The SAGES masters program presents the 10 seminal articles for laparoscopic sleeve gastrectomy.

BACKGROUND: The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) Masters Program includes eight distinct clinical pathways. The Bariatric Surgery Pathway focuses on three anchoring procedures, including the laparoscopic sleeve gastrectomy (LSG) which is the most commonly performed bariatric procedure in the United States. In this article, we present and discuss the top 10 seminal articles regarding the LSG. METHODS: The literature was systematically searched to identify the most cited papers on LSG. The SAGES Metabolic and Bariatric Surgery committee reviewed the most cited article list, and using expert consensus elected the seminal articles deemed most pertinent to LSG. These articles were reviewed in detail by committee members and are presented here. RESULTS: The top 10 most cited sentinel papers on LSG focus on operative safety, outcomes, surgical technique, and physiologic changes after the procedure. A summary of each paper is presented, including expert appraisal and commentary. CONCLUSIONS: The seminal articles presented support the widespread acceptance and use of the LSG by bolstering the understanding of its mechanism of action and by demonstrating its safety and excellent patient outcomes. All bariatric surgeons should be familiar with these 10 landmark articles.

Phase 2 study of tabalumab, a human anti-B-cell activating factor antibody, with bortezomib and dexamethasone in patients with previously treated multiple myeloma.

In this double-blind, Phase 2 study, 220 patients with relapsed/refractory multiple myeloma were randomly assigned 1:1:1 to receive placebo (N = 72), tabalumab 100 mg (N = 74), or tabalumab 300 mg (N = 74), each in combination with dexamethasone 20 mg and subcutaneous bortezomib 1·3 mg/m2 on a 21-day cycle. No significant intergroup differences were observed among primary (median progression-free survival [mPFS]) or secondary efficacy outcomes. The mPFS was 6·6, 7·5 and 7·6 months for the tabalumab 100, 300 mg and placebo groups, respectively (tabalumab 100 mg vs. placebo Hazard ratio (HR) [95% confidence interval (CI)] = 1·13 [0·80-1·59], P = 0·480; tabalumab 300 mg vs. placebo HR [95% CI] = 1·03 [0·72-1·45], P = 0·884). The most commonly-reported treatment-emergent adverse events were thrombocytopenia (37%), fatigue (37%), diarrhoea (35%) and constipation (32%). Across treatments, patients with low baseline BAFF (also termed TNFSF13B) expression (n = 162) had significantly longer mPFS than those with high BAFF expression (n = 55), using the 75th percentile cut-off point (mPFS [95% CI] = 8·3 [7·0-9·3] months vs. 5·8 [3·7-6·6] months; HR [95% CI] = 1·59 [1·11-2·29], P = 0·015). Although generally well tolerated, PFS was not improved during treatment with tabalumab compared to placebo. A higher dose of 300 mg tabalumab did not improve efficacy compared to the 100 mg dose. Nonetheless, BAFF appears to have some prognostic value in patients with multiple myeloma.

Duration of Nil Per Os is causal in hospital length of stay following laparoscopic bariatric surgery.

INTRODUCTION: A recent bariatric surgical study demonstrated an inverse relationship of intraoperative hydration with the incidence of extended hospital length of stay (ehLOS: >1 postoperative hospital day). In that study, a post hoc analysis of the preoperative duration of Nil Per Os (NPO) past midnight revealed a significant dose-response association on the incidence of ehLOS, with the lowest incidence (10-12 %) predicted within the 2-5-h NPO interval. As NPO is associated with a state of compensatory dehydration, the objectives of this study were to prospectively examine the role of decreasing preoperative NPO intervals on the incidence of ehLOS in a similar bariatric surgical population and to establish causality of this association. METHODS: Following IRB approval, 168 bariatric surgeries were analyzed following institution of a revised oral water ad libitum policy until 2 h prior to surgery on the incidence of ehLOS. The role of duration of NPO on the incidence of ehLOS was assessed by logistic fit graphs and misclassification rates on the two groups. A statistical process control chart monitored the efficacy of the revised NPO guidelines. RESULTS: There were statistically significant, but not clinical, differences in the incidences of histories of anemia, gastroesophageal reflux disease, previous percutaneous cardiac intervention/percutaneous transluminal coronary artery angioplasty, or preoperative albumin levels between the two groups. There were no perioperative pulmonary aspirations of gastric contents in either group. Following reduction of the oral hydration interval to ≥2 h, a 13-15 % incidence of ehLOS was observed within the 2-5-h NPO interval with similar misclassification rates observed between the two groups. CONCLUSIONS: Allowing bariatric patients access to ad libitum water for up to 2 h prior to surgery decreased the incidence of ehLOS. Comparison of the dose-response curves within the 2-5-h NPO intervals before and after introduction of the revised NPO guidelines was similar and confirms causality.

