Phase I Trial of Inducible Caspase 9 T Cells in Adult Stem Cell Transplant Demonstrates Massive Clonotypic Proliferative Potential and Long-term Persistence of Transgenic T Cells.

PURPOSE: Inducible caspase 9 (iCasp9) is a cellular safety switch that can make T-cell therapy safer. The purpose of this phase I trial was to investigate the use of iCasp9-transduced T-cell addback in adult patients undergoing haploidentical stem cell transplantation for high-risk hematologic malignancies. PATIENTS AND METHODS: Patients undergoing myeloablative, CD34-selected haploidentical stem cell transplantation were treated with 0.5-1.0 × 106/kg donor-derived iCasp9-transduced T cells on day +25 or 26 post-transplant, with additional doses allowed for disease relapse, infection, or mixed chimerism. RESULTS: Three patients were enrolled. iCasp9-transduced T cells were readily detectable by 4 weeks post-infusion in all patients and remained at high level (114 cells/µL, 11% of T cells) in 1 patient alive at 3.6 years. One patient developed donor-derived Epstein-Barr virus-associated post-transplant lymphoproliferative disease (EBV-PTLD), which was followed by a marked expansion of iCasp9 T cells and cytokine release syndrome (CRS). These iCasp9-transduced T cells infiltrated the affected lymph nodes and secreted IFNγ and IL-10. They peaked at 1,848 cells/µL and were found to be monoclonal by T-cell receptor (TCR) clonotype and oligoclonal by viral integrant analysis, representing a 6-log in vivo expansion of the dominant T-cell clone. These T cells were not autonomous and contracted with the resolution of EBV-PTLD, which did not recur. CONCLUSIONS: iCasp9-transduced T cells could persist long-term. They retained very high in vivo clonotypic proliferative capacity and function, and could cause CRS in response to de novo lymphoma development.

Concurrent chemoradiation with cisplatin and vinorelbine followed by consolidation with oral vinorelbine in locally advanced non-small cell lung cancer (NSCLC): the phase II CONCAVE study.

AIM: Despite recent advances, outcomes for patients with stage III non-small cell lung cancer (NSCLC) with concurrent chemoradiotherapy (CRT) remain poor. We evaluated the combination of ciplatin/vinorelbine and concurrent thoracic radiotherapy followed by consolidation oral vinorelbine in this phase II study. METHODS: Eligible patients with unresectable stage III NSCLC received cisplatin intravenous (IV) 40 mg/m2 and vinorelbine IV 20 mg/m2 on days 1, 8, 22 and 29 concurrent with thoracic radiotherapy of 60 Gy in 30 fractions. Four to eight weeks later, oral vinorelbine 60 mg/m2 day 1 and 8 every 3 weeks was given for 3 cycles. The primary end point was overall response rate (ORR). Secondary end points were safety, quality of life, progression-free survival (PFS) and overall survival (OS). RESULTS: Twenty-seven eligible patients were enrolled from December 2007 to June 2010 before the trial was prematurely closed due to toxicity concerns. The median age was 63 years (range, 42-71), 56% were male, 52% ECOG 0 and 52% stage IIIa. The ORR was 81% (including 37% complete response rate) and disease control rate of 93%. The median PFS was 11 months and median OS was 26 months. Consolidation vinorelbine was associated with significant grade 3/4 toxicity (68%) including grade 3-5 febrile neutropenia (27%) and respiratory infections (36%) including two deaths in the consolidation phase (9%). CONCLUSIONS: Consolidation oral vinorelbine after CRT was associated with significant toxicity. Overall, this regimen achieved a high ORR and survival results comparable to other CRT protocols but the significant toxicity precludes further evaluation of this approach.

Recent advances in radiotherapy for thoracic tumours.

Radiation Oncology technology has continued to advance at a rapid rate and is bringing significant benefits to patients. This review outlines some of the advances in technology and radiotherapy treatment of thoracic cancers including brachytherapy, stereotactic radiotherapy, tomotherapy and intensity modulated radiotherapy. The importance of functional imaging with PET and management of movement are highlighted. Most of the discussion relates to non-small cell lung cancer but management of mesothelioma and small cell lung cancer are also covered. This technology has substantial benefits to patients in terms of decreasing toxicity both in the short and longer term.

