Category III chronic prostatitis/chronic pelvic pain syndrome: insights from the National Institutes of Health Chronic Prostatitis Collaborative Research Network studies.

Chronic prostatitis/chronic pelvic pain syndrome remains an enigmatic medical condition. Creation of the National Institutes of Health-funded Chronic Prostatitis Collaborative Research Network (CPCRN) has stimulated a renewed interest in research on and clinical aspects of chronic prostatitis/chronic pelvic pain syndrome. Landmark publications of the CPCRN document a decade of progress. Insights from these CPCRN studies have improved our management of chronic prostatitis/chronic pelvic pain syndrome and offer hope for continued progress.

Sensitizing acute myeloid leukemia cells to induced differentiation by inhibiting the RIP1/RIP3 pathway.

Tumor necrosis factor-α (TNF-α)-induced RIP1/RIP3 (receptor-interacting protein kinase 1/receptor-interacting protein kinase 3)-mediated necroptosis has been proposed as an alternative strategy for treating apoptosis-resistant leukemia. However, we found that most acute myeloid leukemia (AML) cells, especially M4 and M5 subtypes, produce TNF and show basal level activation of RIP1/RIP3/MLKL signaling, yet do not undergo necroptosis. TNF, through RIP1/RIP3 signaling, prevents degradation of SOCS1, a key negative regulator of interferon-γ (IFN-γ) signaling. Using both pharmacologic and genetic assays, we show here that inactivation of RIP1/RIP3 resulted in reduction of SOCS1 protein levels and partial differentiation of AML cells. AML cells with inactivated RIP1/RIP3 signaling show increased sensitivity to IFN-γ-induced differentiation. RIP1/RIP3 inactivation combined with IFN-γ treatment significantly attenuated the clonogenic capacity of both primary AML cells and AML cell lines. This combination treatment also compromised the leukemogenic ability of murine AML cells in vivo. Our studies suggest that inhibition of RIP1/RIP3-mediated necroptotic signaling might be a novel strategy for the treatment of AML when combined with other differentiation inducers.

Hemostatic abnormalities in untreated cancer: incidence and correlation with thrombotic and hemorrhagic complications.

Over a 2-month period, 40 patients with untreated malignancy were studied for protein-C (PRC), antithrombin-III (AT-III), fibrinopeptide A (FPA), routine hemostatic screens, and presence of liver metastases to determine pretreatment changes of hemostasis and relate them to subsequent development of thrombotic or hemorrhagic complications. These patients were observed for a mean period of 18 months. There were 23 males and 17 females with a median age of 64 years. Nine patients had lung carcinoma, 8 colon carcinoma, 7 lymphoma, 5 breast carcinoma, 5 head and neck carcinoma, 2 acute leukemia, 2 prostate carcinoma, 1 adenocarcinoma of unknown primary, and 1 sarcoma. Eight patients had liver metastases. PRC was measured by ELISA, AT-III by radial immunodiffusion, and FPA by RIA. Four patients had decreased AT-III, 28 had decreased levels of PRC, and 39 had elevated levels of FPA. All patients with liver metastases had low PRC. Albumin levels were lower in patients with low PRC (mean 3.3 g/dL v 4.0 g/dL for others). Eight patients, five with liver metastases, developed thrombotic (4), hemorrhagic (3), or both (1) complications. Statistically significant associations were found between (1) presence of liver metastases and development of thrombotic and hemorrhagic complications (P less than .001), (2) presence of liver metastases and decreased PRC (P = .001), and (3) lower albumin levels and decreased PRC (P = .0001). Our study documents early changes of hemostasis in untreated malignancy. We extend previous observations that decreased PRC levels in malignancy may be due to poor synthetic functions of liver. Presence of liver metastases was the only factor associated with subsequent development of thrombotic and hemorrhagic complications. Biochemical markers of hemostatic abnormalities, even though encountered frequently at the time of presentation, are of little predictive value for development of thrombotic and hemorrhagic complications.

Neurotoxicity associated with systemic high-dose cytosine arabinoside.