Role of intraoperative fluids on hospital length of stay in laparoscopic bariatric surgery: a retrospective study in 224 consecutive patients.

BACKGROUND: Studies are unclear regarding optimal intraoperative fluid management during laparoscopic bariatric surgery. The purpose of this 1-year study was to investigate the role of intraoperative fluid administration on hospital length of stay (hLOS) and postoperative complications in laparoscopic bariatric surgery. METHODS: Patient data analyzed included previously reported demographics, comorbidities, and intraoperative fluid administration on the duration of hLOS and incidence of postoperative complications. RESULTS: Logistic regression analysis of demographic and comorbidity variables revealed that BMI (P = 0.0099) and history of anemia (P = 0.0084) were significantly associated with hLOS (C index statistic, 0.7). Lower rates of intraoperative fluid administration were significantly associated with longer hLOS (P = 0.0005). Recursive partitioning observed that patients who received <1,750 ml of intraoperative fluids resulted in longer hLOS when compared to patients who received ≥ 1,750 ml (LogWorth = 0.5). When intraoperative fluid administration rates were defined by current hydration guidelines for major abdominal surgery, restricted rates (<5 ml/kg/h) were associated with the highest incidence of extended hLOS (>1 postoperative day) at 54.1 % when compared to 22.9 % with standard rates (5-7 ml/kg/h) and were lowest at 14.5 % in patients receiving liberal rates (>7 ml/kg/h) (P < 0.0001). Finally, lower rates of intraoperative fluid administration were significantly associated with delayed wound healing (P = 0.03). CONCLUSIONS: The amount of intravenous fluids administered during laparoscopic bariatric surgery plays a significant role on hLOS and on the incidence of delayed wound healing.

A Single-Institution 5-Year Retrospective Analysis of Laparoscopic Sleeve Gastrectomy Staple-Line Reinforcement: Bioabsorbable Mesh Versus Oversewing.

Background: Staple-line reinforcement has been used to decrease complications such as staple-line bleeding (SLB) and staple-line leaks (SLLs) in patients undergoing laparoscopic sleeve gastrectomy (SG). There is little data comparing bioabsorbable mesh reinforcement (BMR) with oversewing the staple line (OSL). The aim of our study was to compare BMR with OSL in SG. Materials and Methods: This is a single-institution retrospective analysis comparing risks and benefits of BMR (group a) with those of OSL (group b) for SG staple-line reinforcement between 2015 and 2020. Results: In total, 857 patients were identified. There were 452 (52.74%) in group a and 405 (47.26%) in group b. SLB requiring transfusion occurred in 6 (1.32%) patients in group a and 6 (1.48%) patients in group b, NS (P = .848). Zero SLL was identified in either group. One-year mean direct cost of SG in group a was $7881 compared with $6677 in group b. Conclusion: This retrospective study showed that there was low risk of bleeding or leak with either technique of staple-line reinforcement and there was no significant difference in SLB or leak rate with bioabsorbable mesh versus oversewing. The use of bioabsorbable mesh was more expensive than oversewing.

Vidutolimod in Combination With Atezolizumab With and Without Radiation Therapy in Patients With Programmed Cell Death Protein 1 or Programmed Death-Ligand 1 Blockade-Resistant Advanced NSCLC.

