Apparent Clinical Benefit Research Articles

Emerging dilemmas in the diagnosis and management of gastroesophageal reflux disease

Gastroesophageal reflux disease (GERD) is common, but less so than widely reported because of inconsistencies in definition. In clinical practice, the diagnosis is usually based on a symptom assessment without testing, and the extent of diagnostic testing pursued should be limited to that which guides management or which protects the patient from the risks of a potentially morbid treatment or an undetected early (or imminent) esophageal adenocarcinoma or which does both. When testing is pursued, upper gastrointestinal endoscopy is the most useful initial diagnostic test because it evaluates for the major potential morbidities (Barrett’s, stricture, and cancer) associated with GERD and facilitates the identification of some alternative diagnostic possibilities such as eosinophilic esophagitis. However, endoscopy is insensitive for diagnosing GERD because most patients with GERD have non-erosive reflux disease, a persistent diagnostic dilemma. Although many studies have tried to objectify the diagnosis of GERD with improved technology, this is ultimately a pragmatic diagnosis based on response to proton pump inhibitor (PPI) therapy, and, in the end, response to PPI therapy becomes the major indication for continued PPI therapy. Conversely, in the absence of objective criteria for GERD and the absence of apparent clinical benefit, PPI therapy is not indicated and should be discontinued. PPIs are well tolerated and safe, but nothing is perfectly safe, and in the absence of measurable benefit, even a miniscule risk dominates the risk-benefit assessment.

Abstract 3084: Therapeutic implications of sex hormone signaling in melanoma

Abstract Female gender, early age of first birth, and multiparity are associated with less aggressive melanoma; however, the mechanisms underlying the apparent clinical benefit are undefined. Previously we reported that 17β-estradiol drives melanocyte differentiation through G-protein coupled estrogen receptor (GPER), a nonclassical sex hormone receptor. Here, we use genetically-defined human skin xenograft melanoma to show that pregnancy antagonizes oncogenic BRAF and inhibits melanomagenesis. Transient GPER activation drives stable melanocyte differentiation that persists after removal of the activating ligand. Consistent with this, brief exposure of melanoma cells to GPER agonists prior to xenografting inhibited subsequent tumor growth. Systemic treatment with GPER agonists cooperated with PD-1 blockade in melanoma bearing mice to greatly prolong survival longer than that observed with either agent alone. The combination of differentiation-based therapies with immunotherapy may have significant therapeutic benefit for melanoma. Citation Format: Christopher Natale, Junqian Zhang, Ankit Dahal, Todd Ridky. Therapeutic implications of sex hormone signaling in melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3084. doi:10.1158/1538-7445.AM2017-3084

Nivolumab for Patients With Advanced Melanoma Treated Beyond Progression

Immune checkpoint inhibitors have demonstrated atypical response patterns, which may not be fully captured by conventional response criteria. There is a need to better understand the potential benefit of continued immune checkpoint inhibition beyond progression. To evaluate the safety and potential benefit of nivolumab (anti-programmed cell death receptor 1) monotherapy beyond Response Evaluation Criteria in Solid Tumors (RECIST) v1.1-defined progression. Pooled, retrospective analysis of data from phase 3 trials of nivolumab in treatment-naive patients with advanced melanoma (CheckMate 066 or CheckMate 067) conducted at academic and clinical cancer centers. Participants were patients treated beyond first disease progression, defined as those who received their last dose of nivolumab more than 6 weeks after progression (TBP group); and patients not treated beyond progression, who discontinued nivolumab therapy before or at progression (non-TBP group). Data analyses were conducted from November 6, 2015, to January 11, 2017. Nivolumab (3 mg/kg every 2 weeks) administered until progression or unacceptable toxic effects. Patients could be treated beyond progression if deriving apparent clinical benefit and tolerating study drug, at the investigator's discretion. Tumor response and safety in TBP and non-TBP patients. Among 526 randomized patients (39% [n = 203] female; median age, 62 years [range, 18-90 years]), 306 (58%) experienced disease progression, including 85 (28%) TBP patients and 221 (72%) non-TBP patients. Twenty-four (28%) of the TBP patients had a target lesion reduction of greater than 30% after progression compared with baseline (TBP>30% group). At the time of this analysis, 65 (76%) TBP patients and 21 (87%) TBP>30% patients were still alive; 27 (32%) and 11 (46%), respectively, continued to receive treatment. Median (range) time from progression to last dose of treatment was 4.7 (1.4-25.8) months for TBP patients and 7.6 (2.4-19.4) months for TBP>30% patients. Median (range) time from progression to greater than 30% tumor reduction was 1.4 (0.2-7.0) months. Treatment-related select grade 3 to 4 adverse events were similar in the TBP and non-TBP groups (5 [6%] and 9 [4%], respectively). A substantial proportion of selected patients treated with frontline nivolumab who were clinically stable and judged to be eligible for treatment beyond RECIST v1.1-defined progression by the treating investigators derived apparent clinical benefit without compromising safety. Further analysis will help define the potential benefit of continued nivolumab treatment beyond progression. clinicaltrials.gov Identifiers: NCT01721772 (CheckMate 066) and NCT01844505 (CheckMate 067).

