National Institutes Of Health Consensus Research Articles

Systematic Review and Meta-Analysis on Role of Adiponectin to Leptin Ratio in Women with Polycystic Ovarian Syndrome

Objective: PCOS or Polycystic Ovarian Syndrome, a multifaceted disorder marked by disruptions in endocrine and metabolic processes, influences reproductive age women. The most commonly used criteria for diagnosing this condition are the Rotterdam 2003 and the National Institutes of Health Consensus 1990 guidelines. Recent studies are currently focusing on novel biomarkers, such as adiponectin and leptin to gain deeper insights on the intricate pathophysiology of PCOS. Therefore, this review aimed to consolidate the importance of the A:L (adiponectin to leptin) ratio as a potential and promising biomarker for PCOS. Materials and Methods: The method followed the PRISMA 2020 guidelines. Furthermore, MEDLINE, Proquest, and EBSCOhost databases were used to obtain eligible studies published up to February 2023. This study was registered in PROSPERO on April 2, 2023 with registration number CRD42023411754. ESHRE/ASRM or Rotterdam Guideline was used as the diagnosis criteria for women with PCOS. To examine the studies' heterogeneity, the I2 statistic and Cochran's Q test were utilized. Meanwhile, the evaluation on publication bias visually employed a funnel plot and was confirmed through Egger's test and rank correlation test. Data analysis was conducted with JASP 0.17.1, and statistical significance was characterized as a p-value below 0.05. Results: In the systematic review, a total of nine studies were incorporated, and seven studies were used in the subsequent meta-analysis. Each paper showcased a reduced A:L ratio in women with PCOS, with a standardized mean difference (SMD) among PCOS and control groups of 0.49 (CI: 0.37 - 0.61). The residual heterogeneity test yielded a p-value of 0.069, and no publication bias indication both pre and post intervention (p=0.002). Conclusion: Referring to the findings, the A:L ratio was notably lower in PCOS patients. Consequently, the A:L ratio holds promise as a novel and potential biomarker for PCOS.

Phase I/II Study of Reduced Dosing of Post-Transplantation Cyclophosphamide (PTCy) after HLA-Identical Peripheral Blood Hematopoietic Stem Cell Transplantation

Introduction Post-transplant cyclophosphamide (PTCy)-based prophylaxis for acute graft versus host disease (aGvHD) has become a standard protocol in HLA haploidentical bone marrow transplantation. Preliminary evidence indicates that compared to the standard dosage (50 mg/kg on days +3 and +4 post-transplantation), a regimen of half the typical cyclophosphamide dosage is both feasible and effective. However, the optimal dosage and timing of PTCy for aGvHD prophylaxis in a HLA identical setting, using peripheral stem cells as the graft, remain unknown. This study aims to investigate the efficacy and safety of a reduced PTCy dosage regimen in patients undergoing peripheral blood stem cell transplants (PBSCT) with HLA indentical donors. Methods This prospective, single-center phase I/II study enrolled patients scheduled for PBSCT with HLA identical donors. The aGVHD prophylaxis regimen comprised PTCy on days +3 and +4, followed by cyclosporine initiation from day 5 post-transplant. In the phase I stage, an initial cohort of five patients received PTCy at a dosage of 50 mg/kg/day on days +3 and +4 (designated as dose level 1, DL1). This was followed by a 3+3 dose de-escalation design with subsequent dose levels as follows: DL2, 50 mg/kg on day +3 and 25 mg/kg on day +4; and DL3, 25 mg/kg on both day +3 and +4. The dose-limiting toxicity for this de-escalation was defined as the occurrence of grade III-IV aGVHD within the first 100 days post-transplantation. The phase II stage comprised an expansion cohort, which was based on the optimal dose identified during phase I. aGvHD classification was established using the Mount Sinai Acute GVHD International Consortium (MAGIC) criteria, while chronic GvHD (cGvHD) was assessed per the latest National Institutes of Health Consensus on cGvHD. Patients were closely followed-up at +1, +2, +3, +4, +6, +9, +12, +18, and +24 months post-transplant. Results In the first stage, a total of 11 patients (5 in DL1, 3 in DL2, and 3 in DL3) were included, and no patient developed grade III-IV aGVHD. Based on this, DL3 was selected as the PTCy dose for phase II, which comprised 18 patients. Overall, 29 patients (17 females, 12 males) with a median age of 39 years (range 17-65) were included, and the median follow-up duration was 12.7 months (range 2.2-22.1). Patient and disease characteristics are summarized in Table 1. By day +30 post-ASCT, all patients achieved complete remission (CR) and minimal residual disease (MRD) clearance. No patient developed grade III-IV aGVHD within 100 days post-transplantation. There was no significant difference in the neutrophil and platelet engraftment interval among the three groups (Figure 1A, B). Among the 21 patients who received the DL3 dose of PTCy, the estimated cumulative incidence of grade II to IV aGVHD at day +100 was recorded at 28.6%, and the incidence of aGVHD at day +100 presented no difference among the three DL groups (Figure 1C). In addition, 1 patient in DL3 developed grade IV intestinal aGVHD on day +141 and died one month later. The estimated 1-year cumulative incidence of hemorrhagic cystitis (HC) and cytomegalovirus (CMV) reactivation was 19.3% and 19%, respectively (Figure 1D). Five patients (all in DL3) experienced relapse, with a median interval of 6.7 months and an estimated 1-year cumulative incidence of 10.6%. A total of 5 fatalities occurred during our study (1 in DL1, and 4 in DL3), 1 due to relapse, 2 from COVID-19-associated pulmonary aspergillosis, 1 from severe septicemia and 1 due to grade IV aGVHD as mentioned above. The estimated 6-month cumulative incidence of NRM was 9.5%, presenting no difference among the three DL groups (Figure 1E). Among the 20 evaluable patients, the estimated 1-year cumulative incidence of chronic GVHD (cGVHD) and moderate cGVHD was 37.3% and 16% (Figure 1F), respectively, with no severe cGVHD observed. No cases of patient relapse were reported. The estimated 1-year progression-free survival (PFS) and overall survival (OS) were 61.2% and 80.4%, respectively (Figure 1G). Conclusion The findings of this study substantiate that a two-day regimen of PTCy at 25 mg/kg/day serves as an effective and safe prophylactic measure against aGVHD, comparable to the standard dosing protocol. However, to definitively establish whether the de-escalated PTCy dosage provides superior outcomes to the standard regimen, longer-term follow-up and comparative studies are warranted.

