Ballistic trans-urethral resection of the prostate - A case report of gunshot injury to the posterior urethra.

We report a case of penetrating gunshot injury to the posterior urethra sustained by a low-velocity projectile during a civilian drive-by shooting. The bullet passed through the prostatic urethra, missing other vital organs and both the internal and external urethral sphincters. Following a period of urethral catheterisation, the patient made a complete recovery with good continence and sexual function.

Complete remission of advanced, locally invasive basal cell carcinoma with vismodegib.

We report the case of a 71-year-old woman who developed advanced basal cell carcinoma (BCC) affecting the right eyebrow, invading the orbit. Globe displacement resulted in visual disturbances. Following multidisciplinary assessment, the tumour was deemed technically resectable for excision and right orbital exenteration. The patient however refused ablative surgical treatment; in view of her multiple comorbidities, the tumour was considered unresectable for her. Targeted therapy with vismodegib (Erivedge; Roche Pharmaceuticals) was therefore initiated in accordance with the patient's desire to avoid disfiguring surgery. After nine 28-day cycles of treatment, the tumour showed dramatic regression both clinically and radiographically. Mapping biopsies taken after 9 months confirmed the absence of any residual tumour, negating the need for ablative surgery. Grade 1 adverse events including muscle cramps, loss of taste, and reduced appetite were reported. Treatment was discontinued at 15 months owing to cumulative toxicity. The patient remains in remission 14 months after cessation of vismodegib. The use of vismodegib for advanced BCC is emerging and a number of reports exist. However, its application is mainly reserved for patients with locally advanced or metastatic disease, patients who are medically unfit for surgery, and cases where primary surgical resection would cause unacceptable disfigurement.

Adjuvant bevacizumab for melanoma patients at high risk of recurrence: survival analysis of the AVAST-M trial.

Background: Bevacizumab is a recombinant humanised monoclonal antibody to vascular endothelial growth factor shown to improve survival in advanced solid cancers. We evaluated the role of adjuvant bevacizumab in melanoma patients at high risk of recurrence. Patients and methods: Patients with resected AJCC stage IIB, IIC and III cutaneous melanoma were randomised to receive either adjuvant bevacizumab (7.5 mg/kg i.v. 3 weekly for 1 year) or standard observation. The primary end point was detection of an 8% difference in 5-year overall survival (OS) rate; secondary end points included disease-free interval (DFI) and distant metastasis-free interval (DMFI). Tumour and blood were analysed for prognostic and predictive markers. Results: Patients (n=1343) recruited between 2007 and 2012 were predominantly stage III (73%), with median age 56 years (range 18-88 years). With 6.4-year median follow-up, 515 (38%) patients had died [254 (38%) bevacizumab; 261 (39%) observation]; 707 (53%) patients had disease recurrence [336 (50%) bevacizumab, 371 (55%) observation]. OS at 5 years was 64% for both groups [hazard ratio (HR) 0.98; 95% confidence interval (CI) 0.82-1.16, P = 0.78). At 5 years, 51% were disease free on bevacizumab versus 45% on observation (HR 0.85; 95% CI 0.74-0.99, P = 0.03), 58% were distant metastasis free on bevacizumab versus 54% on observation (HR 0.91; 95% CI 0.78-1.07, P = 0.25). Forty four percent of 682 melanomas assessed had a BRAFV600 mutation. In the observation arm, BRAF mutant patients had a trend towards poorer OS compared with BRAF wild-type patients (P = 0.06). BRAF mutation positivity trended towards better OS with bevacizumab (P = 0.21). Conclusions: Adjuvant bevacizumab after resection of high-risk melanoma improves DFI, but not OS. BRAF mutation status may predict for poorer OS untreated and potential benefit from bevacizumab. Clinical Trial Information: ISRCTN 81261306; EudraCT Number: 2006-005505-64.

Safe discharge of patients with low-risk upper gastrointestinal bleeding (UGIB): can the use of Glasgow-Blatchford Bleeding Score be extended?