Phase II study of gemcitabine (G), trastuzumab (H), and pertuzumab (P) for HER2-positive metastatic breast cancer (MBC) after prior pertuzumab-based therapy.

1037 Background: The combination of taxanes with HP for first line treatment of HER2-positive MBC is associated with improved progression-free (PFS) and overall survival (OS). Treatment per physician’s choice with anti-HER2 therapy after second line therapy is associated with a median PFS of 3 months. While continued use of H in therapeutic combinations after progression on H-based therapy is standard, the efficacy of continuing HP-based treatment after progression on P-based therapy is unknown. Methods: This is a single arm phase II trial of G with HP. Eligible patients (pts) had HER2-positive (IHC 3+ or FISH > 2.0) MBC with prior HP-based treatment and ≤ 3 prior chemotherapies. Pts received G (1200 mg/m2) on days 1 and 8 of a q 3 week (w) cycle, and H (8 mg/kg load → 6 mg/kg) and P (840 mg load → 420 mg) q3w. The primary endpoint is PFS at 3 months. Secondary endpoints include OS, safety and tolerability. An exploratory endpoint is to compare PFS by RECIST criteria versus 18-F FDG-PET response criteria. The study therapy will be considered successful if at least 27/45 (60%) patients are progression free at 3 months. Results: As of 1-27-17, 41 of 45 pts are enrolled; 34 are evaluable at 3 months and 7 have not had 3-month evaluation. At 3 months, 26/34 (76%) are progression free (1 CR, 8 PR, 17 SD); 8 pts progressed. There are no cardiac or febrile neutropenic events to date. 4 pts required G dose reduction (3 grade 3 neutropenia and 1 grade 3 vomiting) and the study was amended to lower initial G dose to 1000 mg/m2. Conclusions: The preliminary 3 month-PFS is 76% in evaluable pts (95% CI 60% to 88%). The updated 3 month-PFS results will be presented. Continuation of P beyond progression is associated with apparent clinical benefit. A randomized trial is justified to confirm this clinically important observation. Clinical trial information: NCT02252887.

Sa1641 Correction of Coagulopathy Prior to Paracentesis Is Associated With Excessive Albumin Administration and No Apparent Clinical Benefit

Sa1641 Correction of Coagulopathy Prior to Paracentesis Is Associated With Excessive Albumin Administration and No Apparent Clinical Benefit

Effect of Hydroxychloroquine Treatment on Dry Eyes in Subjects with Primary Sjögren's Syndrome: a Double-Blind Randomized Control Study.

The effect of hydroxychloroquine (HCQ) on dry eye has not been fully determined. This study aimed to compare the 12-week efficacy of HCQ medication with that of a placebo in the management of dry eye in primary Sjögren's syndrome (pSS). A double-blind, randomized control study was conducted in 39 pSS subjects from May 2011 through August 2013. pSS was diagnosed based on the classification criteria of the American-European Consensus Group. Subjects received 300 mg of HCQ or placebo once daily for 12 weeks and were evaluated at baseline, 6, and 12 weeks, with a re-visit at 16 weeks after drug discontinuance. The fluorescein staining score, Schirmer test score, tear film break-up time (TBUT), and ocular surface disease index (OSDI) were measured, and tears and blood were collected for ESR, IL-6, IL-17, B-cell activating factor (BAFF), and Th17 cell analysis. Color testing was performed and the fundus was examined to monitor HCQ complications. Twenty-six subjects completed the follow-up. The fluorescein staining score and Schirmer test score did not differ significantly. The OSDI improved with medication in the HCQ group but was not significantly different between the groups. TBUT, serum IL-6, ESR, serum and tear BAFF, and the proportion of Th17 cells did not change in either group. HCQ at 300 mg daily for 12 weeks has no apparent clinical benefit for dry eye and systemic inflammation in pSS (ClinicalTrials.gov. NCT01601028).

