6-day intensive treatment protocol for refractory chronic prostatitis/chronic pelvic pain syndrome using myofascial release and paradoxical relaxation training.

PURPOSE: Chronic prostatitis/chronic pelvic pain syndrome continues to elude conventional therapy. Evidence supports the concept that phenotypes of pelvic muscular tenderness and psychosocial distress respond to myofascial trigger point release and specific relaxation training. This case series reports long-term outcomes of a 6-day intensive combination of such therapies in refractory cases. MATERIALS AND METHODS: A total of 200 men with pain for a median of 4.8 years referred themselves to Stanford University Urology for participation in an established protocol. Daily 3 to 5-hour sessions including intrapelvic/extrapelvic physiotherapy, self-treatment training and paradoxical relaxation training provided a solid introduction to facilitate self-management. Subjects answered baseline and followup questionnaires at variable intervals after initiation of therapy including the National Institutes of Health Chronic Prostatitis Symptom Index, global response assessment and a psychological query. RESULTS: We followed 116 men for a median of 6 months. Baseline total symptom index was 26 out of a maximum 43 points. Scores decreased by 30% (p <0.001) at followup with 60% of subjects demonstrating a 6-point or greater decrease (range 6 to 30). Domains of pain, urinary dysfunction and quality of life showed significant improvement (p <0.001). Global response assessment revealed that 82% of subjects reported improvement (59% marked to moderate, 23% slight). CONCLUSIONS: Men with chronic pelvic pain refractory to traditional treatment benefit from intensive myofascial trigger point therapy and concomitant paradoxical relaxation training. Education in techniques for self-administered trigger point release and continued pelvic muscle relaxation help patients reduce pain and dysfunction. Refinement of clinical phenotyping and selection of patients with pelvic muscle tenderness should enhance the success rate with this treatment modality.

Stress induced hypothalamus-pituitary-adrenal axis responses and disturbances in psychological profiles in men with chronic prostatitis/chronic pelvic pain syndrome.

PURPOSE: Chronic pelvic pain in men has a strong relationship with biopsychosocial stress and central nervous system sensitization may incite or perpetuate the pain syndrome. We evaluated patients and asymptomatic controls for psychological factors and neuroendocrine reactivity under provoked acute stress conditions. MATERIALS AND METHODS: Men with pain (60) and asymptomatic controls (30) completed psychological questionnaires including the Perceived Stress, Beck Anxiety, Type A behavior and Brief Symptom Inventory for distress from symptoms. Hypothalamic-pituitary-adrenal axis function was measured during the Trier Social Stress Test with serum adrenocorticotropin hormone and cortisol reactivity at precise times, before and during acute stress, which consisted of a speech and mental arithmetic task in front of an audience. The Positive and Negative Affective Scale measured the state of emotions. RESULTS: Patients with chronic pelvic pain had significantly more anxiety, perceived stress and a higher profile of global distress in all Brief Symptom Inventory domains (p <0.001), scoring in the 94th vs the 49th percentile for controls (normal population). Patients showed a significantly blunted plasma adrenocorticotropin hormone response curve with a mean total response approximately 30% less vs controls (p = 0.038) but no differences in any cortisol responses. Patients with pelvic pain had less emotional negativity after the test than controls, suggesting differences in cognitive appraisal. CONCLUSIONS: Men with pelvic pain have significant disturbances in psychological profiles compared to healthy controls and evidence of altered hypothalamic-pituitary adrenal axis function in response to acute stress. These central nervous system observations may be a consequence of neuropsychological adjustments to chronic pain and modulated by personality.

Psychometric profiles and hypothalamic-pituitary-adrenal axis function in men with chronic prostatitis/chronic pelvic pain syndrome.

