Prospective study on the relationship between clinical efficacy of secondary hormone therapy with flutamide and neuroendocrine differentiation in patients with relapsed prostate cancer after first line hormone therapy.

OBJECTIVE: The aim of this study was to prospectively verify the relationship between the clinical efficacies of secondary hormone therapy for castration-resistant prostate cancer (CRPC) following first line hormone therapy and neuroendocrine differentiation (NED). MATERIAL AND METHODS: Forty-six consecutive patients with CRPC following first line hormone therapy who were treated with flutamide as secondary hormone therapy were prospectively assessed with a median follow-up of 21 months. Serum chromogranin A (CgA), as a marker of NED, was measured using an immunoradiometric assay. RESULTS: Of the 46 patients, 22 (48%) responded to the secondary hormone therapy as a 50% or more reduction from baseline prostate-specific antigen (PSA) with a median response duration of 9.2 months. The PSA response group was correlated with significantly favorable cancer-specific survival (CSS) (92% vs 59% at 5 years, p = 0.0146) compared with the non-response group. Above-normal CgA levels at study entry were detected in 15 patients (33%), but no association with CSS was identified. Data on CgA kinetics were available in 35 patients. The CgA levels before and at 3 months during the treatment were similar. However, eight patients (23%) with an increase in CgA level of a quarter or more from baseline had a tendency for worse CSS (63% vs 84% at 5 years, p = 0.0507) compared with the remaining patients. CONCLUSION: Within limitations, in this study secondary hormone therapy with flutamide was effective for CRPC following first line hormone therapy. The above-normal CgA level in the first hormone resistance phase is mostly unrelated to prognosis. However, some patients with a remarkable increase in CgA in a short duration may have an unfavorable prognosis caused by NED as well.

Metastasectomy for renal cell carcinoma as a strategy to obtain complete remission.

We report a case of 67-year-old Japanese woman with two types of metastasectomy for metachronous metastases of renal cell carcinoma (RCC). The initial nephrectomy for left RCC was performed in April 1977. The pathological diagnosis was clear cell carcinoma grade1-2, pT1b. In May 1996, computed tomography (CT) revealed a tumor in the upper pole of the remaining right kidney. The renal tumor was enucleated in June 1996. The histopathological diagnosis of the tumors was clear cell carcinoma. In December 1998, conventional B-mode ultrasound US detected solid tumors in the uncus, body, and tail of pancreas, and the patient underwent partial pancreatectomy, preserving the pancreatic head. Histologically, the tumor consisted of clear cell carcinoma. Eleven years following the second metastasectomy, patient was disease free without adjuvant therapy.

Effects of α1-Blockers for Lower Urinary Tract Symptoms and Sleep Disorders in Patients with Benign Prostatic Hyperplasia.

OBJECTIVES: We evaluated the association of lower urinary tract symptoms (LUTS) and sleep disorders (SD) in patients with benign prostatic hyperplasia (BPH). We also examined improvement of SD following the α1-blocker therapy for LUTS. METHODS: Sixty-eight male patients were enrolled in the study, consisting of 38 cases with LUTS and BPH (BPH group), and 30 men without significant LUTS or BPH (non-BPH group). The degree of LUTS and SD was evaluated by the International Prostate Symptom Score and the Pittsburg Sleep Quality Index (PSQI), respectively. The patients of BPH group then were treated with α1-blocker for 4 weeks, and were re-examined by all the questionnaires to evaluate the therapeutic efficacies. RESULTS: The correlation analyses showed a significant association of LUTS with SD in BPH group (r = 0.4995, P = 0.0068). Twenty cases (52.6%) in BPH group showed 5.5 or more PSQI scores. Following 4 weeks of α1-blocker administration, the average PSQI decreased significantly from 6.3 to 4.8 points (P < 0.001). Significant improvement was observed in domains of "sleep quality" and "sleep disturbances" among PSQI (P = 0.0215 and 0.0391, respectively). Moreover, significant association between α1-blocker induced improvements of nocturia and SD was identified in patients with 5.5 or more PSQI score at baseline (r = 0.445, P = 0.0334). CONCLUSION: These results suggested that SD is associated with LUTS among BPH patients and therapeutic effects of α1-blockers on LUTS lead to improvements of SD.

Neoadjuvant LHRH analog plus estramustine phosphate combined with three-dimensional conformal radiotherapy for intermediate- to high-risk prostate cancer: a randomized study.

