2D versus 3D laparoscopic total mesorectal excision: a developmental multicentre randomised controlled trial.

AIMS: The role of laparoscopy in rectal cancer has been questioned. 3D laparoscopic systems are suggested to aid optimal surgical performance but have not been evaluated in advanced procedures. We hypothesised that stereoscopic imaging could improve the performance of laparoscopic total mesorectal excision (TME). METHODS: A multicentre developmental randomised controlled trial comparing 2D and 3D laparoscopic TME was performed (ISRCTN59485808). Trial surgeons were colorectal consultants that had completed their TME proficiency curve and underwent stereoscopic visual testing. Patients requiring elective laparoscopic TME with curative intent were centrally randomised (1:1) to 2D or 3D using Karl Storz IMAGE1 S D3-Link™ and 10-mm TIPCAM®1S 3D passive polarising laparoscopic systems. Outcomes were enacted adverse events as assessed by the observational clinical human reliability analysis technique, intraoperative data, 30-day patient outcomes, histopathological specimen assessment and surgeon cognitive load. RESULTS: 88 patients were included. There were no differences in patient or tumour demographics, surgeon stereopsis, case difficulty, cognitive load, operative time, blood loss or conversion between the trial arms. 1377 intraoperative adverse events were identified (median 18 per case, IQR 14-21, range 2-49) with no differences seen between the 2D and 3D arms (18 (95% CI 17-21) vs. 17 (95% CI 16-19), p = 0.437). 3D laparoscopy had non-significantly higher mesorectal fascial plane resections (94 vs. 77%, p = 0.059; OR 0.23 (95% CI 0.05-1.16)) but equal lymph node yield and circumferential margin distance and involvement. 30-day morbidity, anastomotic leak, re-operation, length of stay and readmission rates were equal between the 2D and 3D arms. CONCLUSION: Feasibility of performing multicentre 3D laparoscopic multicentre trials of specialist performed complex procedures is shown. 3D imaging did not alter the number of intraoperative adverse events; however, a potential improvement in mesorectal specimen quality was observed and should form the focus of future 3D laparoscopic TME trials.

EAES classification of intraoperative adverse events in laparoscopic surgery.

BACKGROUND: Surgical outcomes are traditionally evaluated by post-operative data such as histopathology and morbidity. Although these outcomes are reported using accepted systems, their ability to influence operative performance is limited by their retrospective application. Interest in direct measurement of intraoperative events is growing but no available systems applicable to routine practice exist. We aimed to develop a structured, practical method to report intraoperative adverse events enacted during minimal access surgical procedures. METHODS: A structured mixed methodology approach was adopted. Current intraoperative adverse event reporting practices and desirable system characteristics were sought through a survey of the EAES executive. The observational clinical human reliability analysis method was applied to a series of laparoscopic total mesorectal excision (TME) case videos to identify intraoperative adverse events. In keeping with survey results, observed events were further categorised into non-consequential and consequential, which were further subdivided into four levels based upon the principle of therapy required to correct the event. A second survey phase explored usability, acceptability, face and content validity of the novel classification. RESULTS: 217 h of TME surgery were analysed to develop and continually refine the five-point hierarchical structure. 34 EAES expert surgeons (69%) responded. The lack of an accepted system was the main barrier to routine reporting. Simplicity, reproducibility and clinical utility were identified as essential requirements. The observed distribution of intraoperative adverse events was 60.1% grade I (non-consequential), 37.1% grade II (minor corrective action), 2.4% grade III (major correction or change in post-operative care) and 0.1% grade IV (life threatening). 84% agreed with the proposed classification (Likert scale 4.04) and 92% felt it was applicable to their practice and incorporated all desirable characteristics. CONCLUSION: A clinically applicable intraoperative adverse event classification, which is acceptable to expert surgeons, is reported and complements the objective assessment of minimal access surgical performance.

Application of objective clinical human reliability analysis (OCHRA) in assessment of technical performance in laparoscopic rectal cancer surgery.