PURPOSE: Abnormal regulation of the hypothalamic-pituitary-adrenal axis and diurnal cortisol rhythms are associated with several pain and chronic inflammatory conditions. Chronic stress may have a role in the disorder of chronic prostatitis/chronic pelvic pain syndrome related to initiation or exacerbation of the syndrome. We tested the hypothesis that men with chronic pelvic pain syndrome have associated disturbances in psychosocial profiles and hypothalamic-pituitary-adrenal axis function. MATERIALS AND METHODS: A total of 45 men with chronic pelvic pain syndrome and 20 age matched, asymptomatic controls completed psychometric self-report questionnaires including the Type A personality test, Perceived Stress Scale, Beck Anxiety Inventory and Brief Symptom Inventory for distress from physical symptoms. Saliva samples were collected on 2 consecutive days at 9 specific times with strict reference to time of morning awakening for evaluation of free cortisol, reflecting secretory activity of the hypothalamic-pituitary-adrenal axis. We quantified cortisol variations as the 2-day average slope of the awakening cortisol response and the subsequent diurnal levels. RESULTS: Men with chronic pelvic pain syndrome had more perceived stress and anxiety than controls (p <0.001). Brief Symptom Index scores were significantly increased in all scales (somatization, obsessive/compulsive behavior, depression, anxiety, hostility, interpersonal sensitivity, phobic anxiety, paranoid ideation, psychoticism) for chronic pelvic pain syndrome, and Global Severity Index rank for chronic pelvic pain syndrome was 93rd vs 48th percentile for controls (p <0.0001). Men with chronic pelvic pain syndrome had significantly increased awakening cortisol responses, mean slope of 0.85 vs 0.59 for controls (p <0.05). CONCLUSIONS: Men with chronic pelvic pain syndrome scored exceedingly high on all psychosocial variables and showed evidence of dysfunctional hypothalamic-pituitary-adrenal axis function reflected in augmented awakening cortisol responses. Observations suggest variables in biopsychosocial interaction that suggest opportunities for neurophysiological study of relationships of stress and chronic pelvic pain syndrome.

Phase I clinical trials of tezacitabine [(E)-2'-deoxy-2'-(fluoromethylene)cytidine] in patients with refractory solid tumors.

PURPOSE: To evaluate safety, tolerability, and pharmacokinetics of a new nucleoside analogue, tezacitabine [(E)-2'-deoxy-2'-(fluoromethylene)cytidine (FMdC)] in patients with refractory solid tumors. EXPERIMENTAL DESIGN: Seventy patients were enrolled in four separate Phase I trials. Patients had metastatic or relapsed cancer of the colon, breast, pancreas, gastrointestinal tract, lung, and other sites. FMdC was administered by i.v. infusion over 30 min in one of four dose schedules--from once every 3 weeks to twice a week for 3 weeks, with dose escalation in each. Maximum doses ranged from 630 to 16 mg/m(2). RESULTS: Myelotoxicity, especially neutropenia, was the dominant toxicity and was generally dose-related. Grade 3 or 4 neutropenia occurred in 53% of patients but was of relatively short duration (1-8 days) in all of the patients. One patient experienced grade 3 thrombocytopenia and one patient grade 4 (duration 15 and 11 days, respectively). Transient febrile episodes were reported in 82% of patients with drug administration but were easily controlled. Drug-related gastrointestinal events were mild and appeared unrelated to dose. Pharmacokinetics were linear with dose, not appreciably affected by schedules, and not different after single or multiple doses. Terminal half-life was 3-4 h, and 23% of the administered drug was recovered in the urine as unchanged drug. The uridine analogue (FMdU), the deaminated metabolite of FMdC, was the primary metabolite. Objective antitumor activity was observed in eight patients: one exhibited a partial response and seven exhibited stable disease. CONCLUSIONS: In general, FMdC was well tolerated. On the basis of the time to recovery from neutropenia, the recommended schedule for Phase II studies is one treatment every 2 weeks, at a minimum dose of 270 mg/m(2).

Intratumoral cisplatin/adrenaline injectable gel for the treatment of patients with cutaneous and soft tissue metastases of malignant melanoma.

Local therapies have been highly effective in the treatment of melanoma. The objective of this study was to evaluate the use of a novel intralesional chemotherapy - cisplatin/adrenaline injectable gel - for the treatment of refractory or recurrent cutaneous and soft tissue melanoma metastases. The gel is injected directly into the lesion and delivers high concentrations of cisplatin at the injection site, where it is retained for extended periods, with little systemic exposure. A total of 28 patients with refractory or recurrent melanoma were enrolled in this open-label, multicentre study. Of these, 25 patients with 244 lesions were evaluable for efficacy. Lesions were injected with 0.5 ml (2 mg cisplatin + 0.05 mg adrenaline) of gel/cm(3) of tumour. Patients received up to six weekly treatments within an 8 week period. The objective response rate (complete responses [CRs] plus partial responses [PRs]) for all the tumours treated (1-72 per patient) was 53% (130 out of 244; 114 CRs, 16 PRs). The response rate for the target tumours (i.e. each patient's single, most symptomatic, largest or most threatening tumour) was 44%. The median response duration for all tumours was 347 days (range 30-783 days) and median number of treatments per tumour was five (range one to twelve). Systemic toxicity was negligible; local adverse reactions such as erythema, necrosis or pain occurred frequently, but were easily managed in most cases. In conclusion, cisplatin/adrenaline injectable gel was well tolerated, easy to administer, and effective in treating metastatic melanoma confined to the skin or soft tissues.