Clinical characteristics of oral chronic graft-versus-host disease according to the 2014 National Institutes of Health (USA) consensus criteria.

Chronic graft-versus-host disease (cGVHD) is a serious and common complication of allogeneic hematopoietic cell transplantation (alloHCT). The oral cavity is the second most common site affected by cGVHD. In 2014, the 2005 National Institutes of Health (NIH) consensus criteria were revised to address areas of controversy. The aim of this study was to evaluate the clinical characteristics of oral cGVHD using the 2014 NIH consensus criteria. The baseline data of oral manifestation of patients, who were diagnosed with oral cGVHD, in the first dental visit were analyzed (n=22). The oral mucosal disease was evaluated by NIH modified Oral Mucosa Rating Scale (OMRS) and Thongprasom sign score. The salivary gland disease and sclerotic disease were determined by the presence of signs and symptoms. The functional impact was assessed by the organ-specific severity score. The median time from transplant to oral cGVHD diagnosis was 11.9 months. White striae with an erosive area was found in 72.7% of the patients. The mean ± SD of NIH modified OMRS was 6.1 ± 3.0. The most common and severely affected site of lichen planus-like features was buccal mucosa. Xerostomia, superficial mucocele and limited mouth opening were found in 18.2%, 9.1%, and 9.1%, respectively, of the patients. Almost all patients (90.9%) had partial limitation of oral intake. There were no significant differences in NIH modified OMRS or organ-specific severity score among the patient characteristic groups. Moreover, there was no association between the oral manifestations of cGVHD and the patient characteristics. The most common oral manifestation of cGVHD was white striae with an erosive area of oral mucosal disease, followed by xerostomia, superficial mucocele, and limited mouth opening. The 2014 NIH consensus criteria for diagnostic and severity assessment are informative and feasible in real-world practice.

Association of anti-mullerian hormone and free androgen index level on response to clomiphene citrate in PCOS infertile women

BackgroundPolycystic ovary syndrome (PCOS) is the leading cause of anovulatory infertility. Clomiphene citrate, insulin-sensitizing drugs, aromatase inhibitors, gonadotropins, or laparoscopic ovarian drilling are various methods used for ovulation induction in women with PCOS. PCOS women with high levels of anti-mullerian hormone (AMH) and free androgen index (FAI) do not respond well to ovulation induction. This prospective observational study explores the relationship between FAI and AMH levels on ovarian response to clomiphene citrate in infertile women with PCOS. MethodsThis prospective observational study included 40 infertile with PCOS who underwent ovulation induction with clomiphene citrate with dose ranging from 50 to 150 ​mg. Participants were classified into four phenotypes by NIH(National Institute of Health) consensus panel criteria. The clinical and endocrine parameters of participants who were sensitive to clomiphene were compared to those who were resistant. ResultsThe most common phenotype was A, with all three features of PCOS: hyperandrogenism, ovulatory dysfunction, and polycystic ovarian morphology. There was no significant difference in clinical and endocrine parameters among the different phenotypes of PCOS except AMH and FAI values. The mean FAI was 9.39 ​± ​1.11 and AMH 7.26 ​± ​0.48 (ng/ml) in clomiphene resistant and 5.31 ​± ​1.93 and 3.69 ​± ​1.84 (ng/ml) respectively in clomiphene-sensitive women. Women with FAI > 7.5 and AMH >7 ​ng/ml might be resistant to clomiphene. ConclusionFAI and AMH values were significantly higher in women resistant to clomiphene induction. AMH and FAI may help women with PCOS to tailor their ovulation induction protocol.