BACKGROUND: Laparoscopic rectal resection is technically challenging, with outcomes dependent upon technical performance. No robust objective assessment tool exists for laparoscopic rectal resection surgery. This study aimed to investigate the application of the objective clinical human reliability analysis (OCHRA) technique for assessing technical performance of laparoscopic rectal surgery and explore the validity and reliability of this technique. METHODS: Laparoscopic rectal cancer resection operations were described in the format of a hierarchical task analysis. Potential technical errors were defined. The OCHRA technique was used to identify technical errors enacted in videos of twenty consecutive laparoscopic rectal cancer resection operations from a single site. The procedural task, spatial location, and circumstances of all identified errors were logged. Clinical validity was assessed through correlation with clinical outcomes; reliability was assessed by test-retest. RESULTS: A total of 335 execution errors identified, with a median 15 per operation. More errors were observed during pelvic tasks compared with abdominal tasks (p < 0.001). Within the pelvis, more errors were observed during dissection on the right side than the left (p = 0.03). Test-retest confirmed reliability (r = 0.97, p < 0.001). A significant correlation was observed between error frequency and mesorectal specimen quality (r s = 0.52, p = 0.02) and with blood loss (r s = 0.609, p = 0.004). CONCLUSIONS: OCHRA offers a valid and reliable method for evaluating technical performance of laparoscopic rectal surgery.

The selective use of splenic flexure mobilization is safe in both laparoscopic and open anterior resections.

AIM: Splenic flexure mobilization (SFM) is standard practice in anterior resections. No previous studies have compared outcomes with and without SFM in laparoscopic and open colorectal cancer surgery. This study aimed to determine whether routine or selective SFM should be advised. METHOD: Data were collected prospectively on all elective anterior resections for cancer in our unit between October 2006 and November 2009. RESULTS: Of 263 resections, SFM data were recorded in 216; 138 were laparoscopic (32% with SFM, 3.6% converted) and 78 open (68% with SFM). Eighty-eight were low anterior resections (LARs) for mid-low rectal cancers, with 54 laparoscopic (50% with SFM) and 34 open (91% with SFM). Comparing laparoscopic with SFM to without, differences were found in the proportion of LARs (61%vs 29%, P<0.001), defunctioning ileostomy rates (75%vs 46%, P=0.001) and operative time (median 255 vs 185 min, P<0.001), with no differences in age, gender, body mass index, American Society of Anesthesiology score, preoperative treatment, length of stay, lymph node yield, conversion rate, mortality, anastomotic leakage, reoperation, readmission and R0 resection. No differences in outcomes were seen between laparoscopic LARs with and without SFM or between open resections with and without SFM. CONCLUSION: Our results show no disadvantage in short-term clinical or oncological outcomes when SFM was avoided. Laparoscopic anterior resections with SFM take longer. A selective approach to SFM is safe during anterior resection (open or laparoscopic), including mid-low rectal cancers.

Relationship of acute gastrointestinal toxicity and the volume of irradiated small bowel in patients receiving combined modality therapy for rectal cancer.

PURPOSE: To determine the relationship between acute gastrointestinal (GI) toxicity during the combined modality segment and the volume of small bowel in the pelvic radiation field in patients who receive either preoperative or postoperative therapy for rectal cancer. PATIENTS AND METHODS: The patient population was derived from four consecutive phase I dose-escalation trials. Combined modality therapy included fluorouracil (5-FU), leucovorin ([LV] bolus daily x 5, days 1 and 29), and pelvic radiation. RESULTS: Twenty patients who received postoperative therapy had a larger volume of small bowel in the pelvic radiation field as compared with 60 who received preoperative therapy (462 +/- 129 v 212 +/- 44 cm3, P = .002). The most significant relationship between acute GI toxicity and volume of small bowel was seen in 12 patients who were treated on the preoperative sequential low-dose LV trial, all of whom received the maximum-tolerated dose (MTD) of 5-FU. The volume of small bowel in patients who experienced grade 3+ toxicity was 731 +/- 274 cm3, as compared with 145 +/- 58 in those who experienced grade 0 to 2 toxicity (P = .005). Likewise, logistic regression analysis showed that 26 patients who received the MTD of 5-FU had the most significant association between GI toxicity and volume of small bowel (P = .036). CONCLUSION: Our data suggest that the volume of small bowel in the pelvic radiation field may be dose-limiting in the delivery of high-dose 5-FU when combined with LV and radiation therapy.

Irinotecan is an active agent in untreated patients with metastatic colorectal cancer.