The role of intratumoral therapy with cisplatin/epinephrine injectable gel in the management of advanced squamous cell carcinoma of the head and neck.

OBJECTIVE: To determine the safety and efficacy of targeted antitumor therapy with cisplatin/epinephrine injectable gel in patients with advanced squamous cell carcinoma of the head and neck. DESIGN: Two prospective, double-blind, placebo-controlled phase III trials of identical design. Crossover from blinded to open-label phase was permitted for patients with disease progression. SETTING: Tertiary referral centers in North America and Europe. PATIENTS: One hundred seventy-nine intensively pretreated patients with recurrent or refractory squamous cell carcinoma of the head and neck. INTERVENTION: Cisplatin/epinephrine injectable or placebo gel was administered by direct intratumoral injection; up to 6 weekly treatments. Dose was 0.25 mL of active or placebo gel per cubic centimeter of tumor up to 10 mL total. Patient benefit after local tumor control of the most symptomatic tumor was assessed by patients and physicians using the Treatment Goals Questionnaire. MAIN OUTCOME MEASURES: Local tumor response and patient benefit attributable to improvements in tumor-related symptoms. RESULTS: Combined results for the 178 patients with evaluable data in the 2 trials confirmed objective tumor responses in 35 (29%) of 119 patients, including 23 (19%) complete responses achieved with cisplatin/epinephrine gel, vs 1 (2%) of 59 for placebo (P<.001). Tumor response and patient benefit were significantly correlated (P=.006): 47% (17/36) of patients with target tumor responses achieved a rigorously defined benefit based on a prospectively selected treatment goal vs 15% (22/142) of nonresponders. CONCLUSION: Cisplatin/epinephrine injectable gel reduces tumor burden, ameliorates tumor symptoms, and provides a new therapeutic option for treating patients with squamous cell carcinoma of the head and neck.

Clinical benefits in patients with psoriasis after efalizumab therapy: clinical trials versus practice.

Evaluations of efficacy of the new biologic therapies for psoriasis have used both physician-assessed endpoints and patient-reported outcome measures. The Psoriasis Area and Severity Index (PASI) is commonly used in clinical trials but is too labor intensive for clinical practice, which uses more subjective measures (physician global assessment [PGA] of change and Overall Lesion Severity [OLS] scale). Because psoriasis affects quality of life (QOL), patient-reported assessments of their satisfaction with treatment also are important. The purpose of this study was to evaluate some of the measurement tools used in clinical trials to make them more applicable to the practicing dermatologist. We used results of a placebo-controlled clinical study of efalizumab for the treatment of patients with moderate to severe plaque psoriasis. After treatment, ratings of improvement in psoriasis as measured by the PASI and PGA were closely aligned. It was noted the latter tool could provide a more practical and user-friendly evaluation in clinical practice. After 12 weekly subcutaneous injections of efalizumab, patients who achieved > or = 50% but < 75% improvement in PASI had treatment responses rated as primarily good or excellent using the PGA; additionally, the patients treated with efalizumab had statistically significant improvements (P<.001) in all patient-reported QOL assessments compared with placebo-treated patients, as did patients who achieved a > or = 75% improvement in PASI (PASI 75).

OnabotulinumtoxinA office treatment for neurogenic bladder incontinence in Parkinson's disease.