The Evolution of Penile Prosthesis in the Treatment of Erectile Dysfunction

The National Institutes of Health consensus on impotence has defined erectile dysfunction in 1993 as the persistent inability of male to achieve and/or maintain an erect penis to allow satisfactory sexual intercourse. This condition affects millions of men of any age, but its prevalence is closely associated with aging, and it is estimated that about fifty percent of men, aged 40-70, experience some degree of erectile dysfunction. Penile prosthesis has been part of the therapeutic alternatives of erectile dysfunction for several decades. However, in the ‘90s, with the arrival of type-5 phosphodiesterase inhibitors, the treatment of erectile dysfunction evolved significantly. This class of drugs, which is currently considered the first line of treatment, is ineffective in about 30% of patients whom continue to require more invasive treatments. Penile prosthesis has high satisfaction and efficacy rates in the management of erectile dysfunction, and they undergone through some evolutions in the past years. This article intent to underline the evolution of the penile prosthesis in the treatment of erectile dysfunction with their virtues and disadvantages.

Abnormal liver tests are not sufficient for diagnosis of hepatic graft-versus-host disease in critically ill patients.

Hepatic graft‐versus‐host disease (HGVHD) contributes significantly to morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Clinical findings and liver biomarkers are neither sensitive nor specific. The relationship between clinical and histologic diagnoses of HGVHD was assessed premortem and at autopsy. Medical records from patients who underwent HSCT at the National Institutes of Health (NIH) Clinical Center between 2000 and 2012 and expired with autopsy were reviewed, and laboratory tests within 45 days of death were divided into 15‐day periods. Clinical diagnosis of HGVHD was based on Keystone Criteria or NIH Consensus Criteria, histologic diagnosis based on bile duct injury without significant inflammation, and exclusion of other potential etiologies. We included 37 patients, 17 of whom had a cholestatic pattern of liver injury and two had a mixed pattern. Fifteen were clinically diagnosed with HGVHD, two showed HGVHD on autopsy, and 13 had histologic evidence of other processes but no HGVHD. Biopsy or clinical diagnosis of GVHD of other organs during life did not correlate with HGVHD on autopsy. The diagnostic accuracy of the current criteria was poor (κ = −0.20). A logistic regression model accounting for dynamic changes included peak bilirubin 15 days before death, and an increase from period −30 (days 30 to 16 before death) to period −15 (15 days before death) showed an area under the receiver operating characteristic curve of 0.77. Infection was the immediate cause of death in 68% of patients. In conclusion, liver biomarkers at baseline and GVHD elsewhere are poor predictors of HGVHD on autopsy, and current clinical diagnostic criteria have unsatisfactory performance. Peak bilirubin and cholestatic injury predicted HGVHD on autopsy. A predictive model was developed accounting for changes over time. Further validation is needed.

A Randomized Controlled Study of Extracorporeal Photopheresis (ECP) Therapy with UVADEX® (Methoxsalen) for National Institutes of Health (NIH)-Graded Moderate to Severe Chronic Graft-Vs-Host Disease (cGVHD)

A Randomized Controlled Study of Extracorporeal Photopheresis (ECP) Therapy with UVADEX® (Methoxsalen) for National Institutes of Health (NIH)-Graded Moderate to Severe Chronic Graft-Vs-Host Disease (cGVHD)

