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Introduction The use of total neoadjuvant therapy (TNT) for locally advanced rectal cancer has been increasing in recent years, but the long-term overall survival characteristics of this approach is currently unknown. Methods We performed a retrospective study of patients with clinical stage II/III rectal cancer within the National Cancer Database. Patients who received TNT (defined as chemotherapy, followed by CRT, followed by surgery) were propensity score matched to patients who received adjuvant therapy (defined as CRT, followed by surgery, followed by chemotherapy). We compared overall survival (OS) and rates of pathologic complete response (pCR) between the two arms. Results Of the 4,300 patients in our cohort, 3,502 (81%) received adjuvant therapy and 798 (19%) received TNT. At baseline, patients who received TNT were more likely to have higher clinical T and N stages (p Conclusion In this observational study, we found TNT was not associated with a lower OS compared to standard adjuvant chemotherapy. This finding potentially reassures clinicians choosing TNT as an alternative to adjuvant chemotherapy. However, future prospective data are needed to confirm these findings. Microabstract The long-term overall survival characteristics of total neoadjuvant therapy (TNT) for locally advanced rectal cancer has not been well-defined despite its increasing popularity. In a large National Cancer Database cohort, we found that TNT was not associated with worse survival compared to historical controls.

Two cases of desmoid-type fibromatosis developing after laparoscopic hernia repair are described: one in a young male 3 years after laparoscopic umbilical hernia repair and the other in a young female 1 year after laparoscopic incisional hernia repair. The male patient presented with a slowly enlarging non-tender firm abdominal wall mass; the female patient had similar findings. Excision biopsy in the male and core biopsy in the female were consistent with fibromatosis. The young male patient underwent resection of the fibromatosis, and the female patient has been managed conservatively. These are the first documented cases of fibromatosis developing after laparoscopic hernia surgery. Whilst the safety of hernia meshes has been assessed in animal studies, it may be that more detailed study of intraperitoneal placement of these meshes is required.

The oncology community remembers, with great affection, Dr. Robert L. Comis, and his many contributions to the field.

Background Referral of patients with large bowel symptoms is common and increasing. Currently most of these referrals are assessed at an outpatient clinic to determine the need and priority for investigation. Methods Over 21 months, 1131 patients referred by the general practitioner with large bowel symptoms were randomized. Patients in the consultant-led group were assessed by surgeons with a colorectal interest while those in the open access group underwent colonoscopy if they were 55 years or older and flexible sigmoidoscopy if younger. Results The most common symptom among referred patients was rectal bleeding (69·1 per cent) followed by change in bowel habit (48·8 per cent) and abdominal pain (32·3 per cent). There was a significant trend (P < 0·001) for patients in the consultant-led to have more investigations, and more patients in this group had no investigations (P < 0·001). Despite this, the percentage of patients with colonic or other pathology diagnosed was the same in both groups, 63·6 per cent in the consultant-led group compared with 61·8 per cent in the open access group (P = 0·558). Likewise the percentage of patients with cancer or other significant pathology was similar in both groups (13·9 versus 15·4 per cent; P = 0·532). The mean(s.d.) time to diagnose cancer or other significant pathology was 55·1(39·2) days in the consultant-led group compared with 57·4(33·6) days in the open access group (P = 0·514). The cost per patient was almost £105 more for patients in the consultant-led group. Conclusion Patients referred by the general practitioner with large bowel symptoms should go directly to a properly managed and staffed open access large bowel investigation unit. This would enable most patients to have their investigations completed at one hospital attendance.

Background No previous study has attempted to quantify pain from a primary inguinal hernia. The aim of this study was to quantify patients' pain from inguinal hernia at rest and on moving, and to assess the effect of hernia repair on the pain. Methods Linear analogue pain scores at rest and on moving were recorded before operation and at 1 year after surgery in a consecutive series of patients undergoing elective repair of a primary inguinal hernia. Results During the study period 323 patients underwent inguinal hernia repair. Eighty-six patients (26·6 per cent) recorded no pain at rest from the hernia, and 174 (53·9 per cent) had mild pain only (score less than 10). On moving, 53 patients (16·4 per cent) had no pain and 137 (42·4 per cent) had mild pain on moving. Only 1·5 per cent experienced severe pain (score greater than 50) at rest, and 10·2 per cent had severe pain on moving. There was no association between pain and hernia type, direct or indirect, or patient occupation. One year after operation only 24·5 per cent of patients had no pain from the hernia repair site at rest, and 21·6 per cent had no pain from the site on moving. Overall there was a significant reduction in pain score at rest (mean(s.e.m.) decrease from baseline −2·9(1·2), P = 0·019) and on moving (−9·2(1·8), P = 0·001) compared with preoperative values, and this was due mainly to the large effect observed in patients with high preoperative values. Patients who had no pain at rest before operation had significant pain scores at rest at 1 year (P = 0·001). Conclusion Clinical trials are required to evaluate hernia repair in patients with an asymptomatic inguinal hernia. Results from such trials should help to determine whether repair is the treatment of choice for these patients.

