Recurrent malignant melanoma: effect of adjuvant immunotherapy on survival.

Twenty-nine patients referred consecutively to a cancer clinic because of recurrent metastatic malignant melanoma were given 5 mg of Connaught Laboratories bacillus Calmette-Guérin (BCG) by multiple cutaneous puncture at weekly and later at monthly intervals. Eight were also treated with autologous tumour vaccine and three with intralesional BCG. This group was compared with a retrospective control group of 54 patients treated with surgery and radiotherapy alone after recurrence. Prognostic features such as site of primary and of first metastasis, disease-free interval, age and sex were similar in the two groups. However, the median survival from the time of first recurrence was 12 months in the control group but 21 months in the BCG-treated group. The major improvement was in patients with disease limited to the regional lymph nodes: the median survival was 16 months in the control group but over 32 months in the BCG-treated group. Autologous tumour vaccine appeared to have no effect on survival. Serial testing of immunocompetence did not offer any prognostic advantage, although the results of some tests correleated well with extent of disease.     

A controlled trial of BCG immunotherapy in bronchogenic carcinoma treated by surgical resection

Summary Ninety-two patients with bronchogenic carcinoma who were treated by surgical resection of the tumour were subsequently given immunotherapy with BCG (Glaxo). The study was strictly randomised into three groups. Twenty-nine patients received multipuncture BCG (50–250×10⁶ viable units) and 26 patients intradermal BCG (0.4–0.9×10⁶ viable units) treatment being given at 1, 2, 5, 9, 13 and 26 weeks after operation and every 26 weeks thereafter. Thirty-seven control patients did not receive BCG. The patients have been observed for 15–33 months. There was no significant difference in survival between the control group and the two immunotherapy groups or between the two immunotherapy groups. The tumour cell type and presence of mediastinal nodes significantly influenced overall survival but not the response to BCG immunotherapy. The possible reasons for the failure of BCG to prolong survival in this study are discussed.     

Adjuvant BCG immunotherapy for malignant melanoma.

A total of 199 patients with stage I malignant melanoma at Clark''s level 3 to 5 of invasion were entered into a prospectively controlled randomized clinical trial that attempted to assess the value of local and systemic immunotherapy with BCG (bacille Calmette-Guérin) after surgery. The patients were randomly assigned, with stratification by Clark''s level, to receive either routine follow-up or immunotherapy with BCG, administered intradermally with a Heaf gun around the site of wide excision and then given orally for 2 years. Intradermal administration of BCG was repeated after 1 year''s oral therapy with BCG. Of the 99 patients in the treatment group 66 had Clark''s level 3, 28 had level 4, and 5 had level 5 invasion. Of the 100 patients in the control group, 61 had level 3, 36 had level 4, and 3 had level 5 invasion. Other prognostic factors, such as sex, depth of invasion, histologic features, site of disease and type of surgery, were evenly distributed. There were 57 recurrences of the melanoma, 24 in the treatment group and 33 in the control group. However, this trend was not statistically significant (p = 0.194). The suggestion that BCG may reduce the likelihood of local/regional recurrence has not been confirmed with longer follow-up. There were 13 such recurrences in the BCG group, compared with 21 in the control group; the proportions of patients in each group who had such a recurrence were not significantly different. Of the 199 patients 41 died, 24 in the control group and 17 in the treatment group; again, this difference was not significant. While there may be minor activity in selected patients, there appeared to be no benefit from this form of adjuvant BCG therapy in patients with malignant melanoma.     

Various uses of BCG and allogeneic acute leukemia cells to treat patients with acute myelogenous leukemia

Summary Ninety-six remission patients with acute myelogenous leukemia have been treated with various forms of immunotherapy and chemotherapy in three distinct studies and the clinical outcome of these patients has been reported. In the first study 22 patients were maintained on chemotherapy alone and 28 patients were given the same chemotherapy and additional immunotherapy consisting of BCG and irradiated allogeneic AML cells given at separate sites weekly. It was found that there was a significant increase in survival time of the patients who received immunotherapy (median 510 days) compared with the chemotherapy alone patients (270 days). The p value for this was 0.03. The reason for this prolongation of survival was mainly due to a markedly increased survival time of immunotherapy patients after they relapsed when compared with the chemotherapy patients (165 days compared with 75 days median, p equal to 0.0005). In the second sequential study 24 patients were given immunotherapy alone consisting of irradiated allogeneic AML cells and BCG given at separate sites, and this was compared with unirradiated allogeneic cells and BCG given to 22 patients. There was no difference in the remission length or survival between these two groups. In the third study 13 patients received irradiated cells and BCG as in Study 1 and a further 11 patients received the same immunotherapy but also received a mixture of cells and BCG given during the first three months. There was no difference in the remission and survival of these two groups. The significance of these results is discussed.     