Dasatinib Modulates Invasive and Migratory Properties of Canine Osteosarcoma and has Therapeutic Potential in Affected Dogs

BACKGROUND: This investigation sought to elucidate the relationship between hepatocyte growth factor (HGF)–induced metastatic behavior and the tyrosine kinase inhibitors (TKIs) crizotinib and dasatinib in canine osteosarcoma (OS). Preliminary evidence of an apparent clinical benefit from adjuvant therapy with dasatinib in four dogs is described. METHODS: The inhibitors were assessed for their ability to block phosphorylation of MET; reduce HGF-induced production of matrix metalloproteinase (MMP); and prevent invasion, migration, and cell viability in canine OS cell lines. Oral dasatinib (0.75 mg/kg) was tested as an adjuvant therapy in four dogs with OS. RESULTS: Constitutive phosphorylation of MET was detected in two cell lines, and this was unaffected by 20-nM incubation with either dasatinib or crizotinib. Incubation of cell lines with HGF (MET ligand) increased cell migration and invasion in both cell lines and increased MMP-9 activity in one. Dasatinib suppressed OS cell viability and HGF-induced invasion and migration, whereas crizotinib reduced migration and MMP-9 production but did not inhibit invasion or viability. CONCLUSIONS: Invasion, migration, and viability of canine OS cell lines are increased by exogenous HGF. HGF induces secretion of different forms of MMP in different cell lines. The HGF-driven increase in viability and metastatic behaviors we observed are more uniformly inhibited by dasatinib. These observations suggest a potential clinical benefit of adjuvant dasatinib treatment for dogs with OS.

Microsurgical Unilateral Approach Bilateral Decompression in Symptomatic Lumbar Spinal Canal Stenosis: Midterm Results in 89 Patients

Introduction Surgical decompression is the gold standard in the treatment of symptomatic lumbar spinal canal stenosis (LSCS) without clinically significant instability. With the advent of microsurgical techniques and better accessories such as the tubular retractor system (TRS), unilateral approach bilateral decompression (UABD) has been advocated as the decompressive technique of choice because of the preservation of anatomically important stabilizing structures. This retrospective study evaluates the midterm results of UABD performed with and without the TRS in a regional hospital. Patients and Methods From April 2008 till November 2013, 89 patients with symptomatic LSCS without clinical instability had UABD performed. On the basis of the surgeons' preference, 56 cases were operated with the TRS employed. The mean follow-up was 30.8 months. Clinical outcomes were evaluated by the Visual Analogue Scale (VAS), Japanese Orthopaedic Association lumbar spine score (JOA score), Oswestry Disability Index (ODI), and Roland Morris Disability Quotient (RMDQ). Complications, rate of reoperation, and patient's subjective satisfaction were also evaluated. Results A total of 150 levels were decompressed (average, 1.7 levels per patient). The average operation time and blood loss per level was 99.4 minutes and 67.9 mL, respectively. The mean postoperative hospital stay was 4.5 days. The average leg VAS, JOA score, ODI, and RMDQ improved from 7.1, 15.5, 48.3% and 13.1 to 3.3, 22.1, 35.4% and 11.5, respectively, at final follow-up. The subjective satisfaction was 64%. Given the choice, 92% of these patients would choose to have the same procedure again. There were no statistical significant difference between the TRS and no TRS group in age; sex; side of approach; the preoperative, postoperative, and improvement in leg VAS, JOA score, ODI, and RMDQ; follow-up duration; operation time; and subjective satisfaction. Blood loss (67 vs. 178.4 mL, p = 0.09) and postoperation hospital stay (3.9 vs. 5.7 days, p = 0.003) were both in favor of the TRS. Overall, five incidental durotomies in the TRS group (8.9%) and 3 (9%) in non-TRS group were registered, giving rise to a total 9% of the incidental durotomy rate. All of these eight cases were treated conservatively and none of them needed any further procedures as a remedy. Otherwise, no remarkable perioperative morbidities had been recorded. Within the evaluation period, two cases from the TRS group need re-decompression with instrumented fusion because of symptomatic recurrence, equivalent to an overall 2.2% reoperation rate. Conclusion Microsurgical UABD generates satisfactory clinical outcomes in selected patients with symptomatic LSCS without clinical instability. No apparent clinical benefit was found in employing the TRS other than an average 1.8 day short postoperative hospital stay.