PURPOSE: To determine the response rate, survival, and toxicity of the new anticancer agent, irinotecan (CPT-11), in the treatment of metastatic colorectal cancer. PATIENTS AND METHODS: Forty-one chemotherapy-naive patients with measurable metastatic colorectal cancer were treated with a 90-minute infusion of irinotecan 125 mg/m2 administered weekly for 4 weeks every 6 weeks. Pretreatment tumor biopsies to assess topoisomerase-I (Topo-I) activity were obtained from 11 patients. The pharmacokinetics for irinotecan and its active metabolite, SN-38, were determined in 18 patients. RESULTS: Thirteen of 41 patients (32%) had a partial response (PR; 95% confidence interval, 18% to 46%). The median response duration was 8.1 months (range, 4.0 to 16.0) and the median survival time was 12.1 months (range, 2.1 to 21.7) for all 41 patients. Grade 3 or 4 toxicities were diarrhea (29% of patients) and neutropenia (22% of patients). Grade 3 or 4 diarrhea was substantially more prevalent in the initial 18 patients on study, with an incidence rate of 56%; a significant reduction in the incidence of severe diarrhea to 9% was noted with strict adherence to an antidiarrheal regimen of loperamide and diphenyldramine. No correlations were seen between pharmacokinetics of irinotecan/SN-38 and the clinical parameters of response, survival, or incidence of diarrhea. CONCLUSIONS: Irinotecan has activity in the treatment of patients with metastatic colorectal cancer. Strict adherence to an antidiarrheal regimen of diphenhydramine/loperamide significantly reduced the incidence of diarrhea; the agent was thereafter well tolerated in the majority of patients.

Biochemical modulation of bolus fluorouracil by PALA in patients with advanced colorectal cancer.

PURPOSE: N-(phosphonacetyl)-L-aspartic acid (PALA) is a pyrimidine synthesis inhibitor that modulates fluorouracil (FU) cytotoxicity. Two previous studies of patients with colorectal carcinoma documented complete response (CR) and partial response (PR) rates of 40% and 43% using weekly low-dose PALA followed by a 24-hour FU infusion. We investigated whether comparable results could be obtained with biochemical modulation by low-dose PALA using bolus instead of infusional FU. PATIENTS AND METHODS: Forty-five patients without prior chemotherapy who had advanced colorectal carcinoma were treated with PALA 250 mg/m2 followed 24 hours later by bolus FU at three dose levels, 600, 700, 800 mg/m2, repeated weekly for 6 weeks followed by a 2-week break. RESULTS: The CR and PR rate was 15 of 43 patients or 35% (95% confidence interval [CI], 21% to 49%), with an overall median survival of 18 months. Grade 3 or 4 diarrhea was the major toxicity observed in 24% of patients receiving FU at 700 mg/m2 and in 43% of patients receiving 800 mg/m2. Hematologic toxicity was observed only with an FU dose of 800 mg/m2, and 29% (four of 14) of patients developed grade 4 leukopenia. We also noted the development of ascites in six patients, mild hyperbilirubinemia in 16 patients, and a decreased albumin level in 22 patients; these abnormalities occurred more frequently in responding patients. CONCLUSIONS: The observed response rate, median survival, and toxicity in this study are similar to those obtained with PALA plus infusional FU and with other methods of FU modulation. Larger phase III studies are needed to compare bolus FU/PALA regimens with other PALA and non-PALA-containing combinations. Our future focus will be attenuate this regimen's toxicity while maintaining or improving its response rates and survival.

Randomized trial of hepatic arterial floxuridine, mitomycin, and carmustine versus floxuridine alone in previously treated patients with liver metastases from colorectal cancer.

PURPOSE: This study was designed to determine if hepatic arterial therapy with floxuridine (F), mitomycin, and carmustine (BCNU) (FMB) is superior to hepatic arterial therapy with F alone in previously treated patients with hepatic metastases from colorectal cancer. PATIENTS AND METHODS: Ninety-five patients were randomized to intrahepatic FMB versus intrahepatic F. All patients had tumor progression after systemic chemotherapy (either therapeutic or adjuvant). RESULTS: There was no significant difference in response rate (47% FMB v 33% F; P = .17). Median survival was similar in the two groups, 19.1 months for the FMB group compared with 14.0 months for the F group (P = .23). The overall median survival was 16.8 months. In patients who received prior adjuvant therapy, there was no difference between the two groups, but response rate was high in both (50% FMB v 62% F). The response rate for all patients who had received only prior adjuvant therapy versus all those who had received prior therapy for metastatic disease was 57% and 35%, respectively (P = .066). In the subset of patients whose disease had progressed with prior systemic chemotherapy, the response rate to FMB was greater than that to F (47% v 23%; P = .035). CONCLUSION: The overall partial response rate of 39% and the overall survival of 16.8 months from initiation of intrahepatitis therapy show that hepatic arterial therapy is a reasonable treatment option for patients whose tumor does not respond to systemic therapy or whose disease progresses after adjuvant therapy for colorectal cancer.

Trial of sequential trimetrexate, fluorouracil, and high-dose leucovorin in previously treated patients with gastrointestinal carcinoma.