A retrospective analysis of survival outcomes for two different radiotherapy fractionation schedules given in the same overall time for limited stage small cell lung cancer.

PURPOSE: To compare survival outcomes for two fractionation schedules of thoracic radiotherapy, both given over 3 weeks, in patients with limited stage small cell lung cancer (LS-SCLC). METHODS AND MATERIALS: At Radiation Oncology Mater Centre (ROMC) and the Royal Brisbane & Women's Hospital (RBWH), patients with LS-SCLC treated with curative intent are given radiotherapy (with concurrent chemotherapy) to a dose of either 40 Gy in 15 fractions ('the 40 Gy/15# group') or 45 Gy in 30 fractions ('the 45 Gy/30# group'). The choice largely depends on institutional preference. Both these schedules are given over 3 weeks, using daily and twice-daily fractionation respectively. The records of all such patients treated from January 2000 to July 2009 were retrospectively reviewed and survival outcomes between the two groups compared. RESULTS: Of 118 eligible patients, there were 38 patients in the 40 Gy/15# group and 41 patients in the 45 Gy/30# group. The median relapse-free survival time was 12 months in both groups. Median overall survival was 21 months (95% CI 2-37 months) in the 40 Gy/15# group and 26 months (95% CI 1-48 months) in the 45 Gy/30# group. The 5-year overall survival rates were 20% and 25%, respectively (P = 0.24). On multivariate analysis, factors influencing overall survival were: whether prophylactic cranial irradiation (PCI) was given (P = 0.01) and whether salvage chemotherapy was given at the time of relapse (P = 0.057). CONCLUSIONS: Given the small sample size, the potential for selection bias and the retrospective nature of our study it is not possible to draw firm conclusions regarding the efficacy of hypofractionated thoracic radiotherapy compared with hyperfractionated accelerated thoracic radiotherapy however hypofractionated radiotherapy may result in equivalent relapse-free survival.

Limited chemotherapy and shrinking field radiotherapy for Osteolymphoma (primary bone lymphoma): results from the trans-Tasman Radiation Oncology Group 99.04 and Australasian Leukaemia and Lymphoma Group LY02 prospective trial.

PURPOSE: To establish benchmark outcomes for combined modality treatment to be used in future prospective studies of osteolymphoma (primary bone lymphoma). METHODS AND MATERIALS: In 1999, the Trans-Tasman Radiation Oncology Group (TROG) invited the Australasian Leukemia and Lymphoma Group (ALLG) to collaborate on a prospective study of limited chemotherapy and radiotherapy for osteolymphoma. The treatment was designed to maintain efficacy but limit the risk of subsequent pathological fractures. Patient assessment included both functional imaging and isotope bone scanning. Treatment included three cycles of CHOP chemotherapy and radiation to a dose of 45 Gy in 25 fractions using a shrinking field technique. RESULTS: The trial closed because of slow accrual after 33 patients had been entered. Accrual was noted to slow down after Rituximab became readily available in Australia. After a median follow-up of 4.3 years, the five-year overall survival and local control rates are estimated at 90% and 72% respectively. Three patients had fractures at presentation that persisted after treatment, one with recurrent lymphoma. CONCLUSIONS: Relatively high rates of survival were achieved but the number of local failures suggests that the dose of radiotherapy should remain higher than it is for other types of lymphoma. Disability after treatment due to pathological fracture was not seen.

Human immunodeficiency virus (HIV) in older people.

The number of older people living with human immunodeficiency virus (HIV) in the UK is rising. Older people are at risk of acquiring HIV infection for a multitude of reasons. This, combined with effective HIV treatment which has significantly prolonged life expectancy, means that health care professionals working in the UK can expect to see increasing numbers of older people with HIV infection. In this review article, we summarise the epidemiology of HIV amongst older people, including data from our local cohort in the city of Sheffield, UK. We discuss specific and practical issues in older patients including why older people are at risk, how to make a diagnosis and the importance of doing so early, guidelines for HIV testing and an update on anti-retroviral therapy including drug interactions and side effects.

Demographics and outcomes at American Society for Metabolic and Bariatric Surgery Centers of Excellence.