Randomised controlled trial of health promotion in general practice for patients at high cardiovascular risk.

OBJECTIVE--To assess the value of health education for patients with angina in reducing risk factors for cardiovascular disease and lessening the effect of angina on everyday activities. DESIGN--Randomised controlled trial of personal health education given every four months. SETTING--18 general practices in the greater Belfast area. SUBJECTS--688 patients aged less than 75 years and known to have had angina for at least six months; 342 randomised to receive education and 346 to no education. MAIN OUTCOME MEASURES--Restriction of everyday activities, dietary habit, smoking habit, frequency of physical exercise; blood pressure, body mass index, and serum total cholesterol concentration at entry to trial and after two years. RESULTS--317 in the intervention group and 300 in the control group completed the trial. At the two year review more of the intervention group (140, 44%) reported taking daily physical exercise than the control group (70, 24%). The intervention group also reported eating a healthier diet than the control group and less restriction by angina in any everyday activity. No significant differences were found between the groups in smoking habit, systolic or diastolic blood pressure, cholesterol concentration, or body mass index. CONCLUSION--Despite having no significant effect on objective cardiovascular risk factors, personal health education of patients with angina seems to increase exercise and improve dietary habits and is effective in lessening the restriction of everyday activities.     

Chemoimmunotherapy of advanced breast cancer: prolongation of remission and survival with BCG.

Forty-five patients with disseminated breast cancer were given a trial of combination chemotherapy consisting of fluorouracil, adriamycin, and cyclophosphamide (FAC) and immunotherapy with BCG given by scarification. The results were compared with those in a comparable group of 44 patients treated with FAC alone immediately before the chemoimmunotherapy study. The remission rates (73% and 76% for FAC and FAC-BCG respectively) were similar in both studies. The durations of remission for patients on FAC-BCG (medium 12 months) were longer than remissions achieved for patients given FAC alone (median 8 months) (P = 0.068). The most notable effect of BCG was on survival. Thus 21 out of 34 patients achieving remission on FAC-BCG were alive at the time of the last follow-up examination (median over 22 months) compared with 11 out of 32 patients achieving remission on FAC (median 15 months) (P = 0.01). Twenty-six of the 45 patients given FAC-BCG were alive at the time of the last follow-up examination (median over 22 months) compared with 12 of the 44 patients given FAC (median 15 months) (P = 0.005). Although the apparent benefit of BCG could be explained by a maldistribution of some prognostic factors, the data suggest that further trial of chemoimmunotherapy of breast cancer should be carried out.     

Adjuvant BCG immunotherapy for stage I and II malignant melanoma.

Initial adjuvant immunotherapy trials have demonstrated a greater disease-free interval in patients treated with bacille Calmette-Guérin (BCG) compared with historical controls. In this study 149 patients at high risk of recurrence after surgical treatment of local or regional malignant melanoma were given BCG for 2 years and were followed up for a median of 28 months from the start of immunotherapy. The 36 patients in the comparison group had a higher rate of recurrence than the patients treated with BCG, and the rate in the treatment group was close to that reported from a similar study at the University of California at Los Angeles. The relatively long disease-free interval for the high-risk comparison patients in this study suggests that the control groups at other centres may have included patients with unrecognized additional risk. The rates of survival in the Canadian treatment group were also comparable to those reported by other centres. However, reports of a favourable BCG-mediated pattern of recurrence could not be confirmed. Therefore, the routine use of adjuvant BCG immunotherapy is not recommended.     

Bacille Calmette-Guérin as maintenance therapy for non-Hodgkin's lymphoma.

Following complete remission of non-Hodgkin''s lymphoma by chemotherapy, irradiation or both, 44 patients were studied to assess the value of bacille Calmette-Guérin (BCG) as maintenance therapy. Patients with stage LI, EI or EII disease were allocated at random to receive BCG or no further maintenance therapy, and those with stage LII, LIII, EIII or IV disease received BCG therapy or orally administered cyclophosphamide. BCG had no effect on the duration of remission or the overall survival from the time of randomization. However, after the first recurrence there was a significant improvement in survival in the patients who had received BCG maintenance therapy.     