Introduction: Vidutolimod, a CpG-A TLR9 agonist, was investigated in a phase 1b study (CMP-001-003; ClinicalTrials.gov, NCT03438318) in combination with atezolizumab with and without radiation therapy (RT) in patients with advanced NSCLC. Methods: Patients with progressive disease after anti-programmed cell death protein 1 or programmed death-ligand 1 therapy received either vidutolimod and atezolizumab (part A) or vidutolimod, atezolizumab, and RT (part B). The primary objective was to evaluate the safety of vidutolimod and atezolizumab with and without RT. Key secondary end point was best objective response rate per Response Evaluation Criteria in Solid Tumors, version 1.1. Results: Between March 28, 2018, and July 25, 2019, a total of 29 patients were enrolled and received at least one dose of vidutolimod (part A, n = 13; part B, n = 16). Intratumoral injections of vidutolimod were administered successfully, including injection of visceral lesions. The most common treatment-related adverse events (≥30%) were flu-like symptoms and hypotension. No objective responses were observed; 23.1% and 50.0% of the patients in parts A and B, respectively, had stable disease as best response. In parts A and B, 15.4% and 25.0% of the patients, respectively, had tumor shrinkage (<30% decrease in tumor size, nonirradiated). Enrollment was stopped owing to lack of objective responses. In the two patients with initial tumor shrinkage in part A, a strong serum induction of C-X-C motif chemokine ligand 10 was observed. Conclusions: Vidutolimod and atezolizumab with and without RT had a manageable safety profile, with minimal clinical activity in heavily pretreated patients with programmed cell death protein 1 or programmed death-ligand 1 blockade-resistant NSCLC.

Increased inflammatory low-density neutrophils in severe obesity and effect of bariatric surgery: Results from case-control and prospective cohort studies.

BACKGROUND: Low-density neutrophils (LDN) are increased in several inflammatory diseases and may also play a role in the low-grade chronic inflammation associated with obesity. Here we explored their role in obesity, determined their gene signatures, and assessed the effect of bariatric surgery. METHODS: We compared the number, function, and gene expression profiles of circulating LDN in morbidly obese patients (MOP, n=27; body mass index (BMI) > 40 Kg/m2) and normal-weight controls (NWC, n=20; BMI < 25 Kg/m2) in a case-control study. Additionally, in a prospective longitudinal study, we measured changes in the frequency of LDN after bariatric surgery (n=36) and tested for associations with metabolic and inflammatory parameters. FINDINGS: LDN and inflammatory markers were significantly increased in MOP compared to NWC. Transcriptome analysis showed increased neutrophil-related gene expression signatures associated with inflammation, neutrophil activation, and immunosuppressive function. However, LDN did not suppress T cells proliferation and produced low levels of reactive oxygen species (ROS). Circulating LDN in MOP significantly decreased after bariatric surgery in parallel with BMI, metabolic syndrome, and inflammatory markers. INTERPRETATION: Obesity increases LDN displaying an inflammatory gene signature. Our results suggest that LDN may represent a neutrophil subset associated with chronic inflammation, a feature of obesity that has been previously associated with the appearance and progression of co-morbidities. Furthermore, bariatric surgery, as an efficient therapy for severe obesity, reduces LDN in circulation and improves several components of the metabolic syndrome supporting its recognized anti-inflammatory and beneficial metabolic effects. FUNDING: This work was supported in part by grants from the National Institutes of Health (NIH; 5P30GM114732-02, P20CA233374 - A. Ochoa and L. Miele), Pennington Biomedical NORC (P30DK072476 - E. Ravussin & LSU-NO Stanley S. Scott Cancer Center and Louisiana Clinical and Translational Science Center (LACaTS; U54-GM104940 - J. Kirwan).

Phase I study of LY2469298, an Fc-engineered humanized anti-CD20 antibody, in patients with relapsed or refractory follicular lymphoma.