PURPOSE: Trimetrexate (TMTX) is a dihydrofolate reductase inhibitor, which, like methotrexate (MTX), has been shown to potentiate fluorouracil (FU) cytotoxicity by increasing phosphoribosylpyrophosphate (PRPP) levels. We investigated the safety and efficacy of a sequential TMTX/FU/leucovorin (LV) combination. PATIENTS AND METHODS: Forty-one patients with advanced gastrointestinal carcinoma (mostly colorectal) received variable doses of TMTX followed 24 hours later by FU/LV (500 mg/m2 of each drug). Almost all patients had received previous chemotherapy. The initial 19 patients were treated on a 3-week-on/1-week-off schedule without any significant toxicity; the remaining patients were treated for 6 consecutive weeks followed by a 2-week rest period. TMTX was escalated in 30-mg/m2 increments from 20 to 110 mg/m2 in separate patient cohorts. When the 110-mg/m2 dose of TMTX was reached, the FU dose was escalated from 500 mg/m2 to 600 mg/m2. RESULTS: The partial response (PR) rate in assessable patients with colorectal cancer (all previously treated) was 20% (seven of 35; 95% confidence interval, 7% to 33%), and with other gastrointestinal cancers was one of four patients. Median survival has not been reached with a median follow-up of 13.5 months. The maximum-tolerated dose (MTD) was 110 mg/m2 for TMTX, 500 mg/m2 for FU, and 500 mg/m2 for LV on a 6-weeks-on/2-weeks-off cycle. The principal toxicities were grade 3 or 4 diarrhea, which occurred in 17% of patients, and hypersensitivity reactions, which occurred in 26% of patients. CONCLUSION: TMTX can be administered at maximal doses in combination with FU and LV without increasing toxicity. The PR rate of 20% in advanced colorectal carcinoma patients previously treated with chemotherapy is encouraging and merits further study.

Phase II study of hepatic arterial floxuridine, leucovorin, and dexamethasone for unresectable liver metastases from colorectal carcinoma.

PURPOSE: To determine the toxicity, response rate, and survival of a regimen of hepatic arterial floxuridine (FUDR) with leucovorin (LV) and dexamethasone (Dec) for the treatment of unresectable hepatic metastases from colorectal carcinoma. PATIENTS AND METHODS: Sixty-two patients with hepatic metastases (33 previously untreated with chemotherapy) were treated with FUDR (0.30 mg/kg/d) and LV (15 mg/m2/d) and Dec (20 mg total dose) as a 14-day hepatic arterial infusion via an implantable pump alternating with 2 weeks of saline. RESULTS: The complete response (CR) plus partial response (PR) rate was 78% in previously untreated patients, with a median survival duration of 24.8 months; 1- and 2-year survival rates were 91% and 57%, respectively. In the previously treated group, the response rate was 52%, with a median survival duration of 13.5 months. Only 3% of patients (two of 62) developed biliary sclerosis; this was significantly lower than the 21% biliary sclerosis rate observed in our previous trial of hepatic arterial FUDR and LV without Dec (P = .002). CONCLUSION: The addition of Dec to hepatic arterial FUDR and LV reduces biliary toxicity while maintaining an excellent response rate and survival. We recommend that this treatment be studied further.

A comparison of umbilical cord blood gas values between newborns with and without true knots.

OBJECTIVE: To compare umbilical cord blood gas values in newborns with and without true knots, and to assess the potential impact of true knot formation on cord blood gases. METHODS: Twelve newborn infants with true umbilical cord knots were identified and compared with a random control population of 104 newborn infants without true knots. The two groups were analyzed for 11 maternal-fetal variables to determine if they were comparable. Subsequently, the principal outcome variable of the study was evaluated: a comparison between the umbilical arterial and venous blood gas results of the true knot and control populations. RESULTS: The true knot and control populations were comparable with respect to the maternal-fetal variables analyzed. The umbilical cord blood gas values did not differ between groups, except for a slightly lower umbilical artery bicarbonate value in the control group (22.0 mEq/L) versus the true knot group (24.5 mEq/L), P = .025. There was no significant difference in the incidence of acidemia (umbilical artery pH less than 7.20) between the two groups. CONCLUSION: The presence of true umbilical cord knots does not alter the incidence of umbilical artery acidemia or change umbilical cord blood gas values. Review of the pertinent obstetric literature supports the hypothesis that true umbilical cord knots lack clinical significance.

Colon carcinoma metastatic to the trachea. Report of a case and a review of the literature.