High doses of cytosine arabinoside (ara-C) have been used in the treatment of refractory forms of acute nonlymphoblastic leukemia (ANLL) and ANLL occurring after previous antineoplastic therapy. In addition to the usual toxicities associated with antimetabolites, neurotoxicity, mainly in the form of cerebellar dysfunction, develops in a significant proportion of patients receiving high-dose cytosine arabinoside HDara-C. This study was performed to determine the incidence of cerebellar dysfunction in our patients and to determine any factors that predict its development. In this series of 30 consecutive patients receiving HDara-C, confusion with cerebellar signs and symptoms developed in seven (23%). Factors that appear to predispose patients to the development of neurotoxicity are (1) past history of neurologic dysfunction and (2) preexisting and progressive hepatic dysfunction. No peripheral neuropathy was seen. In contrast to previous reports, we did not find neurotoxicity to be dose related. Prophylactic use of pyridoxine does not prevent neurotoxicity.

Phase II trial of recombinant human interferon alpha in myelodysplastic syndromes.

Twenty patients with myelodysplastic syndromes were treated with daily subcutaneous injections of interferon alpha 2a, at the initial dose of 3 x 10(6) U/m2. Hemogram, chemistry profile, natural killer (NK) cell activity and lymphokine-activated killer (LAK) cell cytotoxicity were monitored serially. Bone marrow with cytogenetic analysis was done before therapy and every three months afterwards. Normalization to the complete blood count, and wherever applicable, decrease in blast count of 5% or less were defined as a complete response. Improvement in hemoglobin level to 12 g/dl, neutrophil count to 1000/mm3 and platelets to 100,000/mm3 was considered a partial response. The median age was 71 (range 59-83) years and 16 of the patients were males. Two patients withdrew from the treatment in the first week and were considered ineligible. Among the other 18, two had refractory anemia, two refractory anemia with ringed sideroblasts, four chronic myelomonocytic leukemia, eight refractory anemia with excess blasts, and two refractory anemia with excess blasts in transformation to acute leukemia. Twelve patients were treated for six months, the other six were taken off the treatment after six to eight weeks because of disease progression. Only one patient with chronic myelomonocytic leukemia had a partial response for two months. NK cell activity remained unchanged before (18.3 +/- 4.6 lytic units) and during interferon therapy (19.6 +/- 5.3 lytic units). LAK cytotoxicity was not detected in any patient before therapy and was seen in only one patient (not the responder) during therapy (5.7 lytic units). The toxicity of the interferon therapy was substantial. Seventeen patients required a dose reduction and fifteen lost greater than 10% of body weight. Eleven patients (61%) developed infections requiring antibiotic therapy, and eight (44%) required hospitalization. Seven patients developed neurologic toxicity. Interferon alpha 2a is an ineffective but toxic therapy in these elderly patients with myelodysplastic syndromes.

Red cell fragmentation syndrome with the use of subclavian hemodialysis catheters.

The red cell fragmentation syndrome can occur due to abnormalities of the heart or the blood vessels or vascular malformations. We describe three patients who developed symptomatic hemolytic anemia due to red cell fragmentation with the use of single-lumen subclavian hemodialysis catheters. Retrospective analysis of 75 other patients who had undergone dialysis through this catheter disclosed five additional cases. Red cell fragmentation appears to be associated with partial catheter occlusion by thrombus or development of a clot at the catheter tip or both. The fragmentation resolved in all cases on withdrawal of the catheter. All patients with this catheter should be closely monitored for the red cell fragmentation syndrome, and the catheter should be withdrawn if it develops. White cell fragmentation was also seen in one patient.

Ciprofloxacin or tamsulosin in men with chronic prostatitis/chronic pelvic pain syndrome: a randomized, double-blind trial.