Patients with follicular lymphoma (FL), where position 158 of FcγR-IIIa is heterozygous valine/phenylalanine or homozygous phenylalanine (F-carriers), have natural killer cells with lower binding affinity to IgG than valine homozygote patients. In addition, F-carriers show less efficacy with rituximab treatment than patients homozygous for valine. LY2469298 is a humanized IgG1 monoclonal antibody targeting CD20, with human germline framework regions, and specific amino acid substitutions engineered into the Fc region to increase effector function in antibody-dependent cell-mediated cytotoxicity. This dose-escalation, phase I study was conducted to assess the safety, pharmacokinetics and preliminary efficacy of LY2469298 in Japanese patients with previously treated, CD20-positive FL who had not relapsed or progressed within 120 days of prior rituximab. LY2469298 was administered by intravenous infusion at 100 or 375 mg/m(2) weekly for 4 weeks. Ten patients were enrolled (median age, 60 years); all had previously been treated with rituximab. Nine patients were F-carriers while one was homozygous for valine at position 158 of FcγRIIIa. No patients developed dose-limiting toxicities, and the most frequent adverse events were lymphopenia, pyrexia, leukopenia, chills and neutropenia. Five (50%) of the ten patients responded to LY2469298 treatment (three complete responses, one unconfirmed complete response and one partial response). Serum LY2469298 was eliminated in a biphasic manner and the pharmacokinetic profiles were not different from those in a preceding study in the United States. In conclusion, LY2469298 was well tolerated and clinical activity was observed in FL patients pretreated with rituximab, mostly consisting of F-carriers. Further investigation of FL is warranted.

A phase I safety study of enzastaurin plus bortezomib in the treatment of relapsed or refractory multiple myeloma.

The purpose of this study was to assess the safety and identify the recommended doses of enzastaurin and bortezomib in combination for future Phase II studies in patients with relapsed or refractory multiple myeloma. Three dose levels (DLs) of oral enzastaurin and intravenous bortezomib were used according to a conventional "3 + 3" design. A loading dose of enzastaurin (250 mg twice/day [BID]) on Day 1 was followed by enzastaurin 125 mg BID for 1 week, after which bortezomib was added (Cycle 1, 28 days, 1.0 mg/m(2) : Days 8, 11, 15, and 18; seven subsequent 21-day cycles, 1.3 mg/m(2) : Days 1, 4, 8, and 11). Twenty-three patients received treatment; all patients received prior systemic therapy. Most patients received ≥3 regimens; 17 patients were bortezomib-refractory. A median of four treatment cycles (range 1-24) was completed. No dose-limiting toxicities were observed; thus, DL 3 was the recommended Phase II dose. The most common drug-related Grade 3/4 toxicities were thrombocytopenia (n = 6) and anemia (n = 2). No patients died on therapy. One patient (DL 1) achieved a very good partial response; three patients (DLs 2 and 3), a partial response; nine patients, stable disease; and four patients, progressive disease. The recommended Phase II doses in patients with relapsed or refractory multiple myeloma are as follows: enzastaurin loading dose of 375 mg three times/day on Day 1 followed by 250 mg BID, with bortezomib 1.3 mg/m(2) on Days 1, 4, 8, and 11 of a 21-day cycle. The combination was well-tolerated and demonstrated some antimyeloma activity.

Arginase Therapy Combines Effectively with Immune Checkpoint Blockade or Agonist Anti-OX40 Immunotherapy to Control Tumor Growth.

