into the healthcare arena. This pilot study provides a foundation on which to build the next step, which includes a national nursing workforce study.

Assessment of objective responses using volumetric evaluation in advanced thymic malignancies and metastatic non-small cell lung cancer.

INTRODUCTION: Measurement of tumor response by standard response criteria is challenging in thymic malignancies, especially when the pleura is involved, as it often is in stage IV disease. In this study, we aimed to determine the effectiveness of volumetric response evaluation criteria in solid tumors (volumetrics) for evaluating response in patients with thymic malignancies treated on a phase II study of belinostat. METHODS: We evaluated the tumor responses of 25 patients with thymic cancer using computed tomography-based RECIST, World Health Organization (WHO), modified RECIST, and volumetrics. As a control, we assessed 37 patients with non-small cell lung cancer (NSCLC) with RECIST and volumetrics. RESULTS: Agreement analyses in 23 patients with thymic cancer at the time of RECIST-determined progressive disease (PD) compared volumetrics with RECIST, modified RECIST, and WHO criteria. Use of volumetrics was associated with 22% discordance compared with RECIST, 15% versus modified RECIST, and 22% versus WHO criteria. Volumetrics revealed PD 72 days earlier than RECIST (p = 0.016). In another cohort of 35 patients with NSCLC, there was 9% discordance between volumetrics and RECIST at the time of PD. Volumetrics demonstrated PD 32 days earlier than RECIST in NSCLC (p = 0.0078). CONCLUSIONS: Our study suggests that volumetrics might improve detection of PD. Prospective evaluation of this technique in a larger series of patients with thymic malignancies will be required.

Correlation of pretransplant and early post-transplant response assessment with outcomes after reduced-intensity allogeneic hematopoietic stem cell transplantation for non-Hodgkin's lymphoma.

BACKGROUND: Chemotherapy sensitivity, defined simply as at least a partial response to chemotherapy, is an important outcome predictor for non-Hodgkin lymphoma (NHL) patients undergoing reduced-intensity allogeneic hematopoietic stem cell transplantation (allo-HCT). The authors hypothesized that further differentiation of chemotherapy sensitivity by specific response, complete remission (CR) versus partial remission (PR) versus stable disease (SD) versus progression of disease (PD), correlates with post-transplant outcomes. METHODS: The impact of pretransplant and early (28 days) post-transplant disease response on transplant outcomes was analyzed in 63 NHL patients treated with reduced-intensity allo-HCT. RESULTS: The 3-year event-free survival (EFS) and overall survival (OS) (median potential follow-up after reduced-intensity allo-HCT = 58 months) for all patients was 37% and 47%, respectively. The 3-year EFS based on pretransplant response was: CR = 50%; PR = 66%; SD = 18%; no patient with PD pretransplant reached 3-year follow-up. The 3-year OS based on pretransplant response was: CR = 63%; PR = 69%; SD = 45%. The 3-year EFS based on post-transplant response was: CR = 57%; PR = 32%; SD = 33%; no patient with PD post-transplant reached 3-year follow-up. The 3-year OS based on post-transplant response was: CR = 65%; PR = 43%; SD = 50%. In multivariate analyses, pretransplant response was the best predictor of EFS (P < .0001). Pretransplant response (P < .0001) and age (P = .0035) were jointly associated with OS. CONCLUSIONS: These data suggest that NHL patients with pretransplant SD, generally considered inappropriate candidates, may benefit from reduced-intensity allo-HCT, and patients with pretransplant PD should only receive this therapy in clinical trials.

Assessment of the hematopoietic cell transplantation comorbidity index in non-Hodgkin lymphoma patients receiving reduced-intensity allogeneic hematopoietic stem cell transplantation.

The hematopoietic cell transplantation comorbidity index (HCT-CI), a weighted index of 17 pretransplantation comorbidities, has been validated in nonmyeloablative and myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) studies, but it has not been specifically tested in patients with non-Hodgkin lymphoma (NHL) receiving reduced-intensity conditioning (RIC). We performed a retrospective analysis to assess the impact of the HCT-CI on outcomes of NHL patients treated with HSCT relative to treatment-related mortality (TRM), disease-related mortality (DRM), with a specific emphasis on overall survival (OS). Individual pretransplantation and disease-related factors also were analyzed with HCT-CI relative to their impact on OS. All patients were uniformly treated with an identical pretransplantation induction regimen and an identical RIC regimen (cyclophosphamide [Cy]/fludarabine [Flu]), and received T cell-replete allografts from HLA-matched siblings. The analysis included 63 NHL patients with a median HCT-CI score of 2 (range, 0 to 11). The HCT-CI (0 to 2 comorbidities vs 3+ comorbidities) demonstrated a potential association with TRM, but not with DRM, at 100 days (4.5% vs 26.3%) and at 1 year (13.6% vs 36.8%) posttransplantation. The factor most strongly associated with OS was response to pretransplantation chemotherapy (P= .0001), based on a composite measure. In a Cox model, pretransplantation chemotherapy response remained the most important factor (P< .0001) relative to OS, and there was a trend (P= .056) toward HCT-CI adding predictive value for OS. Although HCT-CI may be useful for predicting TRM, our data further underscore the importance of response to chemotherapy before transplantation as a predictor of overall transplantation outcome in NHL patients being considered for RIC allogeneic HSCT.

Clinical and immunologic assessment of patients with psoriasis in a randomized, double-blind, placebo-controlled trial using recombinant human interleukin 10.

BACKGROUND: In several open-label studies, recombinant human interleukin 10 (rhIL-10), a type 2 anti-inflammatory cytokine, has been reported to improve psoriasis, a disease characterized by type 1 cytokine inflammation. OBJECTIVE: To evaluate the safety, efficacy, and immunologic parameters in individuals with psoriasis treated with rhIL-10. DESIGN AND INTERVENTION: Patients received rhIL-10 (20 micro g/kg) or placebo subcutaneously 3 times weekly for 12 weeks in a randomized, double-blind manner. SETTING AND PATIENTS: National Institutes of Health Clinical Center in Bethesda. Twenty-eight patients with moderate-to-severe psoriasis as defined by a Psoriasis Area Severity Index (PASI) score of 10 or higher. MAIN OUTCOME MEASURE: The primary clinical end point was the mean percentage change in the PASI score comparing baseline and week 12 scores. Intracellular cytokine production by peripheral blood mononuclear cells (PBMCs) was measured by flow cytometry. RESULTS: There was no significant difference in the mean percentage change in the PASI score from baseline to week 12 between the rhIL-10-treated group and control patients (17% vs 13% improvement, respectively; P =.69), although a modest trend toward improvement in patients receiving rhIL-10 was documented at both the 6- and 8-week points. Interestingly, proinflammatory and type 1 cytokine production by PBMCs progressively declined in the rhIL-10-treated patients during the entire 12-week study period. CONCLUSIONS: Treatment with rhIL-10 resulted in only temporary clinical improvement in psoriasis, despite sustained systemic decreases in proinflammatory and type 1 cytokine production. These data suggest that immunotherapy that decreases the ratio of systemic type 1 and type 2 cytokine production does not necessarily lead to improvement of type 1 cytokine-mediated disease.