INTRODUCTION: Surgery is currently an effective long-term therapy for morbid obesity and its complications. A variety of surgical procedures can now offer durable and safe weight control as well as previously unrealized full remission of costly comorbidities. This is a preliminary investigation of patient characteristics and outcomes at Bariatric Surgery Centers of Excellence) (BSCOE) hospitals. METHODS AND PROCEDURES: Data were analyzed from 235 American Society for Metabolic and Bariatric Surgery (ASMBS) BSCOE hospitals receiving Full Approval status from August 2005 to May 2007. Metrics for the 66,339 bariatric surgeries performed at these hospitals included type, volume and distribution of various bariatric surgical procedures performed at each hospital, patient demographics, payer information, and adverse outcomes. RESULTS: Data from these analyses demonstrate significant differences in terms of surgical procedure selection (laparoscopic gastric bypass 61%), patient demographics (females 83%, White 60%, mean age 43 years) and type of payer (private insurance 78%), and adverse outcomes (readmission 5%, re-operation 2%, mortality 0.36%). CONCLUSIONS: The collective performance of ASMBS BSCOE hospitals in bariatric outcomes of readmissions, re-operations, and mortality are equivalent to, or more favorable, than currently reported outcomes. However, risk assessment and risk adjustment of the patients and each of the bariatric procedures will be necessary to appropriately evaluate these rates.

Use of individual fraction size data from 3756 patients to directly determine the alpha/beta ratio of prostate cancer.

PURPOSE: To examine the effect of fraction size and total dose of radiation on recurrence of localized prostate cancer. METHODS AND MATERIALS: A total of 3756 patients treated with radiation monotherapy at three institutions were analyzed, including 185 high-dose-rate brachytherapy (HDRB) boost patients. The 5th to 95th centiles of external beam radiotherapy (EBRT) fraction sizes and doses were 1.8 to 2.86 Gy, and 57.4 to 77.4 Gy, respectively, and HDRB fractional doses were between 5.5 and 12 Gy, totaling 147 unique fractionation schedules. Failure was defined by one biochemical (nadir + 2 ng/ml) and two advanced disease endpoints. The alpha/beta ratios were estimated via a proportional hazards model stratified by risk severity and institution. RESULTS: The alpha/beta ratio using biochemical recurrence was 3.7 Gy (95% confidence interval [95% CI], 1.1, infinity Gy) for EBRT-only cases and 2.6 Gy (95% CI, 0.9, 4.8 Gy) after the addition of HDRB data. This estimate was highly dependent on an HDRB homogeneity correction factor (120% HDRB dose increase; alpha/beta ratio 4.5 Gy, 95% CI 1.6, 8.7 Gy). A 5-Gy increase in total dose reduced the hazard of failure by 16% (95% CI 11, 21%, p < 0.0001), and had more impact as follow-up matured (p < 0.0003). The clinically advanced endpoints concurred with the biochemical failure results, albeit with less precision. CONCLUSIONS: This study supports the concept that the alpha/beta ratio of prostate cancer is low, although considerable uncertainty remains in the estimated value. Outcome data from EBRT studies using substantially higher doses per fraction are needed to show increased precision in these estimates.

The ASBS Bariatric Surgery Centers of Excellence program: a blueprint for quality improvement.

BACKGROUND: Variations in the techniques of bariatric surgery, coupled with the lack of a common database, has led to variable and, sometimes negative, outcomes from bariatric surgery. Thus, in November 2003, the American Society for Bariatric Surgery established Surgical Review Corporation (SRC) as an independent nonprofit entity for quality control of bariatric surgery and as a resource for data collection and analysis. METHODS: In November 2003, the leadership of the American Society for Bariatric Surgery founded SRC as an independent nonprofit entity for quality control of bariatric surgery and as resource for research. A national set of standards for the Bariatric Surgery Centers of Excellence program was developed using a meta-analysis of the relevant published English language data, a consensus conference at Georgetown University, and participation by stakeholders from industry, third-party payors, and malpractice carriers. A software program was developed to provide uniformity in data collection and ease of analysis. RESULTS: SRC developed standards that have been accepted by the bariatric surgical community and put in place. A system was developed for the designation of two levels for the centers, provisional and full. The growth of the Centers of Excellence program has been rapid. At present, 135 hospitals and 265 surgeons have achieved full approval. The centers for Medicare and Medicaid Services have recognized the program. On the basis of the reports of 55,567 patients from the first 176 applicants for full approval and confirmed by SRC during site inspections, the 90-day operative mortality rate was 0.35%. CONCLUSIONS: The first phase of development has gone well. Future steps include the development of a network of bariatric physicians and the development of a consortium for research.