Metabolic dysregulation is a hallmark of cancer. Many tumors exhibit auxotrophy for various amino acids, such as arginine, because they are unable to meet the demand for these amino acids through endogenous production. This vulnerability can be exploited by employing therapeutic strategies that deplete systemic arginine in order to limit the growth and survival of arginine auxotrophic tumors. Pegzilarginase, a human arginase-1 enzyme engineered to have superior stability and enzymatic activity relative to the native human arginase-1 enzyme, depletes systemic arginine by converting it to ornithine and urea. Therapeutic administration of pegzilarginase in the setting of arginine auxotrophic tumors exerts direct antitumor activity by starving the tumor of exogenous arginine. We hypothesized that in addition to this direct effect, pegzilarginase treatment indirectly augments antitumor immunity through increased antigen presentation, thus making pegzilarginase a prime candidate for combination therapy with immuno-oncology (I-O) agents. Tumor-bearing mice (CT26, MC38, and MCA-205) receiving pegzilarginase in combination with anti-PD-L1 or agonist anti-OX40 experienced significantly increased survival relative to animals receiving I-O monotherapy. Combination pegzilarginase/immunotherapy induced robust antitumor immunity characterized by increased intratumoral effector CD8+ T cells and M1 polarization of tumor-associated macrophages. Our data suggest potential mechanisms of synergy between pegzilarginase and I-O agents that include increased intratumoral MHC expression on both antigen-presenting cells and tumor cells, and increased presence of M1-like antitumor macrophages. These data support the clinical evaluation of I-O agents in conjunction with pegzilarginase for the treatment of patients with cancer.

Overcoming PD-1 Blockade Resistance with CpG-A Toll-Like Receptor 9 Agonist Vidutolimod in Patients with Metastatic Melanoma.

Patients with advanced melanoma that is resistant to PD-1 blockade therapy have limited treatment options. Vidutolimod (formerly CMP-001), a virus-like particle containing a CpG-A Toll-like receptor 9 (TLR9) agonist, may reverse PD-1 blockade resistance by triggering a strong IFN response to induce and attract antitumor T cells. In the dose-escalation part of this phase Ib study, vidutolimod was administered intratumorally at escalating doses with intravenous pembrolizumab to 44 patients with advanced melanoma who had progressive disease or stable disease on prior anti-PD-1 therapy. The combination of vidutolimod and pembrolizumab had a manageable safety profile, and durable responses were observed in 25% of patients, with tumor regression in both injected and noninjected lesions, including visceral lesions. Patients who responded to vidutolimod and pembrolizumab had noninflamed tumors at baseline and induction of an IFNγ gene signature following treatment, as well as increased systemic expression of the IFN-inducible chemokine CXCL10. SIGNIFICANCE: In this phase Ib study in patients with advanced melanoma, intratumoral TLR9 agonist vidutolimod in combination with pembrolizumab had a manageable safety profile and showed promising clinical activity, supporting the further clinical development of vidutolimod to overcome PD-1 blockade resistance through induction of an IFN response. See related commentary by Sullivan, p. 2960. This article is highlighted in the In This Issue feature, p. 2945.

Pharmacokinetics and pharmacokinetic/pharmacodynamic associations of ofatumumab, a human monoclonal CD20 antibody, in patients with relapsed or refractory chronic lymphocytic leukaemia: a phase 1-2 study.

The purpose of this phase 1-2 study was to investigate the association between the pharmacokinetic properties of ofatumumab, a human monoclonal CD20 antibody, and outcomes in 33 patients with relapsed/refractory chronic lymphocytic leukaemia receiving 4 weekly infusions of ofatumumab. The ofatumumab concentration profiles were fitted well by a two-compartment model with different elimination rate constant at first infusion compared to the remaining infusions in line with the observed rapid and sustained B-cell depletion. Exposure to ofatumumab was linked to clinical outcomes: high exposure was associated with higher probability of overall clinical response and longer progression-free survival. This association still remained statistically significant even when adjusting for relevant baseline covariates including tumour burden.

Minimally invasive esophagectomy without the use of postoperative nasogastric tube decompression.

A nasogastric tube (NGT) is commonly used in the postoperative period after esophagectomy for decompression of the gastric conduit. The aim of this study was to evaluate the safety of a minimally invasive esophagectomy without the use of NGT decompression. We performed a retrospective review of 124 patients who underwent minimally invasive esophagectomy. Ninety-eight patients had an NGT placed for postoperative decompression and 26 patients did not. The main outcome measure was postoperative complications in regard to the gastric conduit and esophageal anastomosis. There were 96 males with a mean age of 65 +/- 11 years. Three (3%) of 98 patients with operative NGT placement developed postoperative complications directly related to the NGT, which included perforation of the gastric conduit (n = 1) and perforation of the anastomosis (n = 2). In the 26 patients without operative NGT decompression, one patient (3.8%) had distention of the gastric conduit requiring placement of a NGT under fluoroscopic guidance on postoperative Day 1. There was no significant difference in the leak rate between the groups with NGT decompression compared with the group without NGT decompression (9.2 vs 7.7%, respectively). In conclusion, the use of NGT decompression during minimally invasive esophagectomy can be safely omitted. In cases with postoperative gastric conduit distention, an NGT can be safely placed under fluoroscopic guidance.