C-reactive protein (CRP) may be useful in predicting postoperative complications [1]. We investigated the sensitivity and specificity of postoperative CRP for infective complications after elective colorectal surgery.One hundred and sixty consecutive patients (72 years old; interquartile range, 63-79) undergoing elective resection for colorectal cancer treated between September 2003 and October 2006 were studied. Details of the postoperative course were prospectively entered into a database. Of the 160 patients, 10 had incomplete CRP data and were excluded from further analysis.Infective complications occurred in 21%, with an overall complication rate of 29%. Infective complications occurred as follows: respiratory (10), wound (9), urinary tract (2) and central line infection (1), anastomotic leakage (5), intra-abdominal abscess (3) and septicaemia of unknown origin (2). There were three postoperative deaths. The positive predictive value for infection of CRP145 mg/l on postoperative day 4 was 61%. The negative predictive value of CRP145 mg/l on postoperative day 4 for an infective complication was 96%.A CRP145 mg/l on day 4 has high specificity and sensitivity for infective complications following elective colorectal resection.

Chronic pain is the most serious long-term complication of inguinal hernia repair. Up to one-third of patients will complain of some sort of pain at 1 year postoperatively, and in 3–4% of patients this pain will be severe and disabling [1, 2]. The causes of this pain are poorly understood, but factors such as nerve and tissue injury may be important. Psychological factors are also implicated, and more recently, the type of mesh used has been considered [3].

A 40-year-old mother and her 7-year-old son underwent colectomy for polyposis coli. Both colectomy specimens contained predominantly juvenile polyps. The mother's specimen also had numerous tubular adenomas and one 5-cm severely dysplastic villous adenoma without invasive carcinoma. Foci of adenomatous change in juvenile polyps were present in the son's specimen. The histologic features of both cases suggest a sequence of change from juvenile polyps to adenomatous polyps to cancer.

Abnormalities of the thyroid gland are said to be common in patients with dermatitis herpetiformis (DH), treated with dapsone (Thyroid abnormalities in dermatitis herpetiformis. Cunningham andZone, Annals Int.Med. 1985: 102, 194-196). Thepossibility that the goitrogenic effects of dapsone may play a role in this has not been evaluated. We therefore studied thyroid abnormalities in 40 patients with DH, 25 of whom were taking dapsone and 15 of whom were on a gluten free diet alone. All patients were examined clinically for evidence of thyroid dysfunction and blood was drawn for total thyroxine, thyrotrophin levels and thyroid microsomal antibdy titres. Six (24%) of dapsone treated patients had thyroid abnormalities, compared to 1 (7%) of the 15 patients treated with diet alone. Two patients became thyrotoxic when on treatment with dapsone. One patient had myxoedema prior to diagnosis of DH and one developed myxoedema while on dapsone. Two patients with asymptomatic goitres at the time of screening were taking dapsone and one patient on dapsone had thyroid antibodies. Thus it seems likely that the increased incidence of thyroid abnormalities in DH may be related to the effects of the sulphonamide on thyroid function.

Objective Liver resection is currently the recognised treatment for localised colorectal liver metastases. Hospital stay in recently published series is between seven and 12 days for open surgery and five and eight days for laparoscopic resection. Recently there has been interest in the use of ‘fast-track’ recovery protocols following major abdominal surgery. Our aim was to measure the effect of such a protocol on hospital stay following liver resection. Methods Data was collected prospectively from 12 consecutive patients undergoing open liver resection between August 2003 and September 2004. All patients had a large subcostal incision with full mobilisation of the liver. A ‘fasttrack’ protocol was employed consisting of intra venous fluid restriction, patient controlled analgesia and early diet and mobilisation. Data on postoperative complications and hospital stay was recorded. Results Twelve patients with a median age of 60 (range 43-74) years underwent liver resection. Resection consisted of one hepatic lobectomy, two trisegmentectomies, three bisegmentectomies and six segmentectomies. Median hospital stay was four (range two to seven) days. One epileptic patient developed carbamazepine toxicity delaying their discharge. A further patient developed a collection requiring no intervention. Conclusion Early discharge following major liver resection using a ‘fast-track’ recovery protocol is both safe and achievable.