BACKGROUND: Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) in men is principally defined by pain in the pelvic region lasting more than 3 months. No cause of the disease has been established, and therapies are empirical and mostly untested. Antimicrobial agents and alpha-adrenergic receptor blockers are frequently used. OBJECTIVE: To determine whether 6-week therapy with ciprofloxacin or tamsulosin is more effective than placebo at improving symptoms in men with refractory, long-standing CP/CPPS. DESIGN: Randomized, double-blind trial with a 2 x 2 factorial design comparing 6 weeks of therapy with ciprofloxacin, tamsulosin, both drugs, or placebo. SETTING: Urology outpatient clinics at 10 tertiary care medical centers in North America. PATIENTS: Patients were identified from referral-based practices of urologists. One hundred ninety-six men with a National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) score of at least 15 and a mean of 6.2 years of symptoms were enrolled. Patients had received substantial previous treatment. MEASUREMENTS: The authors evaluated NIH-CPSI total score and subscores, patient-reported global response assessment, a generic measure of quality of life, and adverse events. INTERVENTIONS: Ciprofloxacin, 500 mg twice daily; tamsulosin, 0.4 mg once daily; a combination of the 2 drugs; or placebo. RESULTS: The NIH-CPSI total score decreased modestly in all treatment groups. No statistically significant difference in the primary outcome was seen for ciprofloxacin versus no ciprofloxacin (P = 0.15) or tamsulosin versus no tamsulosin (P > 0.2). Treatments also did not differ significantly for any of the secondary outcomes. LIMITATIONS: Treatment lasting longer than 6 weeks was not tested. Patients who had received less pretreatment may have responded differently. CONCLUSION: Ciprofloxacin and tamsulosin did not substantially reduce symptoms in men with long-standing CP/CPPS who had at least moderate symptoms.

A phase III comparison of high dose ARA-C (HIDAC) versus HIDAC plus mitoxantrone in the treatment of first relapsed or refractory acute myeloid leukemia Southwest Oncology Group Study.

The aim of this study is to determine whether the addition of mitoxantrone to high dose cytarabine improves the outcome of treatment in patients with relapsed or refractory acute myeloid leukemia (AML). One hundred and sixty-two eligible patients, 14-76 years of age, with AML either in first relapse or that failed to respond to initial remission induction therapy, with no CNS involvement were randomized to receive therapy with cytarabine 3 gm/M2 i.v. over 2 h every 12 h for 12 doses on days 1-6 (Arm I) (HIDAC); or HIDAC plus mitoxantrone 10 mg/M2 i.v. daily on days 7 9 (Arm II) (HIDAC + M). Patients achieving complete remission were treated with three courses of consolidation including HIDAC (Ara-C 3 gm/M2 i.v. 12 h days 1 3; 2 gm/M2 over age 50) alone (ARM I) or with mitoxantrone (10 mg/M2 i.v. day 1) (ARM II). Among 162 patients (81 HIDAC, 81 HIDAC + M) evaluated for induction toxicity, there were 10 (12%) induction deaths with HIDAC and 13 (17%) with HIDAC + M (2-tailed P = 0.65). Most early deaths were due to infection and/or hemorrhage. Among 162 patients evaluated for responses to induction therapy, 26/81 (32%) HIDAC and 36/81 (44%) HIDAC + M patients achieved complete remission (two-tailed P = 0.15). Although this difference was not statistically significant in univariate analysis, it was after adjusting for the effects of WBC and PMN percentage in multivariate analysis (P=0.013). Median survivals from study entry were 8 months (HIDAC) and 6 months (HIDAC + M); 2-tailed logrank P = 0.58. Among 48 patients registered for consolidation, the median disease-free survivals from that registration were 8 months with HIDAC and 11 months with HIDAC + M (P = 0.60). There were three treatment-related deaths during consolidation (1 HIDAC, 2 HIDAC + M), all due to infections. In this randomized trial, the addition of mitoxantrone to high-dose cytarabine was associated with a trend toward a higher CR rate. There was less evidence for an advantage in disease-free or overall survival, although any such conclusion is limited by the size of the study.

Bleeding pattern and endometrial changes during continuous combined hormone replacement therapy. The Ogen/Provera Study Group.