INTRODUCTION: Risk stratification of patients with suspected upper gastrointestinal bleeding (UGIB) using either Glasgow-Blatchford Bleeding Score (GBS) or preendoscopy Rockall score to facilitate early safe discharge (GBS=0, pre-Rockall=0) has been reported. This observational study compared score utility and considered the impact of extending the range of GBS or pre-Rockall scores permitting safe discharge. METHODS: Consecutive adult patients presenting to acute medical admissions or the emergency department from September 2008-March 2009 with suspected UGIB had clinical history, vital signs, laboratory and endoscopy results prospectively recorded using electronic databases. GBS, pre-Rockall scores and a composite endpoint (blood transfusion, endoscopic therapy, interventional radiology, surgery or 30-day mortality) were calculated. RESULTS: 388 patients with suspected UGIB were identified of which 92.3% were admitted (median (range) GBS=5 (0-19) and pre-Rockall=2 (0-11)) and 7.7% discharged (GBS=0 (0-4) and pre-Rockall=0 (0-4)). 186 (47.9%) underwent in-patient endoscopy. 151 (38.9%) were found to have the composite endpoint with 77.5% having transfusion, 45.7% endoscopic treatment and an 8.0% mortality within 30 days. AUROC (95% CI) for 30-day composite endpoint was 0.92 (0.89-0.94) using GBS and 0.75 (0.70-0.80) using pre-Rockall scores. Analysis using different GBS thresholds demonstrated that GBS=0, GBS ≤1 and GBS≤2 had superior utility in identifying freedom from an adverse clinical outcome at 30-days than pre-Rockall score 0. CONCLUSIONS: GBS is superior to pre-Rockall score in identifying patients with suspected UGIB who have a low likelihood of an adverse clinical outcome and can be considered for early discharge. Diagnostic performance at different thresholds suggests that patients with GBS≤2 could be considered for early discharge, doubling the number of eligible patients (15.2 to 32.5%). This has important patient safety and resource implications.

Phase II study of single agent capecitabine in the treatment of metastatic non-pancreatic neuroendocrine tumours.

BACKGROUND: This study sought to determine the safety of single agent capecitabine, a pro-drug of 5FU, in patients with metastatic non-pancreatic neuroendocrine tumours (NETs). METHODS: Multicentre phase II, first-line study design. Oral capecitabine was administered on days 1-14 of 3-week cycles. RESULTS: Treatment was safe and well tolerated. Common toxicities were diarrhoea and fatigue. CONCLUSION: The study provides evidence to support the use of capecitabine as a substitute for infusional 5FU in the management of NETs.

Impaired p53 function leads to centrosome amplification, acquired ERalpha phenotypic heterogeneity and distant metastases in breast cancer MCF-7 xenografts.

In this study, we establish an MCF-7 xenograft model that mimics the progression of human breast carcinomas typified by loss of p53 integrity, development of centrosome amplification, acquired estrogen receptor (ERalpha) heterogeneity, overexpression of Mdm2 and metastatic spread from the primary tumor to distant organs. MCF-7 cells with abrogated p53 function (vMCF-7(Dnp53)) maintained nuclear ERalpha expression and normal centrosome characteristics in vitro. However, following mitogen stimulation, they developed centrosome amplification and a higher frequency of aberrant mitotic spindles. Centrosome amplification was dependent on cdk2/cyclin activity since treatment with the small molecule inhibitor SU9516 suppressed centriole reduplication. In contrast to the parental MCF-7 cells, when introduced into nude mice as xenografts, tumors derived from the vMCF-7(DNp53) cell line developed a strikingly altered phenotype characterized by increased tumor growth, higher tumor histopathology grade, centrosome amplification, loss of nuclear ERalpha expression, increased expression of Mdm-2 oncoprotein and resistance to the antiestrogen tamoxifen. Importantly, while MCF-7 xenografts did not develop distant metastases, primary tumors derived from vMCF-7(DNp53) cells gave rise to lung metastases. Taken together, these observations indicate that abrogation of p53 function and consequent deregulation of the G1/S cell cycle transition leads to centrosome amplification responsible for breast cancer progression.

A feasibility, pharmacokinetic and frequency-escalation trial of intraperitoneal chemotherapy in high risk gastrointestinal tract cancer.