Sorafenib for patients with pretreated recurrent or progressive high-grade glioma

Therapeutic options for patients with pretreated advanced high-grade glioma (HGG) are limited. Sorafenib, a small molecule with multiple potential beneficial actions, appears particularly promising. We reviewed the outcomes of 30 patients with recurrent or progressive HGG treated with sorafenib within a named patient program. Overall, 16 patients suffered from recurrent or progressive glioblastoma multiforme and 14 patients had grade 3 gliomas. All but four patients had previously undergone surgical debulking; all but one patient had received previous standard multimodal treatment; and 18 patients (60%) had received more than one line of chemotherapy, in median three. Progression-free survival (PFS), defined as the time from initiation of sorafenib to treatment discontinuation because of tumor progression or death, was selected as the endpoint. The use of sorafenib resulted in a median PFS of 3 months [95% confidence interval (CI) 1.9-4.1 months] in patients with glioblastoma and of 3.1 months (95% CI 1.4-4.8 months) in patients with other HGG. The PFS-6 for the whole cohort was 23%. Sixteen patients reported adverse events, mostly moderate, with hypertension as the most frequently reported toxicity (seven patients). One patient died of cerebral bleeding (grade 5 toxicity). The overall survival after initiation of sorafenib was 6 months (95% CI 3.9-8.0 months) for patients with glioblastoma multiforme and 10 months (95% CI 3.1-16.9 months) for patients with HGG. In this retrospective analysis of heavily pretreated patients with HGG, sorafenib monotherapy was associated with tumor stabilization in a small subset of patients. The risk-benefit ratio was acceptable in the context of an apparent clinical benefit in patients with a fatal disease.

Limited utility of routine surveillance imaging for classical Hodgkin lymphoma patients in first complete remission

The objective of this study was to compare the outcomes of patients with classical Hodgkin lymphoma (cHL) who achieved complete remission with frontline therapy and then underwent either clinical surveillance or routine surveillance imaging. In total, 241 patients who were newly diagnosed with cHL between January 2000 and December 2010 at 3 participating tertiary care centers and achieved complete remission after first-line therapy were retrospectively analyzed. Of these, there were 174 patients in the routine surveillance imaging group and 67 patients in the clinical surveillance group, based on the intended mode of surveillance. In the routine surveillance imaging group, the intended plan of surveillance included computed tomography and/or positron emission tomography scans; whereas, in the clinical surveillance group, the intended plan of surveillance was clinical examination and laboratory studies, and scans were obtained only to evaluate concerning signs or symptoms. Baseline patient characteristics, prognostic features, treatment records, and outcomes were collected. The primary objective was to compare overall survival for patients in both groups. For secondary objectives, we compared the success of second-line therapy and estimated the costs of imaging for each group. After 5 years of follow-up, the overall survival rate was 97% (95% confidence interval, 92%-99%) in the routine surveillance imaging group and 96% (95% confidence interval, 87%-99%) in the clinical surveillance group (P = .41). There were few relapses in each group, and all patients who relapsed in both groups achieved complete remission with second-line therapy. The charges associated with routine surveillance imaging were significantly higher than those for the clinical surveillance strategy, with no apparent clinical benefit. Clinical surveillance was not inferior to routine surveillance imaging in patients with cHL who achieved complete remission with frontline therapy. Routine surveillance imaging was associated with significantly increased estimated imaging charges.

Commentary on Shapiro: Clinical Development of Candidate HIV Vaccines: Different Problems for Different Vaccines