Trial of BCG immunotherapy in the treatment of resectable squamous cell carcinoma of the bronchus (stages I and II)

Summary Thirty-nine patients with squamous cell carcinoma of the bronchus were randomized into two groups after radical surgery. The first group of 18 patients received 75 mg of living BCG on a scratched area once a week; the second group of 21 patients received no further treatment. After 2 years 3 patients of the group treated with BCG are dead and 1 is in relapse; 8 patients of the control group are dead and 2 are in relapse.In this study the hope of survival for more than 2 years for patients with squamous cell carcinoma of the bronchus is 66% in the group of patients treated with BCG, and 38% in the control group. From these results we can see the beneficial effect of BCG as a complementary treatment of surgery for patients with squamous cell carcinoma of the bronchus.     

凝结芽胞杆菌(TBC169)片治疗便秘的实验研究和临床疗效

目的观察凝结芽胞杆菌片（BC1）对便秘的药理作用和I临床疗效。方法昆明种雄性小鼠随机分为6组（每组10只）。BC1片（3个剂量）和BCz片治疗组小鼠口服BC。片和BC2片,空白对照组小鼠和模型对照组小鼠口服自来水,每天1次,共7d。之后,两治疗组和模型对照组小鼠在禁食12h后．均口服复方地芬诺酯（CDX）片,引发便秘。成人慢性便秘38例患者随机分为治疗组（20例）和对照组（18例）,分别口服BC1片和金双歧片（BG）,每天3次,共14～21d。结果BC1片能明显地减少便秘小鼠的首次排便时间（P〈0．05）和显著地增加大便粒数及重量（P〈0．05）。在临床试验中,治疗成人慢性便秘,BC1片的治愈率为45％,总有效率为70％,而相对的BG片分别为44％和72％,两药均未见不良反应或副作用。结论BC1片对小鼠实验性便秘和成人慢性便秘均有明显的治疗作用,在临床试验中未见不良反应或副作用。     

诺维本联合希罗达方案与紫杉醇、顺铂方案治疗晚期乳腺癌的疗效对比

目的:比较诺维本联合希罗达方案(NF方案)和紫杉醇联合顺铂方案(TP方案)治疗晚期乳腺癌的疗效及安全性。方法:将117例经病理证实的晚期乳腺癌患者随机分为两组,第一组66例采用紫杉醇135mg/m~2,第1天静点,顺铂20mg,第2-6天静点,21天为一个周期。第二组51例采用诺维本25mg/m~2,第1,8天静点,希罗达2500mg/m~2,每天2次,连服14天,21天为一个周期。两组均以三个周期为一个疗程,至少接受两个疗程化疗。结果:TP组总有效率为42-4%(28/66);NF组为60.8%(31/51),p<0.05。TP组中位无进展时间7.7个月,中位生存时间为16.6个月。NF组分别为10.3个月和22.1个月,p<0.05。恶心呕吐的发生率NF组明显低于TP组,p<0.05。其余不良反应发生率相近,p>0.05。所有不良反应均能耐受。结论:诺维本联合希罗迭方案疗效较好,可作为晚期乳腺癌首选治疗方案。     

Long-term treatment with recombinant interferon alpha-2b prolongs survival of asymptomatic HIV-infected individuals

Rationale and objective: Early long-term treatment with recombinant interferon (IFN) alpha-2b delayed disease progression in asymptomatic Human Immunodeficiency Virus (HIV) carriers in a randomized trial that lasted from October 1987 to February 1992 (14). The aim of the work reported in this paper was to observe if there was also an effect on survival when the same patients were followed-up further. Design and interventions: IFN alpha-2b was given 3 × 10⁶ IU, 3 times weekly. The control group did not receive any treatment. The main end-point for this evaluation was death due to any cause. The deadline was August 1995. Population: Subjects were anti-HIV-1 seropositive, Western blot-confirmed, asymptomatic (CDC group II), or with generalized lymphadenopathies (CDC group III). The groups had 79 (control) and 83 (IFN) patients. Main results: Mean survival was longer in the IFN group (95% CI: 127–152 vs. 101–120 months since infection or 80–90 vs. 70–82 months since the start of treatment). Survival rates were higher in IFN-treated individuals (61–77% vs. 24–54% at 10 years of infection or 53–69% vs. 34–52% at 7 years of treatment or follow-up). It was also confirmed that disease progression is significantly slower in IFN-treated patients. There were 23.4 vs. 3.2% long-term survivors in the IFN and control groups, respectively (p=0.005). IFN-treated patients had fewer AIDS-related malignancies (5 vs. 11), mainly Kaposi’s sarcomas (1 vs. 5). This difference was not statistically significant, but clinically interesting. There was no difference in survival if measured since the onset of AIDS. Conclusion: IFN alpha treatment given from the early stages of infection, but not after the appearance of AIDS symptoms, can prolong survival.     

