Rectal Complications After Prostate Brachytherapy

PURPOSE Prostate brachytherapy is gaining wide popularity as an alternative to resection for the treatment of locally advanced prostate cancer. Rectal-urethral fistula after prostate brachytherapy is a rare but serious complication, and its incidence, presentation, risk factors, and clinical management have not been well described.METHODS From January 1997 to October 2002, seven patients with rectal-urethral fistulas were referred to two institutions (Brigham and Womens Hospital and West Roxbury Veterans Administration Hospital) of a major teaching referral center. Clinical presentation, risk factors, prostate staging, and clinical management were examined in a retrospective fashion.RESULTS Seven rectal-urethral fistulas developed from roughly 700 (1 percent) patients treated with prostate brachytherapy for prostate cancer. The average patient age was 67.7 years, preimplant prostate-specific antigen was 7.1, and Gleason score was 3+3. Symptoms occurred at a mean of 27.3 months after prostate brachytherapy was started and included anorectal pain (57 percent), clear mucous discharge (57 percent), diarrhea (43 percent), and rectal ulceration (43 percent). Coronary artery disease was a common comorbidity (71 percent). Previous transurethral resection of prostate (28 percent) and pelvic irradiation or external beam radiation therapy (14 percent) were not associated with increased risk of rectal-urethral fistula. All patients underwent a diverting colostomy (86 percent) or ileostomy (14 percent), and four patients went on to have definitive therapy. Definitive resection was performed between 5 and 43 months after diverting ostomy and was chosen on the basis of comorbid disease, quality of life, and degree of operation. Two patients required a second diversion after definitive resection because of anorectal pain and a colocutaneous fistula. Postoperative complications included myocardial infarction (14 percent), blood transfusion (14 percent), and bowel perforation (14 percent). Patients became symptom-free nine months after surgery. Six patients are alive and well today; one died from an unrelated cause.CONCLUSIONS Rectal-urethral fistula after prostate brachytherapy is a rare but devastating complication. Patients should be followed for at least three years after prostate brachytherapy because symptoms can develop late in the course. Although diversion of fecal stream does not heal the fistula, all patients diagnosed with rectal-urethral fistula should first undergo diverting ostomy to alleviate symptoms. Then, one should consider definitive resection and ostomy closure.Read at the meeting of The American Society of Colon and Rectal Surgeons, New Orleans, Louisiana, June 21 to 26, 2003.     

Intracranial MEMS based temozolomide delivery in a 9L rat gliosarcoma model

Primary malignant brain tumors (BT) are the most common and aggressive malignant brain tumor. Treatment of BTs is a daunting task with median survival just at 21 months. Methods of localized delivery have achieved success in treating BT by circumventing the blood brain barrier and achieving high concentrations of therapeutic within the tumor. The capabilities of localized delivery can be enhanced by utilizing mirco-electro-mechanical systems (MEMS) technology to deliver drugs with precise temporal control over release kinetics. An intracranial MEMS based device was developed to deliver the clinically utilized chemotherapeutic temozolomide (TMZ) in a rodent glioma model. The device is a liquid crystalline polymer reservoir, capped by a MEMS microchip. The microchip contains three nitride membranes that can be independently ruptured at any point during or after implantation. The kinetics of TMZ release were validated and quantified in?vitro. The safety of implanting the device intracranially was confirmed with preliminary in?vivo studies. The impact of TMZ release kinetics was investigated by conducting in?vivo studies that compared the effects of drug release rates and timing on animal survival. TMZ delivered from the device was effective at prolonging animal survival in a 9L rodent glioma model. Immunohistological analysis confirmed that TMZ was released in a viable, cytotoxic form. The results from the in?vivo efficacy studies indicate that early, rapid delivery of TMZ from the device results in the most prolonged animal survival. The ability to actively control the rate and timing of drug(s) release holds tremendous potential for the treatment of BTs and related diseases.     