OBJECTIVE: To establish the optimum oral daily dose of micronized medroxyprogesterone acetate, given in combination with a fixed oral dose of estrone (E1) sulfate as hormone replacement therapy, that provides endometrial protection and induces cessation of vaginal bleeding. METHODS: This multicenter, randomized, double-blind study was conducted for 2 years. Five hundred sixty-eight postmenopausal women were randomized to take E1 sulfate 1.25 mg daily and one of three doses of medroxyprogesterone acetate (2.5, 5, or 10 mg) daily. Any vaginal bleeding was recorded by patients in a daily diary, and endometrial biopsies were performed at entry into the study and at 3, 12, and 24 months. RESULTS: Forty-two percent of all women reported some bleeding at month 3 of therapy. However, by month 6, 76.5, 80.1, and 80.9% of women were amenorrheic in the 2.5-, 5-, and 10-mg medroxyprogesterone acetate groups, respectively. Over time, the percentage of women with no bleeding increased in each group, and by 24 months 91.5, 89.9, and 94.3% were amenorrheic in the 2.5- and 10-mg medroxyprogesterone acetate groups, respectively. Approximately 10% of women continue to have some bleeding, regardless of the dose of medroxyprogesterone acetate. There were no statistically significant differences in the number of women with bleeding at any time point between the three groups. There were no cases of endometrial hyperplasia reported in the study population over the 2 years. CONCLUSION: All three studied doses of medroxyprogesterone acetate, given in combination with 1.25 mg of E1 sulfate, provide adequate endometrial protection and render approximately 80% of women amenorrheic by 6 months of therapy.

Bone density effects of continuous estrone sulfate and varying doses of medroxyprogesterone acetate. Ogen/Provera Study Group.

OBJECTIVE: To establish the optimum oral daily dose of medroxyprogesterone acetate with estrone sulfate for 2 years to maintain bone density. METHODS: A multicenter, double-blind study involved 568 postmenopausal women given estrone sulfate, 1.25 mg, and randomized to receive 2.5, 5, or 10 mg of medroxyprogesterone acetate. Bone density analyses of the lumbar spine and femoral neck were done at baseline and 12 and 24 months. RESULTS: There was a significant increase from baseline to 24 months in mean lumbar spine (4.0% +/- 0.27%) and femoral neck (3.2% +/- 0.28%) bone density, with no significant differences between the treatment groups. Factors most influencing bone density changes were baseline bone density and treatment duration. Significant increases were seen in the spine over 2 years; in the hip, those occurred in the first 12 months only. In both sites, lower baseline bone density resulted in greater increases. In the spine only, no previous hormone replacement therapy, higher body mass index, more than 2 years postmenopause, and nonsmoking resulted in greater gains. Once those covariates and center-to-center variations were corrected for, in the spine, the 10-mg group had smaller increases than the other groups. Changes were unrelated to age, parity, calcium, and alcohol intakes in either site. CONCLUSION: Daily estrone sulfate, 1.25 mg, with 2.5, 5, or 10 mg medroxyprogesterone acetate was effective for preventing bone loss in postmenopausal women.

MR of leptomeningeal spinal and posterior fossa amyloid.

We report an unusual cause of leptomeningeal MR enhancement, amyloid, along the surfaces of the spinal cord and brain stem and in the spinal subarachnoid space, with sacral intradural and epidural deposition. Type I familial amyloid polyneuropathy may cause amyloid deposition along the leptomeninges of the spinal cord and brain in addition to the visceral organs and the peripheral somatic and autonomic nerves.

Fatigue fracture of the femoral neck.

Fatigue fractures in the necks of femurs removed from fresh cadavers were produced experimentally by applying repeated compression and rotational stresses. We found that a load applied once in a physiological direction may be within the ultimate strength of the bone, but may produce a fracture if applied repeatedly. With increased age, chances of fatigue failure increased age, chances of fatigue failure increased and loads of even physiological magnitude produced fatigue fractures. This may also happen during life. The subcapital fractures produced in these specimens were similar to those seen in patients in a clinical practice. This has been reported many times in new young military recruits. In individuals undergoing unusually strenuous exercises, the stress concentrations can be unusually high.