妈咪爱联合利巴韦林、思密达治疗婴幼儿轮状病毒肠炎的观察

目的观察妈咪爱联合利巴韦林、思密达治疗婴幼儿轮状病毒性肠炎的疗效。方法将轮状病毒性肠炎患儿58例按就诊先后顺序随机分为对照组29例,用利巴韦林、思密达治疗。治疗组29例,在对照组治疗的基础上加用妈咪爱治疗;利巴韦林用法：10mg/（kg·d）,分3次口服;思密达用法：1岁以下,1g/次,1岁以上,1．5g/次,3次／d;妈咪爱用法：1岁以下,0．5g／次,1岁以上,1g,／次,2次／d。结果治疗组的治愈率和总有效率分别为75．86％和96．55％,对照组的治愈率和总有效率分别为48．28％和75．86％,组间比较,其差异有显著性（P〈0．05）。结论妈咪爱联合利巴韦林、思密达治疗婴幼儿轮状病毒性肠炎疗效显著。     

多柔比星脂质体单药和联合洛铂方案治疗复发卵巢癌的临床研究

目的:评价盐酸多柔比星脂质体单药(PLD)与盐酸多柔比星脂质体联合洛铂治疗复发性卵巢癌的安全性和临床疗效。方法:收集2012年4月至2015年10月我科收治的31例复发晚期上皮性卵巢癌患者,根据患者是否存在铂类耐药分为多柔比星组(单药组)15例及多柔比星+洛铂组(对照组)16例。单药组给盐酸多柔比星脂质体50 mg/m~2,静滴;对照组给盐酸多柔比星脂质体20-30 mg/m~2,洛铂30-50 mg/m~2,静脉滴注,两组每21-28天重复一次,观察和比较两组的临床疗效和毒性反应的发生情况。结果:所有患者完成3-8周期,客观有效率(ORR)为38.7%。单药组为33.3%,对照组为占43.8%,两组ORR比较差异无统计学意义(P=0.411)。单药组骨髓抑制的毒副作用较对照组发生率显著升高高(P=0.019),两组其他毒副反应的发生情况比较差异无统计学意义(P0.05)。单药组和对照组中位生存时间(MST)分别为10个月(95%CI:1.242-18.758)、18个月(95%CI:8.261-27.739),中位无进展生存期(PFS)分别为7个月(95%CI:2.210-13.797)、13个月(95%CI:4.368-21.632),两组MST、PFS比较差异均无统计学意义(P0.277)。结论:聚乙二醇脂质体阿霉素单体或聚乙二醇脂质体阿霉素联合洛铂治疗复发性卵巢癌的疗效相当,而聚乙二醇脂质体阿霉素单体的安全性更高。     

Nonspecific and selective stimulation of the immune system in the treatment of carcinoma in humans.

The experience of the Toronto General Hospital in the use of nonspecific stimulation of the immune system with bacille Calmette-Guérin (BCG) for the treatment of cancer of the gastrointestinal tract, malignant melanoma and breast cancer is described. The results are presented in terms of survival curves. The use of BCG administered intraperitoneally in a randomized study of patients with gastric, pancreatic and colorectal cancer proved of no benefit. On the other hand, when BCG was given orally in a randomized study of patients with resectable cancer of the colon and in nonrandomized consecutive studies of patients with malignant melanoma and stage IV carcinoma of the breast survival was increased. In a group of patients with advanced gastrointestinal cancer selective stimulation of the immune system with NED 137 produced a significant increase in survival when compared with the survival of historical controls (the patients given BCG intraperitoneally along with 5-fluorouracil for gastrointestinal cancer). The results of these studies suggest the need for a more rational approach in manipulating the immune response that would combine chemotherapy with selective stimulation of the immune system.     

