Michael J. Solomon

Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells

Abnormalities in CD4+CD25+Foxp3+ regulatory T (T reg) cells have been implicated in susceptibility to allergic, autoimmune, and immunoinflammatory conditions. However, phenotypic and functional assessment of human T reg cells has been hampered by difficulty in distinguishing between CD25-expressing activated and regulatory T cells. Here, we show that expression of CD127, the α chain of the interleukin-7 receptor, allows an unambiguous flow cytometry–based distinction to be made between CD127lo T reg cells and CD127hi conventional T cells within the CD25+CD45RO+RA− effector/memory and CD45RA+RO− naive compartments in peripheral blood and lymph node. In healthy volunteers, peripheral blood CD25+CD127lo cells comprised 6.35 ± 0.26% of CD4+ T cells, of which 2.05 ± 0.14% expressed the naive subset marker CD45RA. Expression of FoxP3 protein and the CD127lo phenotype were highly correlated within the CD4+CD25+ population. Moreover, both effector/memory and naive CD25+CD127lo cells manifested suppressive activity in vitro, whereas CD25+CD127hi cells did not. Cell surface expression of CD127 therefore allows accurate estimation of T reg cell numbers and isolation of pure populations for in vitro studies and should contribute to our understanding of regulatory abnormalities in immunopathic diseases.

Meta-analysis of short-term outcomes after laparoscopic resection for colorectal cancer.

The safety and efficacy of laparoscopic resection (LR) for colorectal cancer remains to be established.

What are the unmet supportive care needs of people with cancer? A systematic review

Goals of workThe identification and management of unmet supportive care needs is an essential component of health care for people with cancer. Information about the prevalence of unmet need can inform service planning/redesign.Materials and methodsA systematic review of electronic databases was conducted to determine the prevalence of unmet supportive care needs at difference time points of the cancer experience.ResultsOf 94 articles or reports identified, 57 quantified the prevalence of unmet need. Prevalence of unmet need, their trends and predictors were highly variable in all domains at all time points. The most frequently reported unmet needs were those in the activities of daily living domain (1–73%), followed by psychological (12–85%), information (6–93%), psychosocial (1–89%) and physical (7–89%). Needs within the spiritual (14–51%), communication (2–57%) and sexuality (33–63%) domains were least frequently investigated. Unmet needs appear to be highest and most varied during treatment, however a greater number of individuals were likely to express unmet need post-treatment compared to any other time. Tumour-specific unmet needs were difficult to distinguish. Variations in the classification of unmet need, differences in reporting methods and the diverse samples from which patients were drawn inhibit comparisons of studies.ConclusionThe diversity of methods used in studies hinders analysis of patterns and predictors of unmet need among people with cancer and precludes generalisation. Well-designed, context-specific, prospective studies, using validated instruments and standard methods of analysis and reporting, are needed to benefit future interventional research to identify how best to address the unmet supportive care needs of people with cancer.

Randomized Trial of Short-Course Radiotherapy Versus Long-Course Chemoradiation Comparing Rates of Local Recurrence in Patients With T3 Rectal Cancer: Trans-Tasman Radiation Oncology Group Trial 01.04

PURPOSE To compare the local recurrence (LR) rate between short-course (SC) and long-course (LC) neoadjuvant radiotherapy for rectal cancer. PATIENTS AND METHODS Eligible patients had ultrasound- or magnetic resonance imaging-staged T3N0-2M0 rectal adenocarcinoma within 12 cm from anal verge. SC consisted of pelvic radiotherapy 5 × 5 Gy in 1 week, early surgery, and six courses of adjuvant chemotherapy. LC was 50.4 Gy, 1.8 Gy/fraction, in 5.5 weeks, with continuous infusional fluorouracil 225 mg/m(2) per day, surgery in 4 to 6 weeks, and four courses of chemotherapy. RESULTS Three hundred twenty-six patients were randomly assigned; 163 patients to SC and 163 to LC. Median potential follow-up time was 5.9 years (range, 3.0 to 7.8 years). Three-year LR rates (cumulative incidence) were 7.5% for SC and 4.4% for LC (difference, 3.1%; 95% CI, -2.1 to 8.3; P = .24). For distal tumors (< 5 cm), six of 48 SC patients and one of 31 LC patients experienced local recurrence (P = .21). Five-year distant recurrence rates were 27% for SC and 30% for LC (log-rank P = 0.92; hazard ratio [HR] for LC:SC, 1.04; 95% CI, 0.69 to 1.56). Overall survival rates at 5 years were 74% for SC and 70% for LC (log-rank P = 0.62; HR, 1.12; 95% CI, 0.76 to 1.67). Late toxicity rates were not substantially different (Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer G3-4: SC, 5.8%; LC, 8.2%; P = .53). CONCLUSION Three-year LR rates between SC and LC were not statistically significantly different; the CI for the difference is consistent with either no clinically important difference or differences in favor of LC. LC may be more effective in reducing LR for distal tumors. No differences in rates of distant recurrence, relapse-free survival, overall survival, or late toxicity were detected.