To evaluate CA 15-3, a new breast cancer associated antigen, and to compare it with carcinoembryonic antigen (CEA), all patients presenting with breast cancer had preoperative and serial (3-monthly) postoperative levels measured. Of 124 patients with primary breast cancer, 23% had an elevated CA 15-3 (greater than 25 units/ml) while 11% had an elevated CEA (greater than 5 ng/ml) (p = not significant). Neither marker was an indicator of spread to regional lymph nodes in primary breast cancer. In 45 recurrences of breast cancer, CA 15-3 was elevated at the time of first recurrence in 58% while CEA was elevated in 47% (p = not significant). Of 17 patients with locoregional recurrence alone, none had a CA 15-3 above 40 units/ml while 11 of 12 with synchronous locoregional and distant recurrence had a CA 15-3 level greater than 40 units/ml (chi 2: 21.36, p less than 0.0001). This study shows that CA 15-3, like CEA, is of little clinical value in primary breast cancer. CA 15-3, however, is an accurate indicator (overall accuracy, 97%) of synchronous distant metastases in patients with locoregional recurrence from breast cancer. This information has important implications for further investigation and management of such patients.

Recurrent hernias account for between 10 and 20% of all inguinal hernias repaired. When addressing the issue of recurrence and pain there are at least three questions that come to mind: 1. Are recurrent hernias more painful than primary inguinal hernias? 2. Is an increase in post-operative pain after primary inguinal hernia repair associated with recurrence? 3. Are recurrent inguinal hernias more likely to be associated with chronic pain after repair?

This study reviews the existing literature examining chronic pain and health-related quality of life (HRQL) outcomes in hernia repair studies. A PubMed/Medline and Embase search was carried out to identify relevant papers. Studies meeting pre-specified inclusion/exclusion criteria were included and fully reviewed. Reference lists were scanned for additional studies. Only studies examining chronic (>3 months) post-operative inguinal hernia repair (IHR)-related pain were included in this review. Twenty-three studies were identified. The majority of studies used the visual analogue scale (VAS) for pain measurement and the Medical Outcomes Study Short-Form 36 (SF-36) for the measurement of HRQL. A reasonably consistent picture emerged from the literature, with the HRQL domains most often affected by pain (social functioning/mental health). Estimates of the prevalence of chronic pain and discomfort following IHR vary widely between studies. This is probably a reflection of the range of methods used for measuring pain, many of which do not have established psychometric properties. Our review suggests that a proportion of patients experience chronic pain and discomfort, which has a significant impact on HRQL. However, the current instruments used in the evaluation of chronic pain after IHR are not comparable and standardisation is required.

3617 Background: BBI608 is an oral first-in-class cancer stemness inhibitor that works by targeting Stat3. Potent preclinical anti-tumor activity was observed in vitro and in vivo, in mono- and com...

Background Use of intravenous fluids is an important part of perioperative management. The aim of this study was to compare outcome following administration of restricted or standard postoperative intravenous fluids and sodium in patients undergoing elective colorectal surgery. Methods Eighty patients were randomized to restricted fluids (less than 2 litres water and 77 mmol sodium for 24 h after surgery) or a standard postoperative fluid regimen (3 litres water and 154 mmol sodium per day for as long as necessary). The primary endpoint was hospital stay. Results The median (i.q.r.) total intravenous fluid intake in the restricted group was 4·50 (4·00–5·62) litres compared with 8·75 (8·00–9·80) litres in the standard group (P < 0·001). Intravenous sodium intake was also significantly less in the restricted group (229 (131–332) versus 560 (477–667) mmol; P < 0·001). There was no difference in median time to first flatus (2·9 versus 2·9 days; hazard ratio (HR) 0·85 (95 per cent confidence interval (c.i.) 0·54 to 1·32); P = 0·466) or first bowel motion (4·7 versus 4·9 days; HR 1·06 (95 per cent c.i. 0·68 to 1·65); P = 0·802) between the restricted and standard groups, or in median hospital stay (7·2 versus 7·2 days; HR 1·03 (95 per cent c.i. 0·66 to 1·61); P = 0·902). Conclusion Restriction of postoperative intravenous fluid and sodium does not reduce hospital stay following elective colorectal surgery.