Hospital volume is not a predictor of outcomes after gastrectomy for neoplasm.

Studies have shown conflicting data with regard to the volume and outcome relationship for gastrectomy. Using the University HealthSystem Consortium national database, we examined the influence of the hospital's volume of gastrectomy on outcomes at academic centers between 2004 and 2008. Outcome measures, including length of stay, 30-day readmission, morbidity, and in-hospital mortality, were compared among high- (13 or greater), medium- (6 to 12), and low-volume (five or less) hospitals. There were 10 high- (n = 593 cases), 36 medium- (n = 1076 cases), and 75 low-volume (n = 500 cases) hospitals. There were no significant differences between high- and low-volume hospitals with regard to length of stay, overall complications, 30-day readmission rate, and in-hospital mortality (2.4 vs 4.4%, respectively, P = 0.06). Despite the small number of gastrectomies performed at the low-volume hospitals, these same hospitals performed a large number of other types of gastric surgery such as gastric bypass for the treatment of morbid obesity (102 cases/year). Within the context of academic medical centers, lower annual volume of gastrectomy for neoplasm is not a predictor of poor outcomes which may be explained by the gastric operative experience derived from other types of gastric surgery.

A First-in-Human Phase I Study of a Bivalent MET Antibody, Emibetuzumab (LY2875358), as Monotherapy and in Combination with Erlotinib in Advanced Cancer.

Purpose: The MET/HGF pathway regulates cell proliferation and survival and is dysregulated in multiple tumors. Emibetuzumab (LY2875358) is a bivalent antibody that inhibits HGF-dependent and HGF-independent MET signaling. Here, we report dose escalation results from the first-in-human phase I trial of emibetuzumab.Experimental Design: The study comprised a 3+3 dose escalation for emibetuzumab monotherapy (Part A) and in combination with erlotinib (Part A2). Emibetuzumab was administered i.v. every 2 weeks (Q2W) using a flat dosing scheme. The primary objective was to determine a recommended phase II dose (RPTD) range; secondary endpoints included tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity.Results: Twenty-three patients with solid tumors received emibetuzumab monotherapy at 20, 70, 210, 700, 1,400, and 2,000 mg and 14 non-small cell lung cancer (NSCLC) patients at 700, 1,400, and 2,000 mg in combination with erlotinib 150 mg daily. No dose-limiting toxicities and related serious or ≥ grade 3 adverse events were observed. The most common emibetuzumab-related adverse events included mild diarrhea, nausea, and vomiting, and mild to moderate fatigue, anorexia, and hypocalcemia in combination with erlotinib. Emibetuzumab showed linear PK at doses >210 mg. Three durable partial responses were observed, one for emibetuzumab (700 mg) and two for emibetuzumab + erlotinib (700 mg and 2,000 mg). Both of the responders to emibetuzumab + erlotinib had progressed to prior erlotinib and were positive for MET protein tumor expression.Conclusions: Based on tolerability, PK/PD analysis, and preliminary clinical activity, the RPTD range for emibetuzumab single agent and in combination with erlotinib is 700 to 2,000 mg i.v. Q2W. Clin Cancer Res; 23(8); 1910-9. ©2016 AACR.

Improved survival of follicular lymphoma patients in the United States.