AIMS: To assess the feasibility, pharmacokinetics and maximum tolerable frequency (MTF) of intraperitoneal (IP) 5-fluorouracil and leucovorin (FU/LV) added, as a regional boost, to intravenous chemotherapy after resection of gastrointestinal cancer. METHODS: Fifty-three patients were recruited following gastrointestinal cancer resection (43 colon; 10 stomach/small bowel) with serosal involvement. Peritoneal ports were implanted and IP fluid distribution evaluated ultrasonically. Twelve patients were studied for pharmacokinetics; 44 (41 evaluable) for MTF. Treatment was weekly intravenous bolus FU/LV for 6 months; to this was added IP FU/LV (400/20 mg/m(2) in 1500 ml 4% icodextrin) with increasing frequency from 4 weekly to 1 weekly in four successive cohorts. RESULTS: Peritoneal fluid distribution was excellent. Intraperitoneal FU exposure (AUC) after IP treatment was >1000-fold plasma AUC after IP treatment (regional pharmacokinetic advantage), and >100-fold plasma AUC after intravenous treatment (regional therapeutic advantage). IP therapy was well tolerated if given every 4, 3 or 2 weeks, but not weekly: 11/13, 7/8, 10/13 and 0/7 patients respectively completed treatment without IP modification in these cohorts. Problems with peritoneal access occurred in 20% of patients. CONCLUSION: Adding fortnightly IP FU/LV to a standard intravenous regimen is safe, tolerable and provides high peritoneal FU exposure. More reliable peritoneal access is needed to improve the feasibility of this otherwise promising therapeutic approach.

Long-term outcomes in patients with prostate cancer managed with intermittent androgen suppression.

OBJECTIVES: To assess the long-term outcomes of patients with prostate cancer managed with intermittent androgen suppression (IAS) following their enrollment in an open, non-randomised feasibility study initiated 10 years ago. PATIENTS AND METHODS: Patients with prostate cancer who developed marked side effects following androgen deprivation were considered for entry into the study. All patients were required to have been managed with androgen deprivation for a minimum of 9 months and to have achieved PSA remissions to levels <4 ng/ml or falls to greater than 90% of pre-treatment levels. Patients remained off treatment until PSA values rose to >20 ng/ml or individuals became symptomatic--at which stage a 9-month cycle of androgen suppression was repeated. Such on-off cycling continued until hormone-resistant disease developed and patients proceeded (off trial) to second-line therapies. RESULTS: 75 patients were recruited to the study following an initial referral with treatment-related side effects specifically associated with androgen deprivation. 86% of these remain alive at a median of 134 months (11 years) since initial histological diagnosis. Survival times and times to hormone resistance (from first cycle hormone deprivation) have also been calculated. Overall there is a median survival time of 95 months (8 years) from initial (first-cycle) androgen deprivation in those presenting with localised or locally advanced disease and a median survival time of 87 months (7 years) for those presenting with metastatic disease. There exists a median of 83 months to hormone resistance in the localised and locally advanced group and a median of 50 months in those presenting with metastatic disease. We have calculated a 100% 5-year actuarial survival rate for those presenting with localised or locally advanced disease (from time of first cycle hormone ablation) and a 70% 5-year actuarial survival rate for those presenting with metastatic. CONCLUSIONS: Long-term outcome figures and actuarial survival rates presented here provide further support for a pulsed or intermittent approach to androgen ablation in patients with prostate cancer. In addition, they serve as valuable extended outcome data for patients managed in this way. Likewise, data presented here suggests that apparent survival advantages appear related, at least in part, to a delay in the onset of androgen resistance and that such a management approach is both safe and effective in those presenting with both metastatic disease as well as those with more localised pathology.

Leucovorin rescue from raltitrexed (tomudex)-induced antiproliferative effects: in vitro cell line and in vivo mouse studies.

Raltitrexed (RTX) is an antifolate thymidylate synthase (TS) inhibitor that is effective for the treatment of advanced colorectal cancer and other solid tumors. However, a small minority of patients receiving RTX monotherapy will experience grade III/IV gastrointestinal toxicity that can be life-threatening, particularly if copresenting with neutropenia. Lack of vigilance in recognition and treatment of symptoms of toxicity or violations of protocol have led to treatment-related deaths in some hospitals. The safety of RTX could be improved if an effective rescue agent was available. Leucovorin (LV) is a reduced folate cofactor that competes with RTX for transport and polyglutamation in both tumor and normal tissues and thus has potential as a rescue agent. In vitro cell studies are presented suggesting that the growth-inhibitory, and potentially cytotoxic, effects of RTX on populations of viable cells can be reversed by the delayed administration of LV. The mechanisms involved are inhibition of further drug uptake and polyglutamation and a redistribution and/or reduction in the concentration of preformed raltitrexed polyglutamates. A more clinically relevant in vivo mouse model was used to test the hypothesis further. BALB/c mice treated with 100 mg/kg/day x 4 days of RTX were used as a model for gastrointestinal and bone marrow toxicity. LV (200 mg/kg), which was given after the onset of severe weight loss and diarrhea (twice daily, days 5-7), prevented further weight loss and induced earlier recovery. This was accompanied by improvement in the histological appearance of the intestine (day 7) and the concentration of neutrophils and platelets in the blood (day 9). BALB/c mice could not tolerate 100 mg/kg daily x 5 days unless LV (200 mg/kg twice daily) was given on days 6-8. Measurement of RTX (polyglutamates) by RIA after 100 mg/kg RTX daily (days 1-4) showed less drug in plasma (3-4-fold), liver (8-11-fold), kidney (3-4-fold), and small intestinal epithelium (3-4-fold) on day 7 in LV-treated mice (100 or 200 mg/kg twice daily) compared with controls. A single injection of 100 mg/kg RTX (day 1) gave plasma levels of 3-4 pmol/ml on day 4 that are more clinically relevant. Administration of LV (100 or 200 mg/kg; twice daily on days 4-6) reduced the RTX concentration in the liver 2-4-fold on days 7, 9, and 11 compared with controls. A model is proposed where LV and/or its anabolic products can compete with RTX uptake into tissues and interfere with the homeostatic regulation of RTX polyglutamates. These data support the use of LV rescue in the small minority of patients treated with RTX who present with a severe pattern of antiproliferative toxicities. The use of LV is not recommended routinely because the antitumor activity of RTX may similarly be reversed.