Immunotherapy of breast cancer,malignant melanoma,and acute leukemia with BCG: Prolongation of disease free interval and survival

Summary Results of immunotherapy with BCG in patients with malignant melanoma, breast cancer, and acute leukemia are described. The first study demonstrated that high doses of living BCG organisms (6×10⁸ viable units) delivered by scarification in the upper arms and legs prolonged the disease-free interval and survival of 52 malignant melanoma patients with regional lymph node metastases compared to 218 comparable surgical control patients. Patients with trunk and extremity, but not head and neck melanoma, benefited from BCG, suggesting the importance of the delivery of BCG into the tumor-involved lymphatics.The second study evaluated the therapeutic efficacy of living BCG organisms by scarification in a group of adult acute leukemia patients after the cessation of chemotherapy. Thirty-seven patients had been in remission on intermittent chemotherapy for 12–24 months. Following late intensive consolidation chemotherapy, 7 consecutive patients received no further therapy and then 30 consecutive patients received BCG. Patients maintained on BCG have had a prolonged disease-free interval compared to those given on no further therapy (P=0.07) or compared to a group of similar patients maintained on chemotherapy alone (P=0.001). Similarly, the survival has been improved for patients maintained on BCG compared to those left unmaintained (P=0.009), or those maintained on chemotherapy (P=0.001).The principles of intermittent chemotherapy combined with BCG immunotherapy, first developed in patients with disseminated melanoma and acute myelogenous leukemia, have been confirmed in a series of patients with disseminated breast cancer. Forty-five patients treated with a combination of 5-FU, adriamycin, and cyclophosphamide (FAC) plus BCG by scarification showed prolongation of remission as well as survival compared to a comparable group of 44 patients treated with FAC chemotherapy without immunotherapy. Thus, 23/44 patients treated with FAC have died (median=14 months) compared to only 5/45 patients on FAC-BCG (median=12⁺ months), P=0.005. The limitations of BCG immunotherapy as well as speculations for future developments of immunotherapy are discussed.This work was supported by Contract No1-CB 33888 from the National Institutes of Health, Public Health Service, Bethesda, Maryland 20014. Drs. Gutterman and Mavligit are the recipients of Career Development Awards (Ca 71007-02 and CA 00130-01, respectively) from the National Institutes of Health, Education, and Welfare, Bethesda, Maryland 20014.     

双歧杆菌三联活菌胶囊联合莫沙比利治疗慢性功能性便秘的疗效比较

目的探讨双歧杆菌三联活菌胶囊联合莫沙比利治疗慢性功能性便秘的疗效比较。方法选取慢性功能性便秘患者72例,采用随机数字表将患者随机分为观察组（n=36例）和对照组（n=36例）。两组患者均予以多饮水、调整饮食结构与纠正不良的饮食习惯。观察组患者予以双歧杆菌三联活菌胶囊（420mg/次,3次/d,温水口服）联合莫沙比利（5 mg/次,3次/d,餐前30 min口服）治疗,对照组患者予以单纯莫沙比利治疗,剂量与方法同观察组,两组均连用6周。观察并记录两组患者治疗后的临床效果和药物不良反应,并比较治疗后6个月和1年内的复发情况。结果治疗6周后,观察组临床总有效率为94.44%,明显高于对照组的77.78%（χ2=4.18,P〈0.05）。治疗中观察组出现不良反应3例（8.33%）,对照组出现5例（13.89%）,症状均较轻,未发生严重的不良反应,两组不良反应发生率比较差异无统计学意义（χ2=0.40,P〈0.05）。治疗后随访观察6个月和1年,观察组分别复发4例（11.11%）和9例（25.00%）,对照组分别复发11例（30.56%）和18例（50.00%）,观察组的复发率明显低于对照组（χ2=4.13和4.80,P〈0.05）。结论双歧杆菌三联活菌胶囊联合莫沙比利治疗慢性功能性便秘的效果确切,可迅速改善患者临床症状,安全性较好,并可降低其复发率,具有预防病情复发作用。     

Immunologic function during adjuvant BCG immunotherapy for malignant melanoma: Induction of anergy