PCN479 PATIENT-REPORTED SYMPTOM BURDEN OF CHRONIC GRAFT VERSUS HOST DISEASE: A SYSTEMATIC LITERATURE REVIEW

Chronic graft versus host disease (cGVHD) is a life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT). This study provides a systematic review of evidence on the patient-reported symptom burden of cGVHD. Systematic literature review was performed using PubMed, Scopus and Cochrane Controlled Register of Trials databases. Literature search was limited to English-language articles published after 2005. Only studies which used the National Institutes of Health (NIH) Consensus Criteria for diagnosing cGVHD and collected patient-reported symptom burden data were included. From the 1211 found references, 122 collected patient-reported data. There were 38 studies which specifically collected symptom burden data from patients, from which 35 used the 2005 and 3 used the 2014 NIH Consensus Criteria to define cGVHD. Different study designs were applied, the most frequently used were prospective (n=18) and cross-sectional cohort study (n=10). The number of involved cGVHD patients ranged from 19 to 584. Majority (n=28) of the studies were conducted in the USA. The Lee cGVHD Symptom Scale was the most frequently used instrument, applied in 28 studies. The NIH symptom scores reported by patients were also used frequently to assess organ-specific symptoms. The other instruments were mainly organ-specific measures (e.g. Ocular Surface Disease Index) or general measures to assess pain (e.g. Visual Analog Scale). Twenty-one studies were organ-specific; oral and ocular cGVHD were the most frequently investigated with 8 and 7 studies, respectively. Severity of the disease seems to be associated with higher symptom burden. The patient-reported symptom burden among patients diagnosed with cGVHD by NIH Consensus Criteria was widely assessed in the literature. The Lee Symptom Scale is the most frequently used instrument in trials. Organ involvement and disease severity are both important factors of the cGVHD’s symptom burden. New treatment options should aim to mitigate symptom burden of cGVHD patients.

Negative impact of polycystic ovary syndrome on bone health: a systematic review and meta-analysis.

Polycystic ovary syndrome (PCOS) has reproductive and metabolic aspects that may affect bone health. Controversial results from different studies regarding the risk of fractures, bone mineral density (BMD) or bone markers led to uncertainty whether PCOS might improve or deteriorate bone health. This study aimed to investigate the impact of PCOS on bone markers, BMD and fracture risk. A systematic review and a meta-analysis were carried out. PubMed, EMBASE and Cochrane databases were searched for eligible studies from 1st of January of 1990 to 9th of October of 2018. Eligible studies enrolled women older than 18years with PCOS, which should be diagnosed according to the Rotterdam Consensus, the Androgen Excess Society, the National Institutes of Health Consensus or the International Classification of Diseases. The studies were grouped according to patient mean BMI: <27kg/m2 or ≥27kg/m2. The results were polled as mean difference (MD), standardized MD (SMD) and hazard ratio (HR). Overall, 921 studies were retrieved, and 31 duplicated studies were removed. After screening the titles and abstracts, 80 studies were eligible for full text reading. Of those, 23 studies remained for qualitative synthesis. With the exception of one study, all studies were considered high quality based on the Newcastle-Ottawa scale (NOS; score ≥6). Meta-analysis was performed in 21 studies, with a total of 31 383 women with PCOS and 102 797 controls. Women with PCOS with BMI <27kg/m2 had lower BMD of the total femur (MD, -0.04; 95% CI, -0.07 to 0.00; I2= 31%; P= 0.22) and spine (MD, -0.07; 95% CI, -0.13 to -0.01; I2= 70%; P< 0.01) when compared with the control group, whereas for women with BMI ≥27kg/m2 no difference was observed (femur: MD, 0.02; 95% CI, -0.02 to 0.05; I2= 20%, P= 0.29; spine: MD, 0.02; 95% CI, -0.06 to 0.05; I2= 0%; P= 0.84). Osteocalcin was remarkably reduced in women with PCOS with BMI <27kg/m2 (SMD, -2.68; 95% CI, -4.70 to -0.67; I2= 98%; P< 0.01), but in women with BMI ≥27kg/m2, there were no differences between PCOS and controls. Few studies (n= 3) addressed the incidence of bone fractures in women with PCOS. The HR for total bone fractures did not identify differences between women with PCOS and controls. On the basis of the available evidence, it is possible to assume that PCOS in women with BMI <27kg/m2 is associated with reduced BMD in the spine and femur, and decreased bone formation, as manifested by lower levels of circulating osteocalcin. These findings suggest that bone parameters in PCOS may be linked, to some extent, to adiposity. These studies included premenopausal women, who have already achieved peak bone mass. Hence, further prospective studies are necessary to clarify the existence of increased risk of fractures in women with PCOS.

Comparison of the Different PCOS Phenotypes Based on Clinical Metabolic, and Hormonal Profile, and their Response to Clomiphene.