Stilboestrol plus adrenal suppression as salvage treatment for patients failing treatment with luteinizing hormone-releasing hormone analogues and orchidectomy.

OBJECTIVE: To investigate the efficacy of low-dose stilboestrol (SB) with hydrocortisone in patients with advanced prostate cancer refractory to androgen suppression. PATIENTS AND METHODS: Thirty-four consecutive patients (median age 70 years, range 51-83) with metastatic disease who progressed on hormone therapy, as shown by recurrent/worsening symptoms and an increase in prostate-specific antigen (PSA) level, were recruited and discontinued hormonal treatment before starting SB. Patients received SB (1 mg/day) combined with hydrocortisone (40 mg/day). In an attempt to reduce the incidence of thrombo-embolic events, aspirin (75 mg/day) was also added. RESULTS: Stilboestrol was the second-line treatment in 19 patients and the third or fourth in 15. The median (range) duration of treatment with SB was 5 (0.5-21) months and the median follow-up 7.5 months, with 18 patients still alive and 14 still on treatment. Of 29 symptomatic patients, 24 had symptomatic improvement and five had no clear benefit; the median duration of benefit was 6 (2-21) months. The PSA level decreased by 0-50% in six patients, by 50-90% in 13 and by > 90% in eight, while there was symptomatic improvement in these three categories in five, 11 and seven patients, respectively. The median times to PSA nadir and progression were 4 and 6 months, respectively. Some thrombo-embolic events and fluid retention occurred but overall the treatment was well tolerated. CONCLUSION: Low-dose SB with hydrocortisone is effective in refractory prostate cancer, although there is some toxicity. Randomized studies against hydrocortisone or SB alone are needed to establish the cost/benefit ratio of this combination.

Balb/c mice as a preclinical model for raltitrexed-induced gastrointestinal toxicity.

Raltitrexed (RTX) is an antifolate thymidylate synthase (TS) inhibitor used for the treatment of advanced colorectal cancer. RTX induces proliferating tissue toxicities that are largely confined to the intestine, with diarrhea being a severe side effect in a small but significant minority of patients. Similarly, weight loss and diarrhea were observed in BALB/c mice, and a maximum tolerated dose (MTD) was determined as approximately 5-10 mg/kg/day x 5 days. At an equivalent dose of 10 mg/kg/day x 5 days (dl-5), DBA2 mice lost considerably less weight, leading to a higher MTD (>500 mg/kg/day x 5 days), and there was no evidence of diarrhea. Histopathological consequences of damage, such as changes in small intestinal crypt architecture and villus atrophy induced by the 10-mg/kg/day dose, were greater and of longer duration in BALB/c mice. A higher dose of RTX (100 mg/kg/day x 5) induced weight loss and histopathological damage similar to that seen in BALB/c mice (10 mg/kg/ day x 5) but was of later onset, nadir, and recovery. Small changes to the colon were only observed in BALB/c mice. Pretreatment levels of plasma thymidine, deoxyuridine (approximately 1 microM), and folate (approximately40 ng/ml) were similar in both mouse strains. A single injection of radiolabeled RTX (5 mg/kg/ day) did not lead to any marked difference 24 h later in the total drug concentration and distribution of polyglutamates (comprising 70-80% of drug extracted) in the liver, kidney, and intestinal epithelium (large and small intestine) between the two mouse strains. Further studies used a RIA to measure RTX polyglutamate formation in tissues at various times and drug doses. This led to the conclusion that, although there was a higher accumulation of RTX in BALB/c small intestinal epithelium (days 4-6), it may be an effect secondary to another undetermined cause of increased drug sensitivity. This model represents a vehicle by which the etiology and treatment of severe clinical toxicity induced by RTX may be evaluated.

