Expression of TIA1 and PAX5 in Classical Hodgkin Lymphoma at Initial Diagnosis May Predict Clinical Outcome.

Although the expression of T-cell antigens and proteins associated with tumor-infiltrating T-lymphocytes (TILs), regulatory T cells (T-regs), and B-cell development have been evaluated in classical Hodgkin lymphoma (cHL), few studies correlate these proteins' expression patterns with clinical outcome. The purpose of this study was to evaluate proteins expressed in the Reed-Sternberg cells (RSCs) and TILs of cHLs at initial diagnosis to determine their prognostic significance. The expression of 12 proteins in RSCs and TILs from 88 diagnostic cHL biopsies was quantitated and correlated to overall survival (OS) and progression-free survival (PFS). CD2, CD3, CD4, CD5, CD7, CD25, PD1, TIA1, MUM1, and ZAP70 expression in RSCs did not correlate with OS or PFS, nor did programmed death 1 (PD1) expression in TILs. High numbers of TIA1-positive TILs (≥50%) correlated with OS (P=0.027), but not PFS (P=0.993) in univariate analysis. Expression of CD2, CD3, CD4, CD5, and/or TIA1 (6%) in RSCs was associated with lymphocyte-rich/mixed-cellularity subtype (P=0.032). High International Prognostic Score (IPS; P=0.036), and high stage (P=0.046) were independent predictors of worse PFS in univariate analysis. Low IPS (P=0.003) and nodular sclerosing subtype (P=0.022) were associated with better OS in univariate analysis. Only the IPS predicted OS in multivariate (P=0.009) analysis. High TIA1+ TILs correlated with worse clinical outcomes for cHLs, as did PAX5-RSCs (P=0.024), although only 2/74 cases were shown to be negative for this marker, suggesting that the tumor microenvironment and a transcription factor crucial for B-cell development are critical biological determinants of the disease course.

CD163 immunohistochemistry is superior to CD68 in predicting outcome in classical Hodgkin lymphoma.

OBJECTIVES: In recent years, research has increasingly focused on the microenvironment of classical Hodgkin lymphoma (CHL) as a predictor of treatment outcome. The focus of this study was to assess the interobserver reproducibility in interpreting macrophage-associated immunohistochemistry (IHC) for CD68 and CD163 in a retrospective cohort of 88 patients with CHL. METHODS: Staining results were correlated with clinical outcome in all patients and those with a high international prognostic score (IPS). RESULTS: The intraclass correlation (ICC) for the five hematopathologists interpreting the IHC was stronger for CD163 (0.70) than for CD68 (0.50). Using a cutoff of 25% mean macrophage reactivity and including all patients, a statistically significant difference in overall survival (OS) was seen only for CD163 (P = .0006) and not for CD68 (P = .414). Patients with a mean CD163 reactivity of 25% or more had a median OS of 71 months vs 101 months for patients with less than 25% reactivity. CD163 retained statistical significance in multivariate analysis. In patients with advanced-stage CHL with high IPS, OS was also significantly worse for those with a mean CD163 reactivity of 25% or higher. CONCLUSIONS: Our study confirms previous reports of a prognostic role of tumor-infiltrating macrophages in CHL, but only for CD163. Although most of the literature supports an increasing role of macrophage IHC as a predictor of clinical outcome, successful clinical translation will require a standardized method and reporting system.

Rituximab is associated with improved survival in Burkitt lymphoma: a retrospective analysis from two US academic medical centers.

BACKGROUND: Burkitt lymphoma (BL) is a rare, highly aggressive B-cell malignancy treated most successfully with brief-duration, high-intensity chemotherapeutic regimens. The benefit of the addition of rituximab to these regimens remains uncertain. We sought to examine the effectiveness of chemotherapy with and without rituximab in patients with BL. METHODS: This study is a retrospective cohort study of all adult patients with BL diagnosed and treated with modern, dose-intense chemotherapeutic regimens from 1998-2008 at two tertiary care institutions. All cases were confirmed by application of WHO 2008 criteria by hematopathologists. Medical records were reviewed for patient-, disease-, and treatment- related factors as well as treatment response and survival. Factors associated with survival were analyzed using Cox proportional hazards modeling. RESULTS: A total of 35 patients were analyzed: 18 patients received rituximab with chemotherapy (R-chemo) and 17 received chemotherapy (chemo) alone. The median age was 42 (range 20-74 years); 57% were male; 71% had Ann Arbor Stage IV disease; 33% had central nervous system involvement; 78% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. R-chemo was associated with significantly longer overall survival (OS) than chemo alone (5-year OS 70% and 29%, respectively, p = 0.040). On multivariate regression analysis, poor performance status and central nervous system involvement were associated with poorer survival. CONCLUSIONS: The addition of rituximab to chemotherapy was associated with improved OS in patients with Burkitt lymphoma. Poor performance status and central nervous system involvement were prognostically significant on multivariate analysis.

Brentuximab vedotin and crizotinib in anaplastic large-cell lymphoma.