OBJECTIVE: The objective of this study is to assess the safety and efficacy of a treatment regimen comprising neoadjuvant conventional androgen deprivation therapy (ADT) plus estramustine phosphate (EMP) combined with three-dimensional conformal radiotherapy (3D-CRT) for patients with intermediate- to high-risk prostate cancer. METHODS: Thirty-nine patients with intermediate- to high-risk prostate cancer classified according to the NCCN practice guidelines recurrence risk group were randomly allocated into two groups: neoadjuvant LHRH agonist plus EMP for 6 months until completion of the 3D-CRT (EMP group, n = 20), or neoadjuvant LHRH agonist alone (LHRH group, n = 19). Both groups received 3D-CRT in daily fractions of 2 Gy for a total dose of 70 Gy. PSA relapse was defined according to the Phoenix definition. RESULTS: The median duration of follow-up was 27.1 months. None of the patients died during the follow-up period, but three patients in the LHRH group developed distant metastasis. The 4-year PSA relapse-free survival outcomes for the EMP group and LHRH group were 61.2 and 49.4%, respectively (P = 0.04). Multivariate Cox regression model analyses of the pretreatment PSA level (>20 ng/ml n = 16 vs. < or =20 ng/ml n = 23), grade (G8 or more n = 11 vs. G7 or less n = 28) and modality (LHRH group n = 19 vs. EMP group n = 20) revealed these factors to be independent predictors of PSA relapse after treatment: pretreatment PSA had a relative risk of 3.84 (95% CI: 1.003-14.722), grade had a relative risk of 4.29 (95% CI: 1.093-16.824), and modality had a relative risk of 8.01 (95% CI: 1.867-34.361). No severe toxicities were observed in either group. CONCLUSIONS: The present results indicate that the combination of neoadjuvant ADT plus EMP combined with 3D-CRT sustains freedom from PSA relapse in patients with intermediate- to high-risk prostate cancer. However, this regimen is insufficient for preventing biochemical failure, and an additional intervention such as adjuvant ADT, radiation dose escalation, or both, is required, especially for patients with a pretreatment PSA level of more than 20 ng/ml and high-grade cancer.

Fluctuating liver functions in siblings with MPV17 mutations and possible improvement associated with dietary and pharmaceutical treatments targeting respiratory chain complex II.

BACKGROUND/AIMS: To describe the clinical and biological findings of two Japanese siblings with novel MPV17 gene mutations (c.451insC/c.509C > T) manifesting hepatic mitochondrial DNA depletion syndrome. METHODS: We observed these brothers and sought to determine the efficacy of treatment targeting respiratory chain complex II for the younger brother. RESULTS: A 3-month-old boy had presented with profound liver dysfunction, failure to thrive, and watery diarrhea. Although he was then placed on a carbohydrate-rich diet, his liver function thereafter fluctuated greatly in association with viral infections, and rapidly deteriorated to liver failure. He underwent liver transplantation at 17 months of age but died at 22 months of age. The younger brother, aged 47 months at the time of this writing, presented with liver dysfunction from 8 months of age. His transaminase levels also fluctuated considerably fluctuations in association with viral infections. At 31 months of age, treatment with succinate and ubiquinone was initiated together with a lipid-rich diet using ketone milk. Thereafter, his transaminase levels normalized and never fluctuated, and the liver histology improved. CONCLUSIONS: These cases suggested that the clinical courses of patients with MPV17 mutations are greatly influenced by viral infections and that dietary and pharmaceutical treatments targeting the mitochondrial respiratory chain complex II may be beneficial in the clinical management of MPV17 mutant patients.

Implications of circulating chromogranin A in prostate cancer.

OBJECTIVE: To evaluate whether measurement of circulating chromogranin A (CgA) levels provides clinicopathological and prognostic information in prostate cancer. MATERIAL AND METHODS: Plasma CgA levels were measured in 57 patients with histologically confirmed prostate cancer (stage B or less, n=22; stage C, n=10; stage D1, n=2; hormone-naive D2, n=12; hormone-refractory D2, n=11) and in 22 with undetected prostate cancer using an enzyme-linked immunoabsorbent assay. RESULTS: Median plasma CgA levels were significantly higher in patients with prostate cancer than in those with undetected cancer (p=0.0271). Higher stage (p<0.0001) and higher grade (p=0.0412) tumours were also significantly associated with higher plasma CgA levels. Above-normal CgA levels were also detected in 4/27 patients (15%) who underwent radical prostatectomy. Postoperative clinical failure was not reported in the prostatectomy patients; however, prostate-specific antigen (PSA) failure was reported in 44% of patients after a median follow-up period of 20.3 months. Multivariate analysis revealed that the pathological stage of the tumour was the only independent predictive variable for postoperative PSA failure (p=0.0494). Preoperative plasma CgA levels had no impact on postoperative PSA failure in the subgroup (prostatectomy patients). Elevated plasma CgA levels were associated with a poor survival prognosis in patients with stage D2 prostate cancer after a median follow-up period of 22.5 months (p=0.0416). CONCLUSIONS: It was demonstrated in this study that plasma CgA levels in prostate cancer increase with the severity of the disease, especially for progressive hormone-refractory prostate cancer (HRPC), after hormone therapy. Although this cross-sectional study involved only a small number of patients, we believe that plasma CgA levels may effectively predict HRPC status and prognosis in metastatic cases.