The indications for pre-operative radiotherapy in rectal cancer are still unclear with the exception of T4 tumours. The aim of this study was to assess local and overall recurrence in patients with T1-T3 rectal cancers undergoing total mesorectal excision (TME).Prospective data was collected from 150 patients with rectal cancer treated in one surgical centre between July 1997 and July 2002. One hundred and twenty-nine primary resections were carried of which 102 were with curative intent. Seventy-nine patients with T1-T3 tumours were included in the analysis. Nine had local resections and 70 underwent TME; 19 of the 70 patients were node positive and 51 were node negative.At a median follow-up of 37 months (range 19-79 months) there were 3 (4.3%) isolated local recurrences. One node positive patient developed isolated local recurrence compared with 2 node negative patients. The node positive patient died from a myocardial infarction while the two node negative patients died as a consequence of local recurrence. Three (4.3%) of 70 patients developed systemic relapse all of whom were node positive. The cancer specific mortality rate over the same follow-up period was 3/19 for node positive patients and 2/51 for node negative patients. Of 9 patients who had local resections, none developed local recurrence or systemic relapse.With TME the rate of local recurrence in T1-T3 tumours is low. Our results do not support the use of pre-operative radiotherapy for these patients.

Objective Endorectal ultrasound (ERUS) is well established as an accurate modality for local staging of rectal tumours. The aim of this study was to identify reasons for inaccurate staging of tumours, and to assess whether difficulties encountered during scanning are likely to influence accuracy. Patients and methods ERUS was performed by a single operator using a 10 MHz rigid instrument. One hundred and seventeen patients that had both ERUS and surgery are included in this study (patients that had pre-operative radiotherapy were excluded). During ERUS, procedural conditions and limiting factors were recorded. Data was collected prospectively. Results In 78 (66.7%) patients no technical difficulty was encountered during ERUS. In this group accuracy was 80% for T-stage and 77% for N-stage. Specific reasons for inaccuracy identified in this group were: inflammatory lymph nodes (from a tumour associated abscess and a colovesical fistula) and deep biopsy causing a submucosal defect with intramural haemorrhage in benign lesions (2 cases). In the remaining 39 (33.3%), the following problems were encountered: stenotic lesions (23), patient discomfort (8), poor bowel preparation (6), and scarring from previous surgery (2). In 11 patients from this group, the scan was considered inconclusive and no stage could be determined. For the other 28, the accuracy for T-stage was 68% and for N-stage 67%. Conclusion A technically difficult ERUS is likely to give an inconclusive or inaccurate result for both T-stage (P = 0.001) and N-stage (P = 0.003). In this situation a repeat scan may be considered (where appropriate). Alternatively, further assessment by MRI or flexible endoscopic ultrasound may be considered.

3086 Background: Lapatinib is an orally active reversible inhibitor of ErbB1/ErbB2 tyrosine kinases. This study evaluated the safety, tolerability and pharmacokinetics (PK) of daily lapatinib in combination with IR/FU/LV (FOLFIRI) q14d. Methods: Cohorts of 3 patients (pts) each (25 total) with solid tumours received lapatinib (1000 or 1250mg daily) and FOLFIRI (80% or 60% of the standard doses) to determine the optimally tolerated regimen (OTR). Additional pts were enrolled at the OTR to evaluate the PK of lapatinib and FOLFIRI alone and in combination. Results: The standard FOLFIRI doses were reduced to 80% and 60% due to DLTs of diarrhea and/or myelosuppression at the starting doses. Toxicity required the lapatinib dose to be interrupted or reduced at these doses. The OTR was defined as lapatinib 1250mg with IR 120mg/m2, FU 240mg/m2 bolus and 360mg/m2 infusion, plus LV 200mg/m2on days 1 and 2, every 14 days. At the OTR, common non-hematological adverse events were grade 1 or 2 diarrhea, nausea/vomiting,...