Systemic anaplastic large-cell lymphoma (ALCL) is a rare, mature T-cell non-Hodgkin lymphoma. Anaplastic large-cell lymphoma cells express the surface antigen CD30, and more than half express the anaplastic lymphoma kinase (ALK) protein. These 2 proteins provide unique therapeutic targets in ALCL. Remission rates in ALCL with combination chemotherapy are approximately 80%, but relapse after first-line therapy is common. Brentuximab vedotin is a US Food and Drug Administration-approved, antibody-drug conjugate that combines an anti-CD30 antibody with monomethylauristatin E, a potent antimicrotubule agent. Response rates to brentuximab vedotin in patients with relapsed/refractory ALK and ALK ALCL have exceeded 80% with frequent complete responses and a median duration of response greater than 1 year. Brentuximab vedotin in combination with chemotherapy is being explored as a first-line therapy in ALCL. Crizotinib is an inhibitor of ALK tyrosine kinase that has been approved for the treatment of ALK non-small cell lung cancer. Successful treatment of ALK ALCL with crizotinib has been reported in pediatric patients and small case series leading to ongoing trials in relapsed/refractory ALCL. Brentuximab vedotin and crizotinib represent major advances in the treatment of ALK and ALK ALCL and will likely result in marked improvement in prognosis for this subset of aggressive lymphomas.

Brentuximab vedotin for the treatment of CD30+ lymphomas.

Brentuximab vedotin is a novel antibody-drug conjugate consisting of the anti-CD30 antibody cAC10 chemically conjugated to monomethylauristatin E, a potent antimicrotubule agent. Preliminary response rates of 75% in relapsed/refractory Hodgkin's lymphoma and 87% in relapsed/refractory systemic anaplastic large-cell lymphoma were recently reported in large Phase II trials. Brentuximab vedotin is well tolerated with manageable side effects including peripheral sensory neuropathy. This antibody-drug conjugate is currently under investigation in numerous clinical trials, including in combination with front-line chemotherapy for high-risk Hodgkin's lymphoma and in a placebo-controlled, Phase III trial for patients with Hodgkin's lymphoma at high risk for residual disease following autologous stem cell transplant. The impressive response rates and limited toxicity of brentuximab vedotin are very promising for relapsed/refractory patients with few treatment options. In addition, the possibilities for incorporation into front-line therapies for both Hodgkin's lymphoma and systemic anaplastic large-cell lymphoma are intriguing.

Anti-CD30 Antibodies for Hodgkin lymphoma.

Treatment of refractory or relapsed classical Hodgkin lymphoma (HL) remains challenging, but targeted immunotherapy has recently emerged as a potential treatment option for these patients. Although first-generation monoclonal anti-CD30 antibodies proved disappointing, current efforts to modify anti-CD30 antibodies to improve binding of effector cells and enhance activity appears more promising, as does the development of novel antibody-drug conjugates (ADCs). ADCs offer the potential to deliver potent therapies with minimal toxicity. One highly active ADC, brentuximab vedotin (SGN-35), combines an anti-CD30 monoclonal antibody and the antitubulin agent monomethyl auristatin E. Initial phase 1 studies of brentuximab vedotin showed a 52% overall response rate in relapsed HL, with minimal toxicity. This article highlights the development of anti-CD30 antibodies and ADCs for relapsed or refractory classical HL.

Pulmonary vein isolation and the Cox maze procedure only partially denervate the atrium.

OBJECTIVES: The effects of ablation lines on myocardial innervation and response to autonomic stimuli are unclear. This study examined the effects of radiofrequency ablation on atrial autonomic innervation and compared pulmonary vein isolation and the biatrial Cox maze procedure. METHODS: In 12 acute canines right and left vagosympathetic trunks and right and left stellate ganglia were isolated. Each nerve was stimulated before bipolar ablation, after pulmonary vein isolation, and after the Cox maze procedure. Nadolol (n = 6) and atropine (n = 6) were administered to block sympathetic and parasympathetic responses, respectively. Changes in heart rate and atrioventricular interval were compared. Changes in QRST area relative to an isoelectric baseline (index of local innervation) were calculated. RESULTS: Sympathetic stimulation of each nerve and parasympathetic stimulation of the vagosympathetic trunks caused significant changes in heart rate and atrioventricular interval. After pulmonary vein isolation, the effect of 33% of the nerves on heart rate changes was eliminated. The Cox maze procedure eliminated right stellate sympathetic effects on heart rate. Fifty percent of the nerves caused heart rate changes after the Cox maze procedure. There was no significant effect of either lesion set on atrioventricular interval changes. Stimulation of 50% of nerves after pulmonary vein isolation produced local area changes significantly different from control area. After the Cox maze procedure, a different 50% of the nerves produced local changes different from those seen after pulmonary vein isolation. CONCLUSIONS: Surgical ablation procedures disrupted innervation, affecting heart rate but not atrioventricular interval. Autonomic innervation affecting the atria was changed by pulmonary vein isolation and additionally by the Cox maze procedure. Residual autonomic effects were present even after the complete Cox maze procedure.