Chronic contained rupture of an abdominal aortic aneurysm mimicking a retroperitoneal tumor.

Chronic contained rupture of an abdominal aortic aneurysm (AAA) is a rare event that is difficult to diagnose due to the atypical and chronic symptoms. We report a case of chronic contained rupture of AAA mimicking a retroperitoneal tumor in a 36-year-old man. The patient presented with weight loss and chronic lower abdominal pain, and was referred to our clinic with a suspected retroperitoneal tumor. Abdominal computed tomography (CT) revealed a distinct mass measuring 15 x 10 x 10 cm in the left retroperitoneal space, involving the abdominal aorta. One week later he experienced sudden abdominal pain radiating to the back. He was subsequently diagnosed with ruptured AAA and aortic dissection. The patient received implantations of both common iliac arteries to the abdominal aorta using Y-grafts and an ascending-to-descending aortic graft in a two-stage operation. His recovery from surgery was uneventful.

Immunohistochemical and ultrastructural features of neuroendocrine differentiated carcinomas of the prostate: an immunoelectron microscopic study.

The purpose of this study was to further define the immunohistochemical and ultrastructural characteristics of neuroendocrine (NE) differentiated prostatic carcinomas. Seventy-seven specimens were obtained from prostatic carcinoma tumors during prostatectomy, transurethral resection of prostate or biopsy in 77 prostate cancer patients, and analyzed by immunohistochemical staining for chromogranin A (CgA). Nine of these tumors were also studied by elctron microscopy and 4 were examined by pre-embedding immunoelectron microscopy. CgA-stained cells were detected in 36 tumors (47%). Clinically advanced tumors or tumors with higher histological grades were associated with increased NE differentiation. Three of the tumors studied by electron microscopy contained cells showing unequivocal NE differentiation revealed by the presence of neurosecretory granules, while the poorly NE-differentiated malignant cells contained pleomorphic granules, which were lysosomal-like rather than NE-type granules. Immunoelectron microscopy demonstrated the presence of CgA immunoreactivity on the pleomorphic granules in the poorly differentiated malignant glands. This study suggests that NE-differentiated malignant cells in prostate cancer tissues may induce aggressive behavior in adjacent proliferating neoplastic cells via a paracrine mechanism.

The impact of angiogenesis on the prognosis of advanced renal cell carcinomas.

We studied the relationship between angiogenic factors and clinical responses in advanced renal cell carcinomas (RCCs) and evaluated the angiogenic factors to clarify the potential impact of these factors on the cancer-specific survival. From January 1990 to December 2000, 148 patients underwent a nephrectomy for RCCs at our institution. Of the 32 patients who had distant metastasis, 17 met the histopathologic analysis requirements for an immuno-histochemical investigation. Fifteen of them were administered interferon-gamma and the remaining two patients were added to interferon-alpha and eight of seventeen patients also underwent radiation therapy. Both thymidine phosphorylase (TP) and Factor VIII immunostaining were performed. The overall survival rates at 1, 5 and 10 years were 82.4%, 30% and 30%, respectively. Three of these patients were diagnosed with lung metastasis and a complete response was seen in two, while a partial response was observed in one. In addition another patient who was diagnosed with bone metastasis also showed a partial response (group A). The remaining 13 patients showed progressive disease (group B). Group A had a higher TP-positive ratio (TP-PR) than that of group B. A multivariate analysis of the clinicopathologic data showed that a positive mean vascular area (PMVA) could be an independent factor regarding the potential impact of these factors on a long survival in advanced RCCS. PMVA was thus found to be an independent factor regarding the prognosis with advanced RCCs.

[Enucleation of renal cell carcinoma in von Hippel-Lindau disease using a microwave tissue coagulator].

The patient was a 37-year-old man who had undergone left nephrectomy under the diagnosis of left renal cell carcinoma associated with von Hippel-Lindau (VHL) disease 4 years ago. Computed tomography (CT) revealed 3 individual tumors 20 mm, 13 mm and 9 mm in maximum diameter in the right kidney. All three renal tumors were enucleated with a microwave tissue coagulator (MTC) without renal pedicle clamping. There were no major complications related to nephron-sparing surgery such as postoperative bleeding, persistent urine leakage and deterioration of renal function. Our findings suggest that renal tumors with VHL disease can be enucleated using a MTC safely and successfully without damaging renal function.

Expression and regulation of tumor suppressor gene maspin in human bladder cancer.