Objective:To compare the different polycystic ovarian syndrome (PCOS) phenotypes based on their clinical, metabolic, hormonal profile, and their differential response to clomiphene.Design:Prospective observational study.Setting:Infertility clinic, a government hospital.Sample Size:164 women with PCOS-related infertility.Materials and Methods:Sample population was divided into four phenotypes based on the NIH (National Institute of Health) consensus panel criteria. The incremental dose of clomiphene from 50 to 150 mg/day over three cycles was given.Outcome Measures:Clinical history, metabolic, hormonal profile, and ultrasound features of each phenotype. Also, the response to clomiphene citrate was studied as presence or absence of ovulation.Results:The prevalence of phenotypes A, B, C, and D were 67.7%, 11%, 17.7%, and 3.6%, respectively. Phenotype A had significantly higher weight, body mass index, clinical, and biochemical hyperandrogenism, menstrual irregularities, ovarian reserve parameters, fasting insulin, HOMA-IR, and more deranged lipid profile (P < 0.05). Clomiphene resistance was significantly more common in phenotype A (P < 0.05). No significant differences were noted in the waist circumference, waist-hip ratio, blood pressure and blood sugar values (fasting, 1-hour postprandial, 2-hour postprandial). Also, the Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH), LH-FSH ratio, 17-hydroxyprogesterone, and vitamin D levels were not significantly different among various PCOS phenotypes.Conclusion:Full-blown PCOS (phenotype A) is at a higher risk of adverse metabolic and cardiovascular outcomes as compared with the others, and phenotype D is the least severe phenotype. Thus, the phenotypic division of patients with PCOS-related infertility can help in prognosticating the patients about the severity of the disease and the fertility outcome.

Bronchopulmonary Dysplasia: Comparison Between the Two Most Used Diagnostic Criteria.

Objectives: To compare the Shennan's and the consensus definition of Bronchopulmonary Dysplasia (BPD) from the National Institutes of Health (NIH) workshop and analyze specific risk factors associated with each definition.Study design: Retrospective analysis of records of 274 infants admitted to a level IV intensive care unit. Infants were classified as having BPD or no BPD by both definitions. Differences in incidence and risk factors were analyzed. Statistical methods included descriptive statistics, comparative tests, and marginal logistic regression modeling.Results: The estimated difference in prevalence was 32% [95% CI: (26%, 37%), (p < 0.0001)] between both criteria. The prevalence of BPD was 80% higher based on the NIH criteria [RR = 1.80; 95% CI: (1.58, 2.06)]. Infants with no BPD by the Shennan definition were breathing room air with or without positive or continuous pressure support and were most likely to be discharged home on oxygen [OR = 4.47, 95% CI: (1.20, 16.61), p = 0.03]. Gestational age, birth weight, and 1-min Apgar score predicted BPD by both definitions. Chorioamnionitis increased the risk of BPD by the Shennan definition but was associated with lower risk by the NIH criteria. IUGR was associated with BPD by the Shennan definition and with severe BPD by the NIH criteria.Conclusion: Compared to the Shennan's definition, the NIH consensus identified 80% more infants with BPD and is a better predictor of oxygen requirement at discharge. Until a new better criteria is develop, the NIH consensus definition should be used across centers.

Between Bench and Bedside: Building Clinical Consensus at the NIH, 1977-2013.

After World War II, the National Institutes of Health (NIH) emerged as a major patron of biomedical research. In the succeeding decades, NIH administrators sought to determine how best to disseminate the findings of the research it supported and manage their relationship with clinicians in the national community. This task of bridging research and practice fell to the Office of Medical Applications of Research (OMAR), which administered the NIH Consensus Development Program (CDP) between 1978 and 2012. This article argues that the CDP represented an unusual attempt to depoliticize biomedical research and medical practice at a particularly controversial time in American medicine. Throughout the program's existence, administrators sought ways to bring new knowledge to the medical community without creating the appearance of regulating clinical practice. For an agency with a mandate to promote the production of new biomedical knowledge, the question remained open as to how far this responsibility extended from the bench to the bedside. In striking this balance, the leadership sought to refine their understanding of the role and mission of the NIH. The history of the CDP has much to tell us about postwar biomedical research, health politics, and the institutional development of the NIH.

Use of the National Institutes of Health Consensus Guidelines Improves the Diagnostic Sensitivity of Gastrointestinal Graft-Versus-Host Disease.

- Graft-versus-host disease of the gastrointestinal tract is a common complication of hematopoietic stem cell transplant associated with significant morbidity and mortality. Accurate diagnosis can be difficult and is a truly clinicopathologic endeavor. - To assess the diagnostic sensitivity of gastrointestinal graft-versus-host disease using the 2015 National Institutes of Health (NIH) histology consensus guidelines and to analyze histologic findings that support the guidelines. - Patients with allogeneic hematopoietic stem cell transplants were identified via a retrospective search of our electronic medical records from January 1, 2005, to January 1, 2011. Endoscopies with available histology were reviewed by 2 pathologists using the 2015 NIH guidelines. The clinical diagnosis was used as the gold standard. A nontransplant set of endoscopic biopsies was used as a control. - Of the 250 total endoscopies, 217 (87%) had a clinical diagnosis of gastrointestinal graft-versus-host disease. Use of the NIH consensus guidelines showed a sensitivity of 86% and a specificity of 65%. Thirty-seven of 58 (64%) cases with an initial false-negative histopathologic diagnosis were diagnosed as graft-versus-host disease on our review. - Use of the NIH histology consensus guidelines results in a high sensitivity and specificity, thereby decreasing false-negatives. Additionally, use of the NIH guidelines aids in creating uniformity and diagnostic clarity. Correlation with clinical and laboratory findings is critical in evaluating the differential diagnosis and to avoid false-positives. As expected, increased apoptosis with decreased inflammation was associated with a pathologic diagnosis of graft-versus-host disease and supports the NIH guidelines.