Longterm changes in creatinine clearance after laparoscopic renal surgery.

BACKGROUND: Controversy exists about the impact of ischemia on renal function. We evaluated the creatinine clearance of patients having undergone laparoscopic renal extirpative and ablative surgery. STUDY DESIGN: The records of patients undergoing laparoscopic procedures for renal masses from February 2000 to March 2004 were examined. Creatinine clearance (CrCl) for each patient was determined using the Cockcroft-Gault equation and ideal body weight. We compared CrCl changes of patients undergoing laparoscopic partial nephrectomy (without renal ischemia [LPN-none], with warm ischemia [LPN-warm], and with cold ischemia [LPN-cold]) with patients undergoing laparoscopic radical nephrectomy (LRN) and laparoscopic cryoablation. Patients predisposed to medical renal disease were substratified and evaluated. RESULTS: All patients who underwent LRN or LPN-warm sustained a significant drop in CrCl on the first postoperative day, compared with patients who had LPN without ischemia or cryoablation (p < 0.01). The CrCl decrease correlated directly with warm ischemia time. Six months postoperatively, CrCl changes were no longer significant. Patients with medical renal disease risk factors were more likely to sustain longterm (1 year postoperatively) renal damage if they had renal ischemia, trending toward statistical significance. CONCLUSIONS: Ischemia causes acute renal damage, which is apparently reversible in patients without evidence of medical renal disease. Patients with known medical renal disease have substantial longterm changes in renal function associated with unilateral renal ischemia. Considering the insensitivity of creatinine-based renal function metrics, only eliminating ischemic time will realize the goal of maximal nephron preservation, particularly in patients with preexisting medical renal disease.

Alteration in irrigant flow and deflection of flexible ureteroscopes with nitinol baskets.

BACKGROUND AND PURPOSE: Introduction of an instrument into the working channel of ureteroscopes adversely affects flow and deflection. We evaluated the alterations in ureteroscope channel flow and deflection caused by available Nitinol(R) baskets. MATERIALS AND METHODS: We compared the effects of 11 Nitinol baskets on irrigation flow and deflection of three flexible ureteroscopes (Olympus P3, ACMI DUR8, and ACMI DUR8 Elite). ANOVA was used to compare the loss of flow and deflection for each basket, with P values adjusted for multiple comparisons by the Tukey method. RESULTS: Ureteroscope flow and deflection were progressively adversely affected by all baskets as their diameter increased. The average baseline irrigant flow (46.6 mL/min) was decreased significantly: by 78.5% (to 9.9 mL/min), with the smaller baskets (Microvasive 1.9F and Cook 2.2F) and by 99.1% (to 0.4 mL/min) with the larger baskets (ACMI 3.0F and Microvasive 3.0F). Similarly, the mean baseline upward deflection (162 degrees) decreased by 2 degrees (1.2%) for the Cook 2.4F N-Compass and by 20 degrees (12.3%) for the ACMI 3.0F. Loss of downward deflection from baseline (170 degrees) ranged from 6 degrees (3.5%) for the Microvasive 1.9F to 17 degrees (10%) for the Microvasive 2.6F grasping forceps. The least deterioration in flow and deflection occurred with the two smallest baskets (Microvasive 1.9F and Cook 2.2F). CONCLUSION: Ureteroscope irrigation flow and deflection deteriorate progressively with larger-caliber Nitinol baskets. The Microvasive 1.9F and Cook 2.2F baskets resulted in the least deterioration of irrigation and deflection metrics. However, basket size is not the only factor responsible for changes in flow and ureteroscope deflection.

Laparoscopic renal parenchymal hypothermia with novel ice-slush deployment mechanism.

OBJECTIVES: To report the development of a novel, simple-to-use method for laparoscopic deployment of fine-quality saline ice slush by way of a 10-mm end-effector for laparoscopic parenchymal hypothermia. METHODS: A mechanism for making fine ice slush was created, and a 10-mm laparoscopic end-effector was designed and constructed for deployment of the ice slush. The novel ice slush deployment system was tested in a porcine model and compared with that of standard open ice slush cooling. After atraumatic hilar clamping, the cortical and medullary temperatures in the upper, middle, and lower poles were measured with thermocouples. RESULTS: Six pigs were evaluated in each group. In all cases, the kidneys were successfully cooled to our goal temperature of 15 degrees to 25 degrees C within 10 minutes and were maintained at the target temperature for 1 hour. The core body temperature for the slush group was decreased by 3 degrees C but did not change in the open group. The renal temperatures quickly returned to normal on unclamping of the renal hilum. One pig in the open group died of acidosis and another in the same group experienced thrombosis of the renal artery. No complications occurred in the laparoscopic group. CONCLUSIONS: We describe a novel, simple-to-use mechanism for producing and delivering fine ice slush in a laparoscopic setting. The technique achieves optimal parenchymal hypothermia expeditiously.