PURPOSE: Despite several new treatment options, single- and multi-institution analyses have not clarified whether survival patterns in follicular lymphoma (FL) patients have changed in recent decades. We undertook a study using a large population-based registry to analyze survival patterns among patients with FL. PATIENTS AND METHODS: Surveillance, Epidemiology, and End Results morphology codes were used to identify 14,564 patients diagnosed with FL between 1978 and 1999. Observed median survival times, Kaplan-Meier survival curves, proportional death hazard ratios, and relative survival rates were calculated. Joinpoint regression analysis was used to identify trends in annual adjusted death hazard ratios. RESULTS: An improvement in survival of all patients with FL was observed between each of three diagnosis eras (1978 to 1985, 1986 to 1992, and 1993 to 1999) by log-rank tests. Among patients with stage-specific data, the median survival time improved from 84 months (95% CI, 81 to 88 months) in the 1983 to 1989 era to 93 months (95% CI, 89 to 97 months) in the 1993 to 1999 era. Similar findings were identified across sex and age groups and for subsets including advanced-stage, large-cell FL and the combined subset of small cleaved- and mixed-cell FL. The inter-era survival advantage observed in white patients was not observed for black patients. The relative risk of death decreased by 1.8% per year over the 1983 to 1999 observation period. CONCLUSION: The survival of patients with FL in the United States has improved over the last 25 years. The survival improvement may be a result of the sequential application of effective therapies and improved supportive care.

Response assessment of aggressive non-Hodgkin's lymphoma by integrated International Workshop Criteria and fluorine-18-fluorodeoxyglucose positron emission tomography.

PURPOSE: To determine whether a response classification based on integration of fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET) into the International Workshop Criteria (IWC) provides a more accurate response assessment than IWC alone in patients with non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Fifty-four patients with aggressive NHL who underwent FDG-PET and computed tomography 1 to 16 weeks after four to eight cycles of chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone were assessed for complete response (CR), unconfirmed CR (CRu), partial response (PR), stable disease (SD), and progressive disease (PD) by the IWC and by integrated IWC and FDG-PET (IWC+PET). Progression-free survival (PFS) was also compared between IWC- and IWC+PET-assigned response designations. RESULTS: By IWC, 17 patients had a CR, seven had a CRu, 19 had a PR, nine had SD, and two had PD. In comparison, by IWC+PET, 35 patients had a CR, 12 had a PR, six had SD, one had PD, and zero had a CRu. In separate multivariate models, PFS was significantly shorter in patients with PR than in those with a CR using IWC (hazard ratio [HR], 8.9; P = .021) or IWC+PET (HR, 29.7; P = .0003). However, when the two classifications were included in the same multivariate model, only IWC+PET was a statistically significant independent predictor for PFS (P = .008 v P = .72 for IWC). In addition, when patients with a PR by IWC and a CR by IWC+PET were compared with those with a CR by IWC and a CR by IWC+PET, there was no significant difference in PFS (HR, 1.6; P = .72), indicating that IWC+PET identified a subset of IWC-PR patients with a more favorable prognosis. CONCLUSION: Compared with IWC, the IWC+PET-based assessment provides a more accurate response classification in patients with aggressive NHL.

Neutropenia and febrile neutropenia in patients with Hodgkin's lymphoma treated with doxorubicin (Adriamycin), bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy.

When uncomplicated neutropenia during doxorubicin (Adriamycin), bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy for the treatment of Hodgkin's lymphoma is encountered, it is unclear whether or not treatment should be modified. In the present study, we determined the incidence of neutropenia, febrile neutropenia, and the relationship of febrile neutropenia to grade III/IV neutropenia and dose modification, in a large university patient population. We reviewed the charts of patients diagnosed with Hodgkin's lymphoma between 1 January 1990 and 31 December 2002 who were treated with ABVD chemotherapy, and seen at the University of Iowa with complete diagnosis, staging, and treatment dosing records. Adequate data was available on 894 treatments in 81 patients with Hodgkin's lymphoma treated with ABVD chemotherapy. Grade III/IV neutropenia was present on the scheduled day of treatment in 187 (20.9%) treatments in 64 (79%) patients. Grade III/IV neutropenia was most common at cycle 1 day 15. Febrile neutropenia developed nine times in eight patients, and eight episodes of febrile neutropenia developed when the treatment-day absolute neutrophil count (ANC) > or =1000. Dose delay of >4 days and/or dose reduction to <80% of original doxorubicin dose following grade III/IV neutropenia occurred in 29 of 187 treatments, with no episodes of febrile neutropenia. With grade III/IV neutropenia on the day of therapy, 158 treatments were administered without dose reduction or dose delay with one subsequent episode of febrile neutropenia. Neutropenia during ABVD is common, and dose modification for uncomplicated neutropenia on the day of treatment may not reduce the risk of febrile neutropenia. It may be possible to maintain dose intensity in the face of uncomplicated neutropenia during ABVD therapy.