Economic and Practical Considerations in the Treatment of Oral Mucosal Chronic Graft-Versus-Host Disease

Chronic graft-versus-host disease (cGVHD) frequently affects the oral mucosa and is generally responsive to topical immunomodulatory therapies. Clinicians may benefit from guidance in choosing the most appropriate therapy with respect to practicality and cost. To assess the economic considerations related to topical immunomodulatory treatments for management of oral mucosal cGVHD and their practical implications. Topical treatments used for management of oral cGVHD were obtained from the National Institutes of Health Consensus document for ancillary and supportive care. Cost data for a standard 1-month prescription was obtained from national databases for commercially available formulations and from compounding pharmacies for formulations requiring compounding. There are numerous topical preparations used for the management of oral cGVHD, many of which require compounding. The average wholesale price of the commercially available agents ranges from $5 to $277/month, and the cost of the compounded preparations ranges from $43 to $499/month. Costs can be influenced by drug-, patient-, and pharmacy-related factors. The costs associated with topical treatment of oral cGVHD are substantial, particularly because the disease is chronic and expenses accumulate over time. Rational prescribing according to a proposed algorithm, including de-escalation of therapy when indicated, can help to minimize associated costs. This has practical implications for patients, physicians, pharmacies, and insurance providers.

2018 update on chronic graft-versus-host disease

Chronic graft-versus-host disease (GVHD) occurs in 30-40% of patients who undergo allogeneic hematopoietic cell transplantation. The symptoms of chronic GVHD resemble those of autoimmune diseases, and many sites, including the eyes, mouth, skin, gastrointestinal tract, liver, lungs, joints, and fascia, can be affected. Severe chronic GVHD increases patients' mortality and decreases their quality of life. The 2014 National Institutes of Health (NIH) Consensus has proposed a three-step model for classification of the mechanisms of chronic GVHD: early acute inflammation, chronic inflammation with dysregulated immunity, and tissue fibrosis. Many drugs targeting specific biological pathways for treating chronic GVHD are under development. The NIH Consensus has also clarified objective response measures, optimal endpoints, and clinical trial designs to be used for drug approval. More than 30 novel drugs for GVHD treatment are currently being tested in over 80 clinical trials worldwide.

Two staging systems for gastrointestinal stromal tumors in the stomach: which is better?

BackgroundThe prognosis of a gastrointestinal stromal tumor (GIST) is influenced by its anatomic site; however, few studies on the prognosis of gastric GISTs have been reported. The aims of this study were to evaluate long-term prognoses of patients who underwent surgical resection for gastric GISTs and to compare the clinical efficacy of two staging systems: the National Institutes of Health (NIH) consensus criteria and the 7th Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) tumor-node-metastasis (TNM) staging system.MethodsWe conducted a retrospective observational study of 145 patients who underwent surgical resection for gastric GISTs between February 2001 and June 2012 at Pusan National University Hospital (Busan, Korea). Recurrence and 5-year recurrence-free survival (RFS) rates were analyzed.ResultsDuring a median follow-up period of 44 months (range, 6–144 months), 11 recurrent lesions were detected in 9 patients (6.4%). On multivariate analysis, tumor size (>5 cm), mitotic count (>5/50 high-power fields), and epithelioid and mixed pathological type were significantly associated with recurrence. The overall 5-year RFS rate was 93.4%. Although no statistically significant differences were detected (C-statistic difference P = 0.886), all metrics showed lower values for the UICC/AJCC TNM staging system than for the NIH consensus criteria, suggesting that the UICC/AJCC TNM staging system may be a better model.ConclusionsThe 5-year RFS rate in patients who underwent curative resection for gastric GISTs was excellent. The UICC/AJCC TNM staging system may be more useful than the NIH consensus criteria for risk categorization of patients with gastric GISTs.

Management of Primary Hyperparathyroidism: Can We Do Better?