Short-term outcomes of the Australasian Randomized Clinical Study comparing laparoscopic and conventional open surgical treatments for colon cancer The ALCCaS Trial

Background:Laparoscopy has revolutionized many abdominal surgical procedures. Laparoscopic colectomy has become increasingly popular. The short- and long-term benefits and satisfactory surgical oncological treatment of colorectal cancer by laparoscopic-assisted resection remain topical. The long-term outcomes of all international randomized controlled trials are still awaited, and short-term outcomes are important in the interim. Methods:Between January 1998 and April 2005, a multicenter, prospective, randomized clinical trial in patients with colon cancer was conducted. Six hundred and one eligible patients were recruited by 33 surgeons from 31 Australian and New Zealand centers. Patients were allocated to colectomy by either laparoscopic-assisted surgery (n = 294) or open surgery (n = 298). Patient demographics and secondary end-points, such as operative and postoperative complications, length of hospital stay, and histopathological data, will be presented in this article. Analysis was by intention-to-treat. Survival will be reported only as the study matures. Results:Histopathological parameters were similar between the two groups, except in regard to distal resection margins. There was no statistically significant difference found in postoperative complications, reoperation rate, or perioperative mortality. Statistically significant differences in quicker return of gastrointestinal function and shorter hospital stay were identified in favor of laparoscopic-assisted resection. A statistically significant increased rate of infective complications was seen in cases converted from laparoscopic-assisted to open procedures but with no difference in reoperation or in-hospital mortality. Conclusions:Laparoscopic-assisted colonic resection gives significant improvements in return of gastrointestinal function and length of stay, with an increased operative time and no difference in the postoperative complication rate.

Effect of Laparoscopic-Assisted Resection vs Open Resection on Pathological Outcomes in Rectal Cancer: The ALaCaRT Randomized Clinical Trial

IMPORTANCE Laparoscopic procedures are generally thought to have better outcomes than open procedures. Because of anatomical constraints, laparoscopic rectal resection may not be better because of limitations in performing an adequate cancer resection. OBJECTIVE To determine whether laparoscopic resection is noninferior to open rectal cancer resection for adequacy of cancer clearance. DESIGN, SETTING, AND PARTICIPANTS Randomized, noninferiority, phase 3 trial (Australasian Laparoscopic Cancer of the Rectum; ALaCaRT) conducted between March 2010 and November 2014. Twenty-six accredited surgeons from 24 sites in Australia and New Zealand randomized 475 patients with T1-T3 rectal adenocarcinoma less than 15 cm from the anal verge. INTERVENTIONS Open laparotomy and rectal resection (n = 237) or laparoscopic rectal resection (n = 238). MAIN OUTCOMES AND MEASURES The primary end point was a composite of oncological factors indicating an adequate surgical resection, with a noninferiority boundary of Δ = -8%. Successful resection was defined as meeting all the following criteria: (1) complete total mesorectal excision, (2) a clear circumferential margin (≥1 mm), and (3) a clear distal resection margin (≥1 mm). Pathologists used standardized reporting and were blinded to the method of surgery. RESULTS A successful resection was achieved in 194 patients (82%) in the laparoscopic surgery group and 208 patients (89%) in the open surgery group (risk difference of -7.0% [95% CI, -12.4% to ∞]; P = .38 for noninferiority). The circumferential resection margin was clear in 222 patients (93%) in the laparoscopic surgery group and in 228 patients (97%) in the open surgery group (risk difference of -3.7% [95% CI, -7.6% to 0.1%]; P = .06), the distal margin was clear in 236 patients (99%) in the laparoscopic surgery group and in 234 patients (99%) in the open surgery group (risk difference of -0.4% [95% CI, -1.8% to 1.0%]; P = .67), and total mesorectal excision was complete in 206 patients (87%) in the laparoscopic surgery group and 216 patients (92%) in the open surgery group (risk difference of -5.4% [95% CI, -10.9% to 0.2%]; P = .06). The conversion rate from laparoscopic to open surgery was 9%. CONCLUSIONS AND RELEVANCE Among patients with T1-T3 rectal tumors, noninferiority of laparoscopic surgery compared with open surgery for successful resection was not established. Although the overall quality of surgery was high, these findings do not provide sufficient evidence for the routine use of laparoscopic surgery. Longer follow-up of recurrence and survival is currently being acquired. TRIAL REGISTRATION anzctr.org Identifier: ACTRN12609000663257.