Immunostimulatory oligodeoxynucleotides induce apoptosis of B cell chronic lymphocytic leukemia cells.

Immunostimulatory oligodeoxynucleotides (IS ODN) can mediate a number of immunologic effects. We previously demonstrated that treatment of B cell chronic lymphocytic leukemia (B-CLL) cells with one class of IS ODN, CpG ODN, alters their phenotype and increases their immunogenicity. Here, we demonstrate that in contrast to the classic understanding of CpG ODN as inhibitors of B cell apoptosis, IS ODN including CpG ODN induce apoptosis in B-CLL cells. It is important that these changes are seen not only with CpG ODN but with ODN that lack the classical CpG motif. B-CLL cells from 20 subjects were treated in vitro with IS ODN for up to 7 days. IS ODN treatment resulted in increased numbers of apoptotic cells in 13 out of 20 B-CLL samples. IS ODN enhanced apoptosis in samples with 13q deletion as a single aberration and had a heterogeneous effect on apoptosis in samples with other aberrations including 17p deletion, 11q deletion, or trisomy 12. Induction of apoptosis did not correlate with expression of the CpG ODN receptor Toll-like receptor 9. Apoptosis was dependent on the activation of caspases and was accompanied by up-regulation of CD95/Fas and its ligand. We conclude that IS ODN including CpG ODN can induce apoptosis of most B-CLL samples. The ability of IS ODN to induce apoptosis differs based on cytogenetic status. Up-regulation of CD95/Fas may play a role in IS ODN-induced apoptosis of B-CLL.

Frequency of skeletal-related events and associated healthcare resource use and costs in US patients with multiple myeloma.

OBJECTIVE: A potential complication for all new multiple myeloma (MM) patients is the clinical presentation of osteolytic lesions which increase the risk for skeletal-related events (SREs). However, the contribution of SREs to the overall economic impact of MM is unclear. The impact of SREs on healthcare resource utilization (HCRU) and costs for US patients with MM was analyzed in Truven Health Marketscan Commercial Claims and Medicare Supplemental Databases. METHODS: Adults diagnosed with MM between January 1, 2005 and December 31, 2010 with ≥2 claims ≥30 days apart (first claim = index date) were included. SREs included: hypercalcemia, pathologic fracture, surgery for the prevention and treatment of pathologic fractures or spinal cord compression, and radiation for bone pain. Rates of HCRU (outpatient [OP], inpatient [IP], emergency room [ER], orthopedic consultation [OC], and ancillary) and healthcare costs were compared between MM patients with and without SREs. Inverse propensity weighting was applied to adjust for potential bias. RESULTS: Of 1028 MM patients (mean age = 67, standard deviation = 13.2), 596 patients with ≥1 SRE and 432 without SREs were assessed. HCRU rates in IP, ER, and ancillary (p < 0.01) and mean total costs of OP, IP, and ER were significantly higher (p < 0.05) for patients with vs without SREs during follow-up. HCRU rates also increased with SRE frequency (p < 0.05 in OP, IP, ER, OC, and ancillary), as did mean total healthcare costs, except for OC (p < 0.001). LIMITATIONS: A broad assessment of pharmacotherapy for the treatment of MM was not an objective of the current study. Bisphosphonate use was evaluated; however, results were descriptively focused on frequency of utilization only and were not included in the broader cost and HCRU analysis. CONCLUSIONS: Among US patients with MM, higher SRE frequency was associated with a significant trend of higher HCRU and total healthcare costs in several settings.