The failure to follow national guidelines in management of various diseases has been previously established. We sought to quantify primary care providers' familiarity with primary hyperparathyroidism as it affects adherence to the 2009 National Institute of Health (NIH) consensus recommendations in treatment of primary hyperparathyroidism. A large primary care group was surveyed to determine their familiarity with the 2009 NIH consensus recommendations for management of primary hyperparathyroidism (PHPT). Retrospective review of the group's records (2009-2011) was performed to verify compliance. Survey responders included 109 clinicians, 31 per cent were familiar with all criteria for surgical intervention in asymptomatic patients and 34 per cent correctly identified appropriate surveillance testing for patients undergoing observation. Chart review identified 124 patients with PHPT. Of the patients who met NIH criteria, 34 per cent had a parathyroidectomy. Younger age, higher intact parathyroid hormone, hypercalciuria, and history of nephrolithiasis were associated with surgery in multivariable analysis. Of the observed patients, 16 per cent had appropriate surveillance studies. In conclusion, this study confirms suboptimal adherence with consensus recommendations in management of PHPT. A minority of clinicians demonstrated solid familiarity with management strategies, paralleling their treatment approach. Educational efforts may improve adherence with upcoming national recommendations.

Gastric gastrointestinal stromal tumor: Does the newly proposed UICC TNM staging system provide better prognostic ability than the National Institutes of Health consensus criteria?

Purpose The main limitation of the National Institutes of Health (NIH) consensus criteria is the biological and prognostic heterogeneity of tumors while the utility of the newly proposed UICC TNM staging system has not yet been validated. Our object is to compare the overall and disease-free survival (DFS) of patients with gastric gastrointestinal stromal tumors (GIST) using the UICC TNM staging system and the NIH consensus criteria and to determine the optimal risk stratification system for GIST. Methods Retrospective analysis of 164 patients who underwent operative management for primary gastric GIST between 1994 and 2004. Results The overall five-year survival rate was 89.6%. In the 149 patients who underwent an R0 resection, the five-year DFS rate was 86.3%. According to the NIH consensus criteria, the five-year survival rate after resection was 100% for patients in the very low-, low-, and intermediate-risk groups and 71.9% for patients in the high-risk group. The UICC TNM stages IA, IB, and II had the same survival rates (100%) and stage IIIA (75.0%) and stage IIIB (69.5%) showed no significant difference in survival compared to the NIH criteria, which precluded better risk stratification. The patients who were included in the high-risk group by NIH consensus criteria (>10 cm, ≤5/50 high power field) and were stage II by the UICC TNM staging system had a 100% five-year survival rate. Conclusion Using the current schemes, one system does not demonstrate superior prognostic ability over the other. However, the high-risk group (T4/low mitotic rate) and stage II patients appear to be appropriately classified. Keywords: Gastrointestinal stromal tumors, Neoplasm staging, Classification

Multicenter Open-Label Phase 2 Study of Ibrutinib in Chronic Graft Versus Host Disease (cGVHD) after Failure of Corticosteroids