Summary Serial tests of immunological function were performed on 28 patients participating in a randomized controlled clinical trial of adjuvant Tice-stain BCG immunotherapy administered by tine technique for malignant melanoma. Cryopreserved lymphocyte samples obtained prior to study entry and at 3 and 6 months there-after were tested by mixed lymphocyte culture (MLC), cell-mediated lympholysis (CML), antibody-dependent cell-mediated cytotoxicity (K cell), and natural killing (NK cell) assays, the last two assays being performed with the Chang cell line. Delayed-type hypersensitivity (DTH) skin tests to recall antigens were performed at the same intervals.At entry to the study in vitro lymphocyte reactivity of patients was similar to that of normal controls, and most (75%) of the patients reacted to at least one recall antigen. Serial lymphocyte reactivity measured by the in vitro tests was not different in the BCG and control groups, but BCG treatment was associated with a marked, statistically significant (P<0.01) reduction in DTH skin test reactivity. BCG therapy was not shown to delay recurrence of the disease.     

腹腔镜解剖性肝切除治疗肝细胞癌的临床观察

目的:探讨腹腔镜解剖性肝切除治疗肝细胞癌的临床效果及安全性。方法:选择2011年2月~2013年8月在我院进行诊治的肝细胞癌患者90例,将其随机分为治疗组与对照组,每组各45例。治疗组采用腹腔镜解剖性肝切除治疗,对照组采用开腹解剖性肝切除,两组术后都常规化疗3个月,观察和比较两组术中出血量、术后肛门排气时间和术后住院时间,并发症的发生情况及术前后血清谷氨酸转移酶(ALT)与天冬氨酸转移酶(AST)的水平。结果:与对照组相比,治疗组的术中出血量、术后肛门排气时间和术后住院时间均明显降低或缩短(P0.05),术后3个月的膈下积液、切口感染、肺部感染、胆漏的发生率明显降低(P0.05)。两组术前血清ALT与AST值对比差异无统计学意义(P0.05);术后1周,两组的ALT与AST值都明显升上(P0.05);术后3个月,治疗组的ALT与AST值明显低于对照组(P0.05)。所有患者随访到2015年8月,治疗组的中位生存期为(18.33±3.11)个月,而对照组为(12.46±2.19)个月,较治疗组明显缩短(P0.05)。结论:腹腔镜解剖性肝切除治疗肝细胞癌具有更好的微创性,能减少近期并发症的发生,促进肝功能的恢复,且能够延长患者的生存时间。     

Immunotherapy for remission maintenance in acute myeloblastic leukemia

Summary Forty-eight patients with acute myeloblastic leukemia in remission were treated with immunotherapy in addition to remission-maintenance chemotherapy. The first 16 patients were treated with weekly BCG and a leukemia cell vaccine (group 1). The next 32 patients were randomly allocated to receive BCG and a leukemia cell vaccine given once monthly (group 2) or BCG given monthly with no leukemia cell vaccine (group 3). There was no significant difference in remission duration or survival between the randomly allocated groups (2 and 3).Comparisons with group 1 are limited by the non-random allocation to this group, but selection bias was unlikely and clinical features were similar in the three patient groups. No significant difference in remission duration or survival was seen amongst the three groups studied. There was no advantage in the addition of leukemia cell vaccine (groups 1 and 2) to BCG alone (group 3) and no advantage to weekly (group 1) versus monthly immunotherapy (groups 2 and 3). Only 7 of the 48 patients achieved a second remission, and 4 of these were short-term partial remissions.The following are contributing members of the Toronto Leukemia Study Group: Doctor's Hospital, Harvey Silver MD; Humber Memorial Hospital, Alan Seidenfeld MD; Mississauga Hospital, Michael King MD; Mount Sinai Hospital, Dominic Amato MD; Northwestern Hospital, Wilhelm Kwant MD; Oshawa General Hospital, Hak Chiu MD; St Michael's Hospital, Bernadette Garvey MD, Kenneth Butler MD; St Joseph's Hospital, H. James Watt MD, Murray Davidson MD; Toronto General Hospital, Gerald Scott MD, William Francombe MD, Kenneth Shumak MD; John Crookston MD, PhD; Toronto Western Hospital, James G. Watt MD, David Sutton MD; Michael Baker MD; Domenic Pantalony MD; Wellesley Hospital, Dale Dotten MD; Women's College Hospital, George Kutas MD; York Finch Hospital, Sam Berger MD