Surgical Approach and Oncologic Outcomes Following Multidisciplinary Management of Retrorectal Sarcomas

Background

Retrorectal sarcomas are rare, and limited data are available on oncologic outcomes following surgery. Our aim was to evaluate outcomes in this patient population at our institution.

Materials and Methods

All patients who underwent surgical resection of a malignant retrorectal/presacral sarcoma between 1985 and 2005 were identified. Data analyzed included demographics, histopathologic diagnosis, surgical morbidity and mortality, use of adjuvant therapy, local and distant recurrence, and survival.

Results

A total of 37 patients were identified (20 males) with a median age of 49 years (range, 22–81 years). The most common histopathologic diagnosis was malignant peripheral nerve sheath tumor (n = 8). Also, 22 tumors were high grade and 15 were low grade. Surgical margin status was R0 in 31 patients and R1 in 6. Adjuvant therapy was given to 26 patients. Postoperative morbidity and mortality was 57% and 3%, respectively. Median length of follow-up in 16 patients alive at last contact was 4.7 years. The 5-year survival free of local (LDFS), distant (DDFS), and local or distant recurrence (DFS) was 51, 58, and 39%, respectively. Patient survival at 2, 5, and 10 years was 75, 55, and 47%, respectively. Disease-free survival was not significantly associated with gender (P = .16), primary vs secondary (P = .94), R0 vs R1 resection (P = .26), low vs high tumor grade (P = .17), or the use of surgery with or without adjuvant therapy (P = .33).

Conclusions

Retrorectal sarcomas are often high grade and locally advanced. Most tumors are resectable with free margins, and long-term survival may be possible in up to one-half of patients following an aggressive surgical approach.     

Successful treatment of portopulmonary hypertension with the selective endothelin receptor antagonist Sitaxentan

Portopulmonary hypertension (POPH) is a rare complication of portal hypertension. Prostanoids have been shown to be effective in the treatment of POPH and have been used as a bridge to liver transplantation. More recently, case series revealed beneficial effects of both the dual endothelin receptor antagonist bosentan and the phosphodiesterase-5 inhibitor sildenafil. The efficacy of sitaxentan, a selective endothelin receptor A (ERA) antagonist in the reversal of POPH, is still unclear. We report a case of POPH that was successfully treated with oral sitaxentan. Haemodynamic and symptomatic improvements were maintained after a 12-week long-term treatment period. Additionally, hepatic vein pressure gradient significantly decreased from 12 mmHg to 8 mm after treatment with sitaxentan. This is the first reported case of a successful therapy with a selective ERA antagonist in a patient suffering from POPH. Oral sitaxentan therapy might be a promising new option for patients suffering from POPH.     

Bleeding and Thromboembolic Outcomes for Patients on Oral Anticoagulation Undergoing Elective Colon and Rectal Abdominal Operations

Purpose  

Patients on chronic oral anticoagulation can be challenging to manage in the perioperative period.     

Interaction between anandamide and sphingosine-1-phosphate in mediating vasorelaxation in rat coronary artery

Background and purpose:

This study establishes a pharmacokinetic/pharmacodynamic (PK/PD) model to describe the time course and in vivo mechanisms of action of the antinociceptive effects of lumiracoxib, evaluated by the thermal hyperalgesia test in rats.

Experimental approach:

Female Wistar fasted rats were injected s.c. with saline or carrageenan in the right hind paw, followed by either 0, 1, 3, 10 or 30 mg·kg⁻¹ of oral lumiracoxib at the time of carrageenan injection (experiment I), or 0, 10 or 30 mg·kg⁻¹ oral lumiracoxib at 4 h after carrageenan injection (experiment II). Antihyperalgesic responses were measured as latency time (LT) to a thermal stimulus. PK/PD modelling of the antinociceptive response was performed using the population approach with NONMEM VI.