Background: Chronic GVHD (cGVHD) is a serious complication of allogeneic stem cell transplantation. Effective therapy for patients (pts) with cGVHD who fail corticosteroids remains an unmet medical need. Both B and T cells play a role in the pathophysiology of cGVHD. In preclinical models, ibrutinib (ibr) reduced the severity of cGVHD through its inhibition of Bruton9s tyrosine kinase (BTK) and interleukin-2-inducible T-cell kinase (ITK) (Dubovsky, J Clin Invest 2014). Ibr has recently been granted a breakthrough therapy designation (BTD) for cGVHD after failure of 1 or more lines of systemic therapy. The request for a BTD was supported by early data from a phase 2 study that evaluated the efficacy and safety of ibr in pts with cGVHD who are in need of additional therapy. The final results of this same study are presented here. Methods: Pts who had received ≤3 prior regimens for cGVHD and had either >25% body surface area erythematous rash or a National Institutes of Health (NIH) mouth score >4 were treated with daily ibr (420 mg) until cGVHD progression or unacceptable toxicity. The primary end point was cGVHD response based on the 2005 NIH consensus response criteria. Secondary end points included rate of sustained response, change in Lee cGVHD symptom scale, changes in corticosteroid requirement over time, and safety end points. The effects of ibr on lymphoid and myeloid cell signaling pathways, and phenotype along with plasma cytokines and chemokines were evaluated. Results: A recommended phase-2 dose of 420 mg was identified in phase 1b (n=6) with no dose-limiting toxicities reported. Of 42 pts treated with ibr, median age was 56 y (range, 19-74). Median duration of cGVHD before study entry was 13.7 mo (range, 1.1-63.2). Median number of prior regimens was 2 (range, 1-3). At a median follow-up of 13.9 mo, overall response rate (ORR) was 67% (28/42 pts; 9 [21%] CR, 19 [45%] PR), with 20/28 (71%) and 12/25 (48%) responders showing a sustained response of ≥20 and ≥32 weeks, respectively (Figure 1). Overall, 21 responders (75%) had corticosteroid doses 3 pts were pneumonia (n=6), fatigue (n=5), and diarrhea (n=4). Serious AEs (SAEs) occurred in 22 pts (52%); grade ≥3 SAEs reported in 17 pts (40%) included pneumonia (n=5), septic shock (n=2), and pyrexia (n=2). Two fatal events (multilobular pneumonia and bronchopulmonary aspergillosis) were reported. Five pts discontinued therapy for progressive cGVHD and 14 for AEs including fatigue (n=3) and pneumonia (n=2). Twelve pts (29%) continued ibr; their treatment duration ranges from 5.6-24.9 mo. Conclusions: With an ORR of 67% and a sustained response rate of ≥20 weeks of 71%, treatment with ibr resulted in clinically meaningful and durable responses in pts who failed at least 1 prior treatment for cGVHD. Most responders were able to reduce steroid dose to an acceptable minimal level. Biomarker changes support an effect of ibr on immune cell subsets in pts with cGVHD. Reported AEs are consistent with those for ibr in B-cell malignancies and pts with cGVHD. Observed response rates in this pretreated, high-risk population support further study of ibr for frontline treatment of cGVHD. Disclosures Miklos: Pharmacyclics, LLC, an AbbVie Company: Consultancy, Other: Travel, Accommodations, and Expenses, Research Funding; Kite Pharma: Research Funding; Roche: Research Funding; Novartis: Research Funding; Sanofi Oncology: Other: Travel, Accommodations, and Expenses. Cutler: Insys: Consultancy; Seattle Genetics: Consultancy; Regimmunie: Consultancy; Incyte: Consultancy. Arora: Takeda Oncology: Consultancy; Pharmacyclics, LLC, an AbbVie Company: Research Funding. Waller: Cerus: Equity Ownership; Chimerix: Equity Ownership; Cambium Medical Technologies: Equity Ownership, Other: Other relationship indicated, Patents & Royalties; Novartis: Consultancy, Honoraria, Research Funding; Helocyte: Consultancy. Jagasia: Theracos: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Flowers: Pharmacyclics, LLC, an AbbVie Company: Research Funding. Logan: Amgen: Consultancy; Jazz: Consultancy; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding; Astellas: Research Funding; Novartis: Research Funding. Nakamura: Seattle Genetics: Consultancy; Amgen: Consultancy. Blazar: Tobira Therapeutics: Consultancy; Vulcan CApital: Consultancy; Idera Pharma: Consultancy; Sidley Austin LLP: Consultancy; Merck Serono: Consultancy; Fate Therapeutics: Consultancy; Merck, Sharpe & Dohme Corp: Consultancy; Bristol-Myers Squibb: Consultancy; Kadmon Pharmaceuticals Inc: Consultancy, Research Funding; Kymab: Consultancy; Five Prime Therapeutics: Consultancy; Vitae Pharmaceuticals, Inc.: Consultancy; Flx Bio: Consultancy; No Company: Patents & Royalties: no company. Li: Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Lal: AbbVie: Equity Ownership; Pharmacyclics, LLC, an AbbVie Company: Employment; Infinity: Equity Ownership; Clovis: Equity Ownership; Reviva Pharmaceuticals: Equity Ownership; The Permanente Medical Group: Employment, Equity Ownership; Gilead Sciences: Employment, Equity Ownership. Dubovsky: Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. James: Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Styles: Pharmacyclics, LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Jaglowski: Pharmacyclics, LLC, an AbbVie Company: Consultancy, Research Funding.

Joint and fascial chronic graft-vs-host disease: correlations with clinical and laboratory parameters.

AimTo determine if there are correlations between joint and fascial chronic graft-vs-host disease (cGVHD) with clinical findings, laboratory parameters, and measures of functional capacity.Methods29 patients were diagnosed with cGVHD based on National Institutes of Health (NIH) Consensus Criteria at the University Hospital Centre Zagreb from October 2013 to October 2015. Physical examination, including functional measures such as 2-minute walk test and hand grip strength, as well as laboratory tests were performed. The relationship between these evaluations and the severity of joint and fascial cGVHD was tested by logistical regression analysis.Results12 of 29 patients (41.3%) had joint and fascial cGVHD diagnosed according to NIH Consensus Criteria. There was a significant positive correlation of joint and fascial cGVHD and skin cGVHD (P < 0.001), serum C3 complement level (P = 0.045), and leukocytes (P = 0.032). There was a significant negative correlation between 2-minute walk test (P = 0.016), percentage of cytotoxic T cells CD3+/CD8+ (P = 0.022), serum albumin (P = 0.047), and Karnofsky score (P < 0.001). Binary logistic regression model found that a significant predictor for joint and fascial cGVHD was cGVHD skin involvement (odds ratio, 7.79; 95 confidence interval 1.87-32.56; P = 0.005).ConclusionJoint and fascial cGVHD manifestations correlated with multiple laboratory measurements, clinical features, and cGVHD skin involvement, which was a significant predictor for joint and fascial cGVHD.