Randomized, controlled trials in surgery

PURPOSE: Although the randomized, controlled trial has gained preeminence as the criterion standard for evaluating pharmaceutical treatments, randomized controlled trials in surgery have been perceived as difficult to surmount. Furthermore, attitudes of surgeons toward randomized, controlled trials are not well understood. We determined the views of Australian surgeons about feasibility of and barriers to surgical randomized trials. METHODS: All members of the Section of Colon and Rectal Surgery of the Royal Australasian College of Surgeons (n=147) and all Australian colorectal subspecialist surgeons (n=72) were mailed a questionnaire that included questions about surgical randomized, controlled trials. RESULTS: A total of 195 surgeons responded (89 percent). Two‐thirds (66.7 percent; 95 percent confidence interval 59.5‐73.1) of respondents agreed that “Randomized controlled trials should be the study design of choice” to evaluate new surgical procedures. Only 19 percent (95 percent confidence interval 13.9‐25.3) endorsed the statement that “too much emphasis is placed on results of randomized controlled trials.” Barriers to conducting surgical randomized, controlled trials identified by the majority included insufficient funding (74.4 percent; 95 percent confidence interval 67.5‐80.2), a lack of support from the wider surgical community (55.9 percent; 95 percent confidence interval 48.6‐62.9), and difficulties in convincing patients to accept random allocation to treatment (62.6 percent; 95 percent confidence interval 55.3‐69.3). CONCLUSION: These results reveal positive attitudes among Australian surgeons toward randomized, controlled trials, although concerns about the feasibility of randomized, controlled trials have been reinforced.PURPOSE: Although the randomized, controlled trial has gained preeminence as the criterion standard for evaluating pharmaceutical treatments, randomized controlled trials in surgery have been perceived as difficult to surmount. Furthermore, attitudes of surgeons toward randomized, controlled trials are not well understood. We determined the views of Australian surgeons about feasibility of and barriers to surgical randomized trials. METHODS: All members of the Section of Colon and Rectal Surgery of the Royal Australasian College of Surgeons (n=147) and all Australian colorectal subspecialist surgeons (n=72) were mailed a questionnaire that included questions about surgical randomized, controlled trials. RESULTS: A total of 195 surgeons responded (89 percent). Two-thirds (66.7 percent; 95 percent confidence interval 59.5–73.1) of respondents agreed that “Randomized controlled trials should be the study design of choice” to evaluate new surgical procedures. Only 19 percent (95 percent confidence interval 13.9–25.3) endorsed the statement that “too much emphasis is placed on results of randomized controlled trials.” Barriers to conducting surgical randomized, controlled trials identified by the majority included insufficient funding (74.4 percent; 95 percent confidence interval 67.5–80.2), a lack of support from the wider surgical community (55.9 percent; 95 percent confidence interval 48.6–62.9), and difficulties in convincing patients to accept random allocation to treatment (62.6 percent; 95 percent confidence interval 55.3–69.3). CONCLUSION: These results reveal positive attitudes among Australian surgeons toward randomized, controlled trials, although concerns about the feasibility of randomized, controlled trials have been reinforced.

META-ANALYSIS OF NON-RANDOMIZED COMPARATIVE STUDIES OF THE SHORT-TERM OUTCOMES OF LAPAROSCOPIC RESECTION FOR COLORECTAL CANCER

Laparoscopic resection remains to be established as the procedure of first choice for operable colorectal cancer. The aim of the study was to conduct a systematic review of non‐randomized comparative studies of laparoscopic resection for colorectal cancer. Published work in English was searched for relevant articles published by the end of 2003. The MOOSE statement was used to conduct the meta‐analysis. Study quality was assessed by two investigators using the MINORS tool and the analysis was conducted using Comprehensive Meta‐analysis software (Biostat, Englewood, NJ, USA) and Microsoft Excel (Microsoft, Redmond, WA, USA). One thousand two hundred and twenty abstracts were reviewed and 398 articles examined in detail. Out of 108 articles reporting the results of relevant studies, 75 were reports of 64 non‐randomized comparative studies. Fifteen studies were excluded. Analysis of the outcomes of 6438 resections showed that the conversion rate was 13.3% with a statistically significant difference between studies with more than 50 versus those with 50 or less attempted resections (11.7 vs 16.5%; P < 0.001). Laparoscopic resection took 27.6% (41 min) longer to carry out than open resection. There was no significant difference between the two groups in early mortality rates (1.2 vs 1.1%; P = 0.787) or likelihood of re‐operation (2.3 vs 1.5%; P = 0.319). Laparoscopic resection was associated with a lower morbidity rate (24.05 vs 30.80%, odds ratio (95% confidence interval) = 0.77 (0.63–0.95); P = 0.014, n = 4111, random‐effects model). Time until passage of first flatus, passage of a bowel motion, tolerating oral fluids and a solid diet was 1.2–1.6 days (26 to 37%) shorter, measurements of pain and narcotic analgesic requirements were 16–35% lower and hospital stay was 3.5 days (18.8%) shorter following laparoscopic resection compared with open resection. The two approaches were 99% similar in terms of adequacy of oncological clearance. Meta‐analysis of non‐randomized comparative studies favours laparoscopic over open resection for colorectal cancer. The results were remarkably similar to those of a contemporaneous meta‐analysis of randomized controlled trials published by the end of 2002.