Results:

A two-compartment model described the plasma disposition. A first-order model, including lag time and decreased relative bioavailability as a function of the dose, described the absorption process. The response model was: LT=LT₀/(1 +MED). LT₀ is the baseline response, and MED represents the level of inflammatory mediators. The time course of MED was assumed to be equivalent to the predicted profile of COX-2 activity and was modelled according to an indirect response model with a time variant synthesis rate. Drug effects were described as a reversible inhibition of the COX-2 activity. The in vivo estimate of the dissociation equilibrium constant of the COX-2-lumiracoxib complex was 0.24 µg·mL⁻¹.

Conclusions:

The model developed appropriately described the time course of pharmacological responses to lumiracoxib, in terms of its mechanism of action and pharmacokinetics.     

Antagonistic and synergistic effects of glucocorticoids and IL-7 on CD4+ T cell activation

Glucocorticoids (GCs) are steroidal compounds widely used to treat chronic and acute inflammatory diseases. In particular, GCs at pharmacological doses induce apoptosis of activated and na?ve T cells, inhibit their proliferation and block pro-inflammatory cytokine secretion. At physiological concentrations, the effect of these steroids on T cell immunity are not yet fully understood, and various studies reported paradoxical roles exerted by GCs on T cell immunity. Here, we show that GCs surprisingly induce proliferation of activated CD4(+) T cells in the presence of IL-7, a cytokine secreted in the thymus and at mucosal sites. Increased proliferation is dependent on a GC-mediated survival of mitotic cells. Moreover, we observe a downmodulation of Th1 cytokine secretion in cells treated with GCs, an outcome which is not affected by the presence of IL-7. GCs exert thus a positive role in the presence of IL-7 by enhancing proliferation of CD4(+) T cells and simultaneously a negative role by suppressing pro-inflammatory cytokine production.     

Cancer genetics-guided discovery of serum biomarker signatures for diagnosis and prognosis of prostate cancer

A key barrier to the realization of personalized medicine for cancer is the identification of biomarkers. Here we describe a two-stage strategy for the discovery of serum biomarker signatures corresponding to specific cancer-causing mutations and its application to prostate cancer (PCa) in the context of the commonly occurring phosphatase and tensin homolog (PTEN) tumor-suppressor gene inactivation. In the first stage of our approach, we identified 775 N-linked glycoproteins from sera and prostate tissue of wild-type and Pten-null mice. Using label-free quantitative proteomics, we showed that Pten inactivation leads to measurable perturbations in the murine prostate and serum glycoproteome. Following bioinformatic prioritization, in a second stage we applied targeted proteomics to detect and quantify 39 human ortholog candidate biomarkers in the sera of PCa patients and control individuals. The resulting proteomic profiles were analyzed by machine learning to build predictive regression models for tissue PTEN status and diagnosis and grading of PCa. Our approach suggests a general path to rational cancer biomarker discovery and initial validation guided by cancer genetics and based on the integration of experimental mouse models, proteomics-based technologies, and computational modeling.     

Repeated in vivo electrochemical activation and the biological effects of microelectromechanical systems drug delivery device

The repeated activation of a microelectromechanical systems (MEMS) drug delivery device was studied in vivo in rats to examine the effect of implantation on the device operation and the effect of electrochemical activation on the inflammatory and wound-healing response. The MEMS devices were fabricated from a silicon wafer into which reservoirs were etched and covered with gold membranes. The membranes were electrochemically removed when an anodic voltage was applied. Devices were implanted subcutaneously both with and without stainless steel mesh cages for 4, 7, 14, 21, or 28 days before activation. Devices were activated every other day for five activations. Leukocyte concentrations indicated that both the application of voltage and the gold corrosion products elevated the inflammatory response which was resolved within 48 h after each activation. The efficiency of gold membrane removal was not impaired throughout the implantation, although a bimodal distribution of background current densities was observed after long implantation times. The thickness of the fibrous capsule surrounding the MEMS devices was similar between activated and control devices explanted at each time point. It was concluded that the repeated activation of MEMS drug delivery devices was successful and the activation produced an acceptable biological response that resolved promptly.