The editors of AIDS Research and Human Retroviruses seek to promote discussion that will stimulate the exchange of ideas and advance the field of HIV research. In the current edition of the journal we publish an opinion piece by Stuart Shapiro, “Clinical Development of Candidate HIV Vaccines: Different Problems for Different Vaccines,”1 that has provoked diverse and sometimes emotional feedback, both positive and negative. After completing the peer review process we thought it essential for the field to consider how HIV vaccine trial endpoints and efficacy would be interpreted relating to the complexities of future vaccine trials in the current realities of HIV infection. To stimulate discussion we sought to obtain two commentaries. We were able to secure Drs. Andrew McMichael and Lucy Dorrell to comment on the positive aspects of the piece and the importance of considering vaccine trial endpoints and efficacy. However, we were not able to recruit authors to openly comment on the perceived negative aspects of the concepts presented by Shapiro. There was an overall reluctance among individuals to express negative reactions to these concepts due to the fact that Dr. Shapiro is a program official within the NIH NIAID Division of AIDS (DAIDS) who occupies a leadership role relating to the support and development of vaccine trials. Because we believe that this debate is important in order to advance the field and policy on this subject, we have chosen to summarize some of the negative feedback we have received relating to the Shapiro commentary. There were several different contrary viewpoints relating to the Shapiro article. During the review process, it was stated by one reviewer that the article was useful in only the most superficial way. Another reader of the article found it dogmatic and outdated. This reader additionally expressed concern that publicly casting dissent against the article could jeopardize future funding. There was concern that the article focused almost exclusively on vaccines that reduce viral load and not on the great majority of HIV vaccine work toward prevention of acquisition. They continued by stating that the article does not recognize that the concept of a vaccine in humans that reduces acquisition has been met [presumably referring to the RV144 trial], but one that reduces viral load has not [referring to the STEP, Phambili, and HVTN 505 trials]. Finally, there was concern that the article did not acknowledge the results of many nonhuman primate (NHP) studies that have predicted reductions in viremia, but ultimately yielded no apparent clinical benefit in humans. These points represent many of the central controversies that permeate the HIV vaccine field, including whether the RV144 trial had a significant effect, whether the STEP, Phambili, and HVTN 505 phase II studies had any beneficial outcome or conversely demonstrated enhancement of acquisition, and whether the NHP SIV/SHIV model accurately predicts vaccine efficacy in humans. We hope that this article by Dr. Shapiro, along with the accompanying commentaries, stimulates discussion relating to future vaccine trial design. We believe that open public discussion is critical in order to advance the field, and invite individuals with opinions relating to this topic to submit a Letter to the Editor of AIDS Research and Human Retroviruses to continue this important debate. As perhaps the most troubling issue regarding the comments we received was the concern that voicing dissent might be viewed negatively by the DAIDS program, we will honor all specific requests for anonymity. However, we believe that these fears may be misplaced and may actually stifle discussion on this important topic. It does not seem reasonable that publishing this work to stimulate debate could lead to a negative impact on individuals participating in that debate. It is best that we work together to discuss these issues in a transparent and productive manner in an effort to advance the field and bring the goal of a successful HIV vaccine to the people of the world. We also invite the submission of further commentaries and perspectives on other important topics relating to HIV research to facilitate more public debate.

Robot-assisted versus endoscopic submandibular gland resection via retroauricular approach: a prospective nonrandomized study

The aim of this study was to compare the short-term clinicopathological results of robot-assisted and endoscopic resection of the submandibular gland by the retroauricular approach.We present a prospective, non-random, study of 35 patients who had endoscope-assisted (n=22), or robot-assisted (n=13), resection of the submandibular gland using a retroauricular approach. Patients selected one of the two methods, and short-term clinical outcomes were then compared, including maximum diameter of the tumour and gland, length of incision, total operating time, amount of operative bleeding, amount and duration of drainage, duration of hospital stay, cosmesis, and complications. The operation was feasible in all patients with no appreciable operative complications or need to convert to a conventional open operation. The operating time of the robot-assisted group (63.4 (6.3)min) was comparable with that of the endoscopic group (66.5 (9.1)min) (p=0.15). There were no differences in the other clinical outcomes between the 2 groups. Both groups of patients were extremely satisfied with their postoperative cosmesis, and did not differ significantly (p=0.89). Robotic and endoscopic resection of the submandibular gland gave comparable early surgical outcomes and excellent cosmetic results. Despite the technical convenience for the surgeon, the robot gave no apparent clinical benefit over the endoscope in this series.

Anticancer activity of combination targeted therapy using cetuximab plus vemurafenib for refractory BRAFV600E-mutant metastatic colorectal carcinoma

Mismatch-repair-deficient colorectal cancers often contain kinase-activating V600E BRAF mutations, but no clinical utility has yet been demonstrated in this setting for monotherapy using oral braf kinase inhibitors such as vemurafenib or dabrafenib. Recent studies have indicated that tumour resistance to braf inhibition is mediated by upregulated epidermal growth factor receptor (egfr) signalling, disruption of which is a routine treatment strategy in KRAS wild-type colorectal cancer. In this report, we describe the clinical course of a heavily pretreated patient who elected to receive off-label dual-targeted braf- and egfr-inhibitory therapy with good tolerance and apparent clinical benefit.