Successful overlapping anal sphincter repair: Relationship to patient age, neuropathy, and colostomy formation

BACKGROUND: Fecal incontinence from single anal sphincter defects are surgically remedial and commonly the result of obstetric injuries. Overlapping anal sphincter repair has previously been associated in small series with good results in 69 to 97 percent of patients. OBJECTIVES: The aims of this study were to assess the results of overlapping anal sphincter repair in one institution and to assess the effects of age, presence of a neuropathy, and addition of a temporary colostomy on the success of surgery. METHODS: A study of 57 overlapping anal sphincter repairs in 56 (54 females) patients at the Royal Prince Alfred Hospital during a six-year period was performed. All patients were investigated preoperatively with endoanal ultrasound and concentric needle electromyography. Patients have been assessed prospectively since 1994 with a questionnaire, including a four-point Likert scale of continence level, the St. Marks incontinence scoring system (range, 0–13), the Pescatori incontinence scoring system (range, 0–6), and patient assessment of success or failure of the overlapping anal sphincter repair. A colostomy was selectively formed in conjunction with an overlapping anal sphincter repair in 21 patients (8 preoperatively, 13 simultaneously), and 18 patients had a concomitant neuropathy (3 unilateral, 15 bilateral). RESULTS: After a median follow-up of 18 months, median continence scores overall had improved from St. Marks incontinence scoring 13 to 3 (P<0.0001) and Pescatori incontinence scoring 6 to 2 (P<0.0001). Forty-nine of 57 (86 percent) repairs have been successful, and 8 are considered to be failures. Twenty-one of 27 (78 percent) repairs in patients younger than 40 years of age were successful, as were 28 of 30 (93 percent) repairs in patients older than 40 years of age (P=0.10). Four of 18 (22 percent) repairs associated with a neuropathy failed compared with 4 of 39 (10 percent) without a neuropathy (P=0.21). Improved or normal continence was achieved in 17 of 21 (81 percent) patients with a stoma and overlapping anal sphincter repair and in 32 of 36 (89 percent) patients with an overlapping anal sphincter repair alone (P=0.32). The presence of a stoma did not improve the rate of wound healing by primary intention (62 percent for stomavs. 64 percent for overlapping anal sphincter repair alone;P=0.55). CONCLUSIONS: Single anal sphincter defects can be successfully treated with an overlapping anal sphincter repair. There is no improvement in primary healing with selective stoma formation. Age of the patient and presence of a neuropathy should not detract from proceeding with overlapping anal sphincter repair when singular anal sphincter defects are detected on endoanal ultrasound in muscle that is still active.

What do patients want? Patient preferences and surrogate decision making in the treatment of colorectal cancer

AbstractPURPOSE: Clinicians often make decisions for their patients, despite evidence that suggests that correspondence between patient and clinician decision making is poor. The management of colorectal cancer presents difficult decisions because the impact of treatment on quality of life might overshadow its survival efficacy. This study investigated whether patients are able to trade survival for quality of life as a means to express their preference for treatment options and to compare their preferences with those expressed by clinicians. METHODS: Patients undergoing curative surgery for colorectal cancer were interviewed postoperatively to elicit their preferences in four hypothetical treatment scenarios. A questionnaire was mailed to all Australian colorectal surgeons and medical oncologists that asked them to respond as if they themselves were patients. RESULTS: One hundred patients (91 percent), 43 colorectal surgeons (77 percent), and 103 medical oncologists (50 percent) participated. In all four scenarios, patients were able to trade survival for quality of life. Patients’ responses varied between scenarios, both in willingness to trade and the average amount traded. There were significant differences between patients and clinicians. Clinicians were more willing than patients to trade survival to avoid a permanent colostomy in favor of chemoradiotherapy. Patients’ strongest preference was to avoid chemotherapy, more than to avoid a permanent colostomy. CONCLUSIONS: Patients are able to trade survival as a measure of preference for quality of life and can do so differentially between treatment scenarios. Patients’ preferences do not always accord with those of clinicians. Unless patients’ preferences are explicitly sought and incorporated into clinical decision making, patients may not receive the treatment that is best for them.