Background Per-anal excision can be an effective method for treating large rectal adenomas and selected rectal cancers. This procedure is suitable for adenomas that are too large for colonoscopic excision and for early rectal cancers in patients that are unfit for major resection. Patients and methods We retrospectively reviewed 37 patients (16 male, 21 female) that had a local resection using a Salvati operating proctoscope. Fifteen had rectal cancer and 22 had rectal adenoma and all have been followed-up for a median of 14 months (range 2–65). Most cancers were staged pre-operatively with endorectal ultrasound and 6 cancer patients received adjuvant therapy. Results There were no intra-operative complications, 6 minor postoperative complications, none requiring re-intervention (1 peri-anal haematoma, 2 postoperative anaemia, 2 chest complications, 1 secondary haemorrhage) and no peri-operative deaths. Lesions were histologically completely excised in 33 (89%). Thirty-four (92%) did not have any recurrence, 2 (5%) adenomas recurred (both successfully treated with further local resection) and 1 (3%) failed to attend for follow-up. Six have since died, all from comorbid conditions. Conclusion Local resection of rectal tumours using the operating proctoscope is a low cost technique with a low complication rate. Outcome of this treatment is good, and similar to other surgical modalities. Local tumour recurrences are uncommon and can be successfully treated with further local treatment.

Background Claims that laparoscopic groin hernia repair is followed by less persisting pain and numbness than open mesh repair were tested by follow-up within a multicentre randomized clinical trial. Methods Participants in the UK Medical Research Council Laparoscopic Groin Hernia Trial were followed up by means of self-completed postal questionnaires from 2 to 5 years after trial entry. The principal measures were pain (groin and testicular) and numbness (groin and thigh). Results Seven hundred and fifty (80·8 per cent) of the original 928 participants returned at least one questionnaire between 2 and 5 years; respondents were similar to the baseline randomized groups. Fewer respondents in the laparoscopic group had groin pain (absolute differences varied between 7·9 and 2·0 per cent, but were of marginal statistical significance); rates of testicular pain were similar in the two groups. Groin numbness was reported about half as commonly at all time points in the laparoscopic group (P < 0·001); there were no significant differences in thigh numbness. Conclusion Laparoscopic surgery was associated with less long-term numbness and probably less pain in the groin.

There is continued debate as to the role of laparoscopy in recurrent, bilateral inguinal and incisional hernias. Further clinical trials are needed in all of these areas. For patients with a primary inguinal hernia laparoscopic repair can no longer be recommended as the repair of choice unless it is undertaken in an expert centre in minimal access surgery.

Cancer patients, especially the elderly, present with a highly variable susceptibility to toxicity from chemotherapy. To estimate correctly a patient's risk for toxicity, both the average toxicity of a chemotherapy regimen and patient-related variables need to be assessed. However, treatment toxicities are typically reported item by item, not summarised per patient. We tested an index derived from a pilot study, the MAX2, on the ECOG database. Studies including 20 or more patients aged 70 years and older per arm were selected. Four studies were identified, representing 2526 patients, 410 (16%) being elderly. The association of the MAX2 index with the per patient incidence of grade 4 haematological and/or grade 3 or 4 non-haematological toxicity was highly significant, both for the overall group and for the elderly subgroup. The MAX2 index is a convenient and reproducible way of comparing the average per patient risk for toxicity from chemotherapy across several regimens.

A multicentre randomised controlled trial needs to recruit sufficiently large numbers of centres, clinicians and patients Delays in reaching recruitment targets are common and often necessitate extended recruitment periods with associated increased costs. The Scottish Back Trial and the MRC Laparoscopic Hernia Trial are used to illustrate how national clinical, economic and political factors can impact on the conduct of a multicentre trial. Changes in clinical practice, restructuring of the NHS and research and development funding, and changes in the procedures for obtaining local research ethics committee approval had adverse effects on recruitment. In addition, the extent to which changes in patient knowledge and attitudes to clinical trials could influence recruitment should not be ignored. In response to these obstacles both trials extended the recruitment period, identified additional recruitment centres and reduced the overall sample size. External factors which could compromise the successful completion of a d trial need to be recognised and addressed at an early stage.