A multicenter study demonstrating discordant results from electronic prostate-specific antigen biochemical failure calculation systems.

PURPOSE: To evaluate the interobserver variation of four electronic biochemical failure (bF) calculators using three bF definitions. METHODS AND MATERIALS: The data of 1200 men were analyzed using the electronic bF calculators of four institutions. Three bF definitions were examined for their concordance of bF identification across the centers: the American Society for Therapeutic Radiology and Oncology consensus definition (ACD), the lowest prostate-specific antigen (PSA) level to date plus 2 ng/mL (L2), and a threshold of 3 ng/mL (T3). RESULTS: Unanimous agreement regarding bF status using the ACD, L2, and T3 definitions occurred in 87.3%, 96.4%, and 92.7% of cases, respectively. Using the ACD, 63% of the variation was from one institution, which allowed the bF status to be reversed if a PSA decline was seen after bF (PSA "bounce"). A total of 270 men had an ACD bF time variation of >2 months across the calculators, and the 5-year freedom from bF rate was 49.8-60.9%. The L2 definition had a 20.5% rate of calculated bF times; which varied by >2 months (median, 6.4; range, 2.1-75.6) and a corresponding 5-year freedom from bF rate of 55.9-61.0%. The T3 definition had a 2.0% range in the 5-year freedom from bF. Fifteen definition interpretation variations were identified. CONCLUSION: Reported bF results vary not only because of bF definition differences, but because of variations in how those definitions are written into computer-based calculators, with multiple interpretations most prevalent for the ACD. An algorithm to avoid misinterpretations is proposed for the L2 definition. A verification system to guarantee consistent electronic bF results requires development.

An international multicenter study evaluating the impact of an alternative biochemical failure definition on the judgment of prostate cancer risk.

PURPOSE: To evaluate the impact of an alternative biochemical failure (bF) definition on the performance of existing plus de novo prognostic models. METHODS AND MATERIALS: The outcomes data of 1,458 Australian and 703 Canadian men treated with external-beam radiation monotherapy between 1993 and 1997 were analyzed using a lowest prostate-specific antigen (PSA) level to date plus 2 ng/mL (L + 2) bF definition. Two existing prognostic models were scrutinized using discrimination (Somers Dxy [SDxy]) and calibration indices. Alternative prognostic models were also created using recursive partitioning analysis (RPA) and multivariate nomogram methods for comparison. RESULTS: Discrimination of bF was improved using the L + 2 definition compared with the American Society for Therapeutic Radiology and Oncology (ASTRO) definition using both the three-level risk model (SDxy 0.30 and 0.22, respectively) or the nomogram (SDxy 0.35 and 0.27, respectively). Both existing prognostic models showed only modest calibration accuracy. Using RPA, five distinct risk groups were identified based primarily on Gleason score (GS) and all subsequent divisions based on PSA. All GS 7-10 tumors were intermediate or high risk. This model and the developed nomogram showed improved discrimination over the existing models as well as accurate calibration against the Canadian data, apart from the 30-50% failure region. CONCLUSIONS: The L + 2 definition of bF provides improved capacity for discrimination of failure risk. New prognostic models based on this endpoint have overall statistical performance superior to those based on the ASTRO consensus definition but continue to have unreliable discrimination in the intermediate-risk region.

Combined-modality therapy for primary central nervous system lymphoma: long-term data from a Phase II multicenter study (Trans-Tasman Radiation Oncology Group).

PURPOSE: To assess, in a multicenter setting, the long-term outcomes of a brief course of high-dose methotrexate followed by radiotherapy for patients with primary central nervous system lymphoma (PCNSL). METHODS AND MATERIALS: Forty-six patients were entered in a Phase II protocol consisting of methotrexate (1 g/m(2) on Days 1 and 8), followed by whole-brain irradiation (45-50.4 Gy). The median follow-up time was 7 years, with a minimum follow-up of 5 years. RESULTS: The 5-year survival estimate was 37% (+/-14%, 95% confidence interval [CI]), with progression-free survival being 36% (+/-15%, 95% CI), and median survival 36 months. Of the original 46 patients, 10 were alive, all without evidence of disease recurrence. A total of 11 patients have developed neurotoxicity, with the actuarial risk being 30% (+/-18%, 95% CI) at 5 years but continuing to increase. For patients aged>60 years the risk of neurotoxicity at 7 years was 58% (+/-30%, 95% CI). CONCLUSION: Combined-modality therapy, based on high-dose methotrexate, results in improved survival outcomes in PCNSL. The risk of neurotoxicity for patients aged>60 years is unacceptable with this regimen, although survival outcomes for patients aged>60 years were higher than in many other series.