Potential of intermittent hormone therapy for M+ and M0 prostate cancer patients.

Increasingly animal and clinical studies suggest that intermittent therapy may improve the duration of hormone dependence in patients with prostate cancer. However there remains uncertainty as to optimal duration of treatment and level of prostate-specific antigen (PSA) before treatment is restarted. The aim of this study was to identify risk factors that predict duration of therapy in prostate cancer patients receiving intermittent hormone therapy. Any patients who had achieved PSA complete remission after hormone therapy for metastatic or locally advanced prostate cancer were included in the study. Fifty patients entered on intermittent hormone therapy after achieving a PSA complete remission. In all, 57% of patients remained off treatment at 12 months and the median time for restarting further hormone therapy was 14 months. At 1 y, 95% of patients retreated are progression free and overall 92% are alive at 3 y. There was some evidence that there was a slower progression to require treatment in older M0 patients and those who had been on treatment for more than 9 months. Although M0 patients receiving radiation concurrently after initial hormone down staging had a slower recurrence rate, 53% of M0 patients treated with hormone alone remained off hormones for more than one year. Clearly selection cannot be excluded as a cause for this good survival. However as overall survival in this study is at least as good as that of patients with M0 disease on hormone therapy in the immediate arm of the MRC immediate vs deferred therapy study, there is a case to extend examination of this approach to a randomized trial. This might also include patients failing to achieve PSA complete remission in order to examine the issue of whether continued androgen withdrawal is required in the terminal treatment phase of hormone-resistant patients to keep the hormone sensitive clone under control. Prostate Cancer and Prostatic Diseases (2000) 3, 286-289

Single agent infusional 5-fluorouracil is not effective second-line therapy after raltitrexed (Tomudex) in advanced colorectal cancer.

Raltitrexed (Tomudex) is currently licensed for first-line treatment of advanced colorectal cancer. We evaluated 101 patients treated with raltitrexed whose data were collected prospectively, in order to study the outcome of second-line treatments used after this drug. Of 98 evaluable patients, 50 received second-line treatments, the commonest being 5-fluorouracil (5-FU)-based therapy (22 patients with 20 evaluable) and mitomycin-c (MMC) (22 patients with 18 evaluable). Only 1 response was seen in a patient treated with 5-FU and MMC and none following other treatments. This patient was not evaluable for outcome of raltitrexed treatment, having stopped after two courses. Patients who had responded to raltitrexed and later progressed off treatment were more likely to be offered second-line 5-FU, but despite the earlier sensitivity to thymidylate synthase inhibition, response rates were minimal. Underlying mechanisms for this lack of activity and proposals for future studies are discussed.

Unknown primary carcinoma: randomised studies are needed to identify optimal treatments and their benefits.

This is a retrospective review of 101 patients with unknown primary carcinoma (UPC) treated between 1989 and 1994, on whom data were collected prospectively. 92 patients received platinum-based chemotherapy and 9 had single agent 5-fluorouracil (5-FU). In the platinum group, an objective response rate of 37.2% was seen, with a median duration of 4.5 months (range 1.9-17.5). There were no responses with 5-FU alone, while median survival was 6.4 months and was not different from the platinum group (P = 0.09). Considerable symptomatic resolution was noted, although the contribution of chemotherapy alone to this is difficult to define. The impact of tumour response on quality of life and survival in UPC requires further elucidation in prospective studies with a "best supportive care' arm. The superiority of platinum-based treatments reported in selected subgroups cannot be applied to the whole spectrum of UPC.

Primary osteosarcoma of the breast.

Osteosarcoma is a rare primary breast tumour. We report on a 55-year-old woman who presented with a left breast lump and a mammogram suggestive of carcinoma. At lumpectomy, a 3 cm mass was removed. Histology was consistent with primary osteosarcoma. There was satisfactory surgical clearance and no evidence of metastasis. She received four courses of adjuvant post-operative chemotherapy and remains free of disease at 14 months from diagnosis.