Background: Many drugs active in mCRC target specific molecular aberrations or cell-signalling pathways and may only be effective in subsets of pts due to molecular differences between tumours. Molecular screening approaches and new biomarkers are required to fully characterize tumours, identify pts most likely to benefit, and predict treatment response. MODUL is a randomised, multicentre, active-controlled, open-label, parallel-group trial of biomarker-driven maintenance therapy for the 1st-line treatment of mCRC. The design permits future adaptation of current cohorts and inclusion of additional treatment cohorts based on novel evidence and corresponding compounds/combinations. Trial design: Eligible pts have measureable, unresectable disease with no prior chemotherapy for mCRC. The study has 3 phases: 1) Induction Treatment (approx. 4 months’ of FOLFOX + bevacizumab [bev]); 2) Maintenance Treatment; 3) Post-Treatment Follow-up. Eligible pts without progressive disease are assigned to a Maintenance Treatment cohort based on results of biomarker assessments obtained from tumour tissue. Current cohorts: Cohort 1–BRAF V600E mutated (BRAFmut); Cohort 2–‘No Biomarker’ cohort. Within each cohort, pts are randomized to either experimental treatment or control (2:1 basis): Cohort 1–experimental (fluoropyrimidine [FP], cetuximab, vemurafenib); Cohort 2–experimental (FP, bev, anti-PD-L1 antibody [MPDL3280A]). The control arm for all cohorts is FP + bev. Co-primary efficacy endpoints: early efficacy (≥20% reduction in tumour size after 2 months of Maintenance Treatment in first 27 pts of experimental arm); PFS (median and 4-month PFS rate from randomisation). Secondary efficacy objectives: overall survival; overall response rate; disease control rate; time to treatment response; duration of response. Safety assessment is based on adverse events, treatment modifications, and clinically significant laboratory values. Recruitment of 1680 pts is expected over approx. 3 years (total 6 years’ duration of trial) from sites in Europe, Asia, Africa, North America and South America. Disclosure: H. Schmoll: Consultant or Advisory Role (Roche) Research Funding (Roche); D. Arnold: Research funding (Roche) Scientific advisory board (Roche); A. De Gramont, M. Ducreux, A. Grothey, P.J. O'Dwyer and J. Tabernero: Scientific advisory board (Roche); B. Bendahmane, F. Hermann, C. Ingold, C. Mancao, S. Osborne and I. Statovci: Employment (Roche); E. Van Cutsem: Scientific advisory board (Roche).

The dithiolethione oltipraz is being developed as a chemopreventive agent for many malignancies, including colorectal cancer, on the basis of its in vivo protective activity against chemically induced tumors in a variety of animal models. This protection has been associated with an enhanced capacity to detoxify reactive carcinogens and, more recently, with increased DNA repair. In a previous single-dose study, elevated detoxification gene expression was observed in the days after oltipraz dosing. Now, in this clinical study, we evaluated the effects of oltipraz when given over a 3-month period. Fourteen individuals with increased risk for colorectal cancer were randomly assigned to one of two oral doses (125 or 250 mg/m2) of oltipraz twice weekly for 12 weeks. Two of seven subjects at the 250 mg/m2 dosage required dose reductions, owing to significant fatigue. The 125 mg/m2 dose level was well tolerated by all patients. Blood or colon tissue (or both) for evaluation of glutathione, glutathione S-transferase, DT-diaphorase activity, and DT-diaphorase mRNA expression were obtained prior to treatment and at weeks 6, 12, and 16. No significant modulation of phase II detoxification enzymes was seen at either dose studied during this period. Phase II trials evaluating a tolerable regimen of oltipraz (as demonstrated in this study) and other possible mechanisms that may be responsible for the protective activity of oltipraz should be pursued.