OBJECTIVE: To evaluate safety and effectiveness of low-dose (100 U) onabotulinumtoxinA (onabotA) bladder injections as an office procedure with topical anesthesia only for patients with Parkinson's disease (PD) and incontinence. METHODS: Qualified patients who failed oral antimuscarinic agents participated in an open-label study. They discontinued antimuscarinics, provided a King's Health Questionnaire (KHQ), voiding symptom score, and 3-day voiding diary. Free uroflowmetry with post-void ultrasounds and cystometrogram pressure/flow studies were performed. Patients underwent flexible cystoscopy and injections of onabotA 100 U (10 U/mL) dispersed into 10-20 submucosal/detrusor sites of the bladder, including the trigone. Voiding diaries, questionnaires, and free uroflowmetry with post-void ultrasound residual urine measurements were repeated after 1, 3, and 6 months. RESULTS: Twelve men and 8 women were treated: mean age, 70.4 years; duration of disease, 10.6 years; median bladder contraction volume, 115 mL; maximum bladder pressure, 62 cm; and post-void volume, 9 mL. Moderate to marked symptom relief at 3 months and a 50% incontinence decrease over 6 months relative to pretreatment was reported in 59% patients (P ≤.02); 5 patients failed to complete the 6-month endpoint. No urinary retention required catheterization. CONCLUSION: Office cystoscopy with low-dose onabotA injection treatment is a potential long-term management strategy for patients with PD and urinary incontinence who fail oral antimuscarinic agents. The treatment seems to be safely utilized for older men with BPH as well as women with potential hypoactive detrusor function.

Palliation of patients with dysphagia due to advanced esophageal cancer by endoscopic injection of cisplatin/epinephrine injectable gel.

BACKGROUND: The aim of therapy for advanced esophageal cancer is relief of dysphagia with minimal treatment-related morbidity. This study assessed the efficacy of endoscopic intratumoral injection of cisplatin/epinephrine gel to relieve obstruction and improve swallowing. The gel is designed to minimize diffusion of active drug away from the tumor injection site. METHODS: Patients with inoperable esophageal cancer and dysphagia caused by exophytic esophageal tumor underwent up to 6 weekly endoscopic injections of the gel. Response was documented objectively (exophytic tumor volume, lumen size, dysphagia grade) and subjectively (achievement of treatment goal). RESULTS: Twenty-four patients were treated. Primary evaluation criteria for 18 evaluable patients were as follows: dysphagia grade improved in 4 (duration 30 to 45 days) and stabilized in 11; lumen patency improved in 6 (duration 29 to 56 days) and stabilized in 10; exophytic tumor volume decreased in 8 (duration 29 to 114 days). Eight patients felt that their ability to swallow improved. One patient with intramural and exophytic tumor developed a tracheoesophageal fistula, possibly related to treatment. Other complications were tolerable and self-limited. No nephrotoxicty or severe nausea/vomiting typical of systemic administration of cisplatin occurred. CONCLUSIONS: Endoscopic injection of cisplatin/epinephrine gel is a straightforward procedure with standard equipment and techniques, which can provide palliation for patients with exophytic malignant tumors of the esophagus. Assessment of this method in conjunction with other therapeutic options such as brachytherapy is warranted.

Intratumoral cisplatin/epinephrine gel in advanced head and neck cancer: a multicenter, randomized, double-blind, phase III study in North America.

BACKGROUND: The objective was to evaluate the efficacy and safety of a novel intratumoral cisplatin/epinephrine injectable gel (CDDP/epi gel) for local control and palliation of tumor-related symptoms in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: Eighty-seven patients were randomly assigned to either CDDP/epi or placebo gel in this phase III, double-blind study. Tumors were < or =20 cm(3); most recurrences (88%) were in a previously irradiated field. The most symptomatic or threatening tumor was designated as the target tumor. DOSE: 0.25 mL CDDP/epi gel/cm(3) tumor volume. TREATMENTS: < or =6 weekly intratumoral injections in an 8-week period. PRIMARY OUTCOMES: target tumor response and symptom relief. RESULTS: During the blinded phase, 34% (21 of 62) of patients achieved an objective response (CR or PR) in the target tumor treated with CDDP/epi gel vs 0% (0 of 24) treated with placebo gel (p <.001). Responses occurred within a median of four treatments (range, 2-6) and were durable (median, 95 days; range, 34-168+ days). More patients treated with CDDP/epi gel achieved palliative benefit than did those treated with placebo gel (37% vs 12%, p =.036). Most frequent side effects were local pain and local cutaneous reactions, which resolved over 3-12 weeks. Renal and hematologic toxicities were rare. CONCLUSIONS: This phase III trial showed that CDDP/epi gel significantly reduces tumor burden, palliates tumor-related symptoms, and is an effective local treatment for recurrent tumors.