Circulation: Cardiovascular Interventions Editors’ Picks

<i>Circulation: Cardiovascular Interventions</i> Editors’ Picks

Efficacy of Perioperative Oral Triiodothyronine Replacement Therapy in Patients Undergoing Off-Pump Coronary Artery Bypass Grafting

The aim of this study was to assess the effects of oral triiodothyronine (T3) therapy on postoperative thyroid hormone concentrations, hemodynamic variables, and outcomes. A prospective, randomized, controlled, double-blind study. Cardiac operating room at a single institution. One hundred patients undergoing elective off-pump coronary artery bypass graft surgery. Patients received either 20 μg of oral T3 or placebo every 12 hours starting 20 minutes before anesthetic induction, for a total of 4 doses. Plasma concentrations of thyroid hormones were measured serially before surgery, upon arrival in the intensive care unit, and 12, 24, and 36 hours after surgery. Hemodynamic variables also were recorded serially. Postoperative inotrope requirement and major morbidity endpoints were assessed. Serum T3 concentrations were significantly higher with fewer patients having T3 concentrations below the normal range in the T3 group than the placebo group throughout the postoperative period. Hemodynamic variables, postoperative inotrope requirement, and outcome variables showed no differences between the groups. Oral T3 therapy significantly attenuated the postoperative decline in T3 concentrations in patients undergoing off-pump coronary artery bypass graft surgery. The lack of apparent clinical benefit merits further investigations in patients with reduced cardiac performance.

Intravenous fat emulsion as treatment for ivermectin toxicosis in three dogs homozygous for the ABCB1–1Δ gene mutation

To describe the outcome of 3 cases of ivermectin toxicosis in dogs homozygous for the ABCB1-1Δ gene mutation treated with intravenous fat emulsion (IFE). One Australian Shepherd and 2 Miniature Australian Shepherds were treated for naturally occurring ivermectin toxicosis with IFE. All 3 dogs were homozygous for the ABCB1-1Δ gene mutation. Serum ivermectin concentrations confirmed ivermectin exposure in each case. All 3 dogs exhibited tremors, ptyalism, and central nervous system depression, which progressed over several hours to stupor in 2 dogs, and to a comatose state requiring mechanical ventilation in the remaining dog. A 20% formulation of IFE(a) was administered as an IV bolus (1.5 mL/kg) followed by a slow IV infusion (7.5-15 mL/kg [0.25-0.5 mL/kg/m], over 30 minutes). No change was observed in the neurologic status of any patient. Lipemia visible upon blood sampling persisted for 36 hours in 1 dog however, no other adverse effects were noted. Flumazenil (0.01 mg/kg IV), followed by a constant rate infusion(CRI) of 0.01 mg/kg/h IV was administered in 1 case, without any apparent clinical benefit or adverse effect. IFE was ineffective in the treatment of ivermectin toxicosis in these ABCB1-1Δ homozygous mutant dogs. Further investigation is necessary to determine why IFE treatment was unsuccessful in these cases and whether its use can be optimized to yield better results.

Final Analysis of a Multi-Center Randomized Controlled Trial (IAPLSG04) to Study the Optimal Duration of Arsenic Trioxide Maintenance Therapy in the Treatment of Newly Diagnosed Acute Promyelocytic Leukemia