The complementary action of gemcitabine and topotecan on DNA metabolism suggested the potential for their use in combination chemotherapy. Gemcitabine, a synthetic cytidine analogue chain terminator, and topotecan, a topoisomerase-1 inhibitor, have been reported to have broad antitumor activity and are approved for clinical use.The cytotoxicity of the combination in various models in vitro was additive. In the current study, the authors conducted a Phase I study to determine the recommended Phase II doses and toxicity profile of gemcitabine and topotecan when administered weekly in combination. Gemcitabine (400--1000 mg/m(2)) was given intravenously over 30 minutes followed by a 15-minute infusion of topotecan (0.75--2.5 mg/m(2)) weekly for 3 consecutive weeks in a 4-week treatment cycle. Thirty-eight patients with advanced refractory solid tumors and good performance status were treated.Myelosuppression in the form of granulocytopenia and thrombocytopenia were the major dose-limiting toxicities. Other toxic effects included anemia, nausea, and elevated hepatic transaminases. Partial responses were observed in two patients (one with nonsmall cell lung carcinoma and one with pancreatic carcinoma). Disease stabilization occurred in five patients (three with pancreatic carcinoma, one with rectal carcinoma, and one with metastatic carcinoma of an unknown primary site). Gemcitabine, 1000 mg/m(2), and topotecan, 2.5 mg/m(2), were the maximum tolerated doses for this combination.The results of the current study showed that the combination of weekly gemcitabine and topotecan for 3 weeks in a 4-week cycle schedule appeared to be well tolerated and was associated with clinical activity. Therefore, this combination is recommended for a further Phase II evaluation.

A femoral hernia accounts for approximately 5-10% of all groin hernias in adults. Misdiagnosis in children, in whom the condition is rare, has been well recognised and documented. The aim of this study was to assess the accuracy of diagnosis in an adult population.An analysis of 379 patients with a groin hernia, presenting electively to a University Department of Surgery and entered into a prospective clinical trial.A femoral hernia was confirmed at operation in 12 (3%) patients while a further 4 had a preoperative diagnosis of a femoral hernia. The correct diagnosis of a femoral hernia was made in only 3 cases by general practitioners and in only 6 by surgical staff of all grades.These data suggest that medical staff of all grades may be poor at diagnosing a femoral hernia and a change in the way we are taught to differentiate between femoral and inguinal hernia needs to be considered.

The dithiolethione oltipraz (OPZ) has activity as a chemopreventive agent in animal models and is in early clinical trials. OPZ undergoes metabolism by molecular rearrangement to yield a pyrrolopyrazine derivative, M3, which we have previously shown to be inactive in the induction of detoxication genes. M3 is metabolized further: at least 10 possible conjugates have been described in three species. We developed a new high-performance liquid chromatography method to simultaneously measure plasma concentrations of OPZ and of M3. This method was applied to serial plasma samples in a Phase I clinical trial, in which OPZ was administered at single doses varying from 125 to 1000 mg/m2. OPZ and M3 concentration-time profiles were highly variable among individuals, and the occurrence of secondary concentration peaks suggested substantial enterohepatic cycling. Absorption was rapid, and the mean time to peak was 2.2 h. Maximum plasma concentration values were proportional to the dose. Harmonic mean half-lives at these doses ranged from 9.3-22.7 h. There were indications of dose-dependent pharmacokinetic properties because apparent clearance and volume of distribution at steady state increased with dose, although these changes were not statistically significant as a result of high interpatient variability. Accordingly, there were less than proportional increases in the OPZ and M3 area under the curve and maximum plasma values. Interpretation of OPZ and M3 disposition is confounded by the unknown bioavailability factor; however, the most likely inferences are that bioavailability of OPZ decreases with increasing dose and that metabolism to M3 is saturable.

Chronic pain is the most serious long-term complication that occurs following repair of a groin hernia. Not only does it affect the individual’s employment status but it also has significant effects on sexual and social activities. Although precise figures for the prevalence of this complication are not available, Cunningham and colleagues indicate that over 10% of patients will have moderate to severe pain at 2 years following hernia repair.

The combination of irinotecan and fluorouracil (5-FU) is synergistic when applied to human colon cancer cell lines in vitro and appears to be schedule-dependent: maximal activity occurs when irinotecan is administered prior to 5-FU. In this phase I study, irinotecan is administered in combination with UFT and leucovorin in patients with advanced solid tumors. Irinotecan is given as a 90-minute intravenous infusion on day 1 followed by twice-daily UFT plus oral leucovorin on days 2 through 15. Cycles are repeated every 21 days. Five patients have been treated to date; four are evaluable for toxicity. Starting doses were irinotecan 200 mg/m2/day, UFT 200 mg/m2/day, and leucovorin 60 mg/day. Preliminary results indicate that irinotecan in combination with UFT plus leucovorin is well tolerated at the initial doses (described in this article).

Most Spigelian hernias occur below the level of the umbilicus close to the level of the arcuate line. We report a case diagnosed by computed tomography in an unusually high anatomical location due to a previous drain site incision.