Tracheal metastases are rarely seen from colorectal carcinoma. We describe the third reported case of colorectal carcinoma metastatic to the trachea and review of the current pathogenesis, diagnosis, and management of endotracheal metastases.

Tetrameres columbicola (Nematoda: Spiruridae) infection of pigeons: ultrastructure of the gravid female in glands of the proventriculus.

The light and electron microscopies of Tetrameres columbicola gravid females in sections of the parasitized proventriculus of pigeons were studied. By light microscopy, the most conspicuous structures in the sectioned parasite were the intestine, ovary, and especially the uterus that contained numerous eggs. By electron microscopy, there was a thick mat of pigment-coated microvilli on the surfaces of the intestinal epithelial cells. The germinal zone of the ovary contained nonmembrane-bound oocytes, but oocytes were confined by a membrane in the growth zone of the ovary. The core of the spermatheca contained oocytes and the periphery harbored sperm. In this location, the unfertilized oocyte had pseudopods; sperm had invaginations of the plasma membrane. After fertilization, there was proliferation of ribosomes within the oocyte. Embryonating eggs in the uterus had thick shells and were partially enveloped by elongations of the uterine epithelial cells. Surfaces of the epithelial cells were pleated and they had electron opaque areas at the points of the pleats. Larvae in eggs had a well developed annulated cuticle and muscular layer. Somatic muscle cells had tailed appendages that protruded into the pseudocoelom. The single layer of cells beneath the hypodermis had lateral processes at the base of the cells that interdigitated with similarly elongated processes of adjacent muscle cells. Striated fibers were present in the central portion of the cells.

Interrelationships of parasites of white-winged doves and mourning doves in Florida.

The parasites of indigenous populations of mourning doves (Zenaida macroura) in north and south Florida were compared with those of an introduced population of white-winged doves (z. asiatica) in south Florida. Thirty-two species of parasites including 5 protozoans, 7 nematodes, 2 trematodes, 2 cestodes, 7 acarines, 7 mallophagans, and 2 dipterans were found. Of these, 16 common to both species of doves. Mourning doves from north Florida showed a more diverse parasite fauna than did the white-winged or mourning dove populations from south Florida. Nematodes were the most common parasites in all three populations; infected doves contained one or two nematode species per dove. Total helminth burdens per infected dove averaged 13.1 for white-winged doves, 19.9 for mourning doves in south Florida, and 6.6 for mourning doves in north Florida. The prevalence of infections by Trichomonas gallinae was higher in white-winged doves (97%) than in mourning doves in south Florida (17%) or in mourning doves in north Florida (1%). The high prevalence of this parasite in expanding populations of white-winged doves may pose a threat to mourning dove populations since some strains of T. gallinae are pathogenic.

Experimental transfer of Trichomonas gallinae (Rivolta, 1878) from white-winged doves to mourning doves.

Isolates of Trichomonas gallinae (Rivolta, 1878) from white-winged doves, Zenaida asiatica (L.), were transferred experimentally to young mourning doves, Zenaida macroura (L.). Twenty-three of 25 mourning doves developed infections with isolates of T. gallinae from 25 white-winged doves. In addition, eight of eight rock doves (Columba livia Gmelin) were infected with duplicate isolates. All infected recipient birds harbored avirulent isolates except for one mourning dove which died from extensive oral lesions. However, repeated attempts using this isolate of T. gallinae to produce lesions in additional recipients were unsuccessful. Despite the findings of this study, it was suggested that future dove management strategies consider the possibility of disease outbreaks involving white-winged doves and susceptible populations of mourning doves.

Varicella pneumonia in the adult.

Chickenpox pneumonia can occur in as many as half of the varicella-zoster infections in adults. Although it usually exhibits a benign course, this complication can cause considerable morbidity and mortality in predisposed groups, including pregnant women and immunosuppressed patients. In these patients, the use of antiviral drugs, most notably acyclovir, has been shown to lessen the morbidity of varicella-zoster infections. Early diagnosis of lung involvement from the chest x-ray or arterial blood gas measurements, even in the absence of symptoms, is essential for optimum efficacy of drug therapy. The use of acyclovir in normal hosts continues to be debated, especially for prophylaxis, because of its potential for nephrotoxicity. Judicious use of acyclovir will reduce the overall mortality from this potentially fatal complication of varicella zoster virus infection.

Hereditary spherocytosis and hematologic malignancy.

We report the development of myeloproliferative disorders in two patients with hereditary spherocytosis diagnosed in adulthood. Eight previously reported cases of the coexistence of hereditary spherocytosis and hematologic malignancy are reviewed.