Abstract 426Single agent arsenic trioxide (ATO) has proven efficacy in the management of newly diagnosed cases of acute promyelocytic leukemia (APL). To validate findings of an initial single center experience (Blood 2006:107; 2627) with this low cost, well tolerated, effective regimen a multicenter study was undertaken in a resource constrained environment. Additionally, in an effort to improve on the earlier experience and study the role of duration of maintenance on reducing late relapses, patients who achieved molecular remission were randomized to 6 vs. 12 months of ATO maintenance.From July, 2004 to December, 2008, 186 patients were initially screened and enrolled based on morphological diagnosis of APL from 7 centers in India. Twenty seven cases were excluded from analysis (6 RT-PCR negative, 4 IC bleed at diagnosis, 5 septicemia/pneumonia at diagnosis, 9 withdrew consent prior to randomization and some were treated with other protocols, 1 withdrawn by investigator prior to randomization). Patients were treated with single agent ATO at standard doses for up to 60 days in induction; this was followed by 28 day consolidation after a 4 week break following induction. Four weeks after completion of consolidation patients who were in molecular remission were randomized to 6 vs. 12 months of maintenance therapy with ATO administered for 10 days/month. Anthracyclines were permitted in induction for patients presenting with or WBC count rising >20×109/L in the first week, >50×109/L in the second week and for those who developed a differentiation syndrome. Hydroxyurea was permitted for control of leucocytosis. Of the 159 patients who could be evaluated 138 (86.8%) achieved hematological remission (CHR), one patient had primary induction failure and was removed from the study the rest were induction deaths at a median of 17 days (range: 4 – 69). 52 (32.7%) received an anthracycline in induction while 116 (73%) received hydroxyurea in induction. A differentiation syndrome was documented in 25 (16%) cases and was fatal in one. Grade III/IV non hematological toxicity was seen in 26 (16.3%), in the majority they resolved after discontinuing ATO for a short period. A protocol change after randomization was done in 3 cases for persistent toxicity. Five (3.6%) patients did not complete the scheduled maintenance regimen due to poor compliance or was discontinued by the investigator. At a median follow up of 48 months the 5 year Kaplan-Meir estimate of overall survival (OS), event free survival (EFS) and disease free surivival (DFS) was 75.7±3.9%, 68±4% and 76.9±4.2% respectively. Twenty five patients relapsed, the median time to relapse was 19.2 months (range: 8.2–51). There were no relapses beyond 4 years of follow up.136 patients who achieved molecular remission after consolidation were randomized in to 6 months (n=63) or 12 months (n=73) of maintenance therapy. The baseline characteristics of the two groups were not significantly different. Post randomization, the two groups were analyzed on an intention to treat basis. The OS, EFS (Figure 1) and DFS of the two groups were not statistically different. There was no evidence that the group that received 12 months of maintenance had any increased incidence of toxicity.This study confirms that this low cost, low intensity single agent ATO based regimen, as reported previously, is well tolerated and results in durable remissions. However, there is no apparent clinical benefit from increasing the duration of maintenance from 6 to 12 months. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Commentary on an article by Sigurd Liavaag, MD, et al.: “Immobilization in External Rotation After Primary Shoulder Dislocation Did Not Reduce the Risk of Recurrence. A Randomized Controlled Trial”

Sigurd Liavaag and coauthors are to be commended for their manuscript, “Immobilization in External Rotation After Primary Shoulder Dislocation Did Not Reduce the Risk of Recurrence. A Randomized Controlled Trial.” This multicenter trial in Norway demonstrated no apparent clinical benefit of three weeks of immobilization in external rotation following primary anterior shoulder dislocation in 188 subjects. The authors of this clinical trial focused on a clinically relevant age group (range, sixteen to forty years), executed an effective stratified block randomization, monitored treatment compliance, and reported excellent follow-up (98% at two years). The findings of Liavaag et al. mirror those of Finestone et al.1, who also reported no apparent benefit of immobilization in external rotation. The patients in the study by Finestone et al. were all male, were younger (mean …

New pathway links γ‐secretase to inflammation and memory while sparing notch

New pathway links γ‐secretase to inflammation and memory while sparing notch

Evidence of in vivo Immune Modulation with Vitamin D3 and Calcium Supplementation in Multiple Sclerosis

We have recently established that high‐dose oral vitamin D3 is safe in MS with apparent clinical benefit. Our objective was to characterize the immunological profile in patients receiving pharmacological doses of vitamin D3 with calcium. A prospective controlled 52‐week trial matched MS patients for demographic and disease characteristics, with randomization to treatment and control groups. Treatment patients received escalating doses of vitamin D3 (4,000–40,000 IU/d) with calcium (1,200mg/d) for one year, and control patients none. PBMC proliferation in response to antigenic stimulation was measured and T cell stimulation (TCS) scores calculated. PBMC proliferation was markedly reduced in treatment patients after one year (WSRT p&lt;0.002) and unchanged in controls. TCS dropped significantly in treatment patients (p=0.0023), but not in controls. The proportion of patients with a TCS below the pre‐determined positive threshold was greater in treatment patients (p=0.0318). There were no differences detected between groups for other inflammatory markers. Patients with MS receiving high dose vitamin D3 with calcium supplementation had significantly reduced PBMC proliferative responses to self‐antigen. Such effects may explain clinical improvement seen in treatment patients.Funding was provided by Direct MS and the Multiple Sclerosis Society of Canada.