Long-term outcome after radiotherapy alone for lymphocyte-predominant Hodgkin lymphoma: a retrospective multicenter study of the Australasian Radiation Oncology Lymphoma Group.

BACKGROUND: The curative potential of radiotherapy (RT) alone as initial treatment for patients with Stage I-II lymphocyte-predominant Hodgkin lymphoma (LPHL) has not been defined well. METHODS: Two hundred two patients who were treated between 1969 and 1995 were evaluated in a retrospective, multicenter study. RESULTS: Patient characteristics were as follows: The median age was 31 years, 75% of patients were male, 80% of patients had Ann Arbor Stage I disease, 1% of patients had bulky disease, 3% of patients had B symptoms, 1% of patients had extranodal involvement, and 80% of patients had supradiaphragmatic disease. The RT fields were a full mantle field in 52% of patients, less than a full mantle field in 24% of patients, an inverted-Y field in 17% of patients, less than an inverted-Y field in 3% of patients, and total lymph node irradiation in 3% of patients. The median dose was 36 Gray. The median follow-up was 15 years. The overall survival (OS) rate at 15 years was 83%, and freedom from progression (FFP) was observed in 82% of patients, including 84% of patients with Stage I disease and 73% of patients with Stage II disease. No recurrent LPHL and only 1 patient with non-Hodgkin lymphoma (NHL) were reported after 15 years. Adverse prognostic factors that were identified on multifactor analysis were as follows: for OS, age 45 years or older (P < 0.0005), the presence of B symptoms (P = 0.002), increasing number of sites (P = 0.015); for FFP, increasing number of sites (P = 0.002). No significant difference was found in FFP in a comparison of patients who received elective mediastinal RT with patients who did not receive mediastinal RT (P = 0.11). Causes of death at 15 years were LPHL in 3% of patients, NHL in 2% of patients, in-field malignancy in 2% of patients, in-field cardiac/respiratory in 4% of patients, and other in 6% of patients. CONCLUSIONS: The current data suggested that RT potentially may be curative for patients with Stage I-II LPHL and raise the possibility that limited-field RT may be used without loss of treatment efficacy. Involved-field RT warrants further investigation for patients with early-stage LPHL.

Both pretreatment prostate-specific antigen level and posttreatment biochemical failure are independent predictors of overall survival after radiotherapy for prostate cancer.

PURPOSE: To assess the impact of pretreatment prognostic factors plus subsequent biochemical failure on overall survival after radiotherapy for prostate cancer. METHODS AND MATERIALS: We analyzed the prostate-specific antigen (PSA) and survival records of 1571 men with clinically localized prostate cancer treated with external beam radiotherapy monotherapy at the former Queensland Radium Institute between 1990 and 1997. The pretreatment PSA level, biopsy Gleason score, clinical stage, patient age, and the development of biochemical failure were assessed in relationship to overall survival and cause-specific survival, using fixed, as well as time-dependent, statistics. RESULTS: The median follow-up was 88.1 months (95 months for those still alive). The actuarial overall survival, cause-specific survival, and biochemical failure-free survival rate at 10 years was 61.1%, 80.9%, and 25.9% respectively. Cause-specific survival was independently influenced by the pretreatment PSA level, Gleason score, clinical stage, and the development of biochemical failure (relative risk, 19.1). Using the overall survival endpoint, multivariate analysis showed age, pretreatment PSA level, Gleason score, and biochemical failure (relative risk 1.27) to be statistically significant variables. CONCLUSION: In addition to previously identified factors, the pretreatment PSA level and occurrence of biochemical failure after radiotherapy for prostate cancer are associated with an increased overall mortality risk. Both pretreatment PSA level and posttreatment biochemical failure are independent predictors of overall survival after radiotherapy for prostate cancer.