Maspin is a member of serine protease inhibitor family with tumor suppressing activity for breast and prostate cancers, acting at the level of tumor invasion and metastasis. However, there have been no published data regarding the role of maspin in human bladder cancer. We evaluated maspin expression in 65 series of bladder cancer samples (22 transurethral resection (TUR) and 43 radical cystectomy) and studied the regulatory mechanism of maspin gene activation in bladder cancer cells. Maspin expression was immunohistochemically detected in four (18.2%) patients with TUR and 22 (51.2%) patients with radical cystectomy whereas no expression was observed in normal transitional cells located at tumor-free area in bladder. The maspin expression was significantly correlated with the development of muscle invasive bladder cancer (P=0.00008). Using a luciferase reporter system, maspin promoter activity was induced in the maspin-positive bladder cancer cell lines as well as maspin-negative RT4 cells. Furthermore, treatment with the DNA methyltransferase inhibitor, 5-aza-2' deoxycytidine, and histone deacetylase inhibitor, trichostatin A, led to re-expression of maspin in RT4 cells. Our results indicate that maspin may contribute to bladder cancer development and that DNA methylation and histone deacetylation may be important for regulating maspin gene activation in bladder cancer cells.

Multicentric liposarcoma.

Abstract A 72-year-old man complaining of upper abdominal discomfort was diagnosed as having retroperitoneal liposarcoma by means of diagnostic imaging. He then underwent an operation. One mass existed on the curvatura ventriculi major, extending to the hilum splenicum and pressing back the pancreal head and body. There was another mass to the left of the first, situated on the ventral side of the left kidney. Also, another mass was intramurally found adjacent to the curvatura ventriculi major. Histologically, the mass on the curvatura ventriculi major ranged from the peritoneal cavity to the retroperitoneum Its intraperitoneal portion was classified as a differentiated lipoma-like type and the retroperitoneal mass was of mucous type. The mass on the left kidney was of a differentiated fibrosing type. The intramural mass in the gastric curvature was found to be a differentiated lipoma-like type. The patient has been under observation for 12 months and has shown no recurrence.

Aplastic anemia during growth hormone (GH) treatment in a girl with idiopathic GH-deficiency.

We report a 12-year-old girl with aplastic anemia accompanied by chromosome 8 trisomy during growth hormone (GH) therapy. When she was six years old she was diagnosed as idiopathic isolated GH deficiency, and GH therapy (0.175 mg/kg/week) was initiated. At the age 12, she began to exhibit petechiae in both lower limbs. Platelet count was 11,000/microL; serum hemoglobin level 11.8 gr/mL; white blood cell count 3,400/microL, with 37% neutrophils, 58% lymphocytes, 4% monocytes and 1% basophils. Bone marrow examination showed that total nucleated cell count and megakaryocyte were 17,000/microL and 0/microL, respectively, suggesting low formation. In addition, 13% of bone marrow cells contained the 3 signals of chromosome 8 marker (trisomy 8). She was diagnosed as aplastic anemia accompanied with chromosome 8 trisomy. GH therapy was stopped immediately, and simultaneous administration of methylprednisolone and anti-thymocyte globulin was initiated. Platelet count improved with treatment, and the 3-signal chromosome 8 abnormality disappeared from the bone marrow cells. The fact that a hematological adverse effect other than leukemia exists in conjunction with GH therapy warrants further investigation into possible hematological changes occurring during or after GH therapy.

[Continuous bilateral sacral neuromodulation as a minimally invasive implantation technique in patients with functional bladder changes]. / Neuromodulación crónica sacra bilateral con una técnica de implantación mínimamente invasiva en pacientes con alteraciones funcionales de la vejiga.

OBJECTIVE: Up to 50% of patients with bladder dysfunctions undergoing sacral neuromodulation treatment are non-responders. The most common treatment method today is the implantable neuromodulation system described by Tanagho and Schmidt; which allows unilateral sacral nerve stimulation. Our aim was to increase the number of responders and to improve the general efficiency of chronic sacral neuromodulation; therefore we have developed the bilateral electrode implantation by minimally invasive laminectomy. METHODS: PNE-tests were carried out to assess which patients were likely to be good responders. Thirty patients (16 with detrusor instability, 14 with hypocontractile detrusors) were subjected to minimally invasive laminectomy and received implants of bilateral electrodes. RESULTS: In those patients with a hyopcontractile detrusor, the level of residual urine of initially 350 ml was reduced to 58 ml, and the maximum detrusor pressure during micturition increased from initially 12 cMH2O to 34 cmH2O. In the other patient group with detrusor instability, the average number of incontinence incidences could be reduced from initially 7.2 to 1 per day, while the bladder capacity rose from 198 ml to 348 ml. The modulation effect did not show any signs of deteriorating in any of the patients. The follow-up period was 28 months on average. CONCLUSIONS: Clinical experience has shown that optimal neuromodulation in patients with bladder dysfunction can be achieved by this new approach involving bilateral electrode implantation. Moreover, the laminectomy implantation method guarantees a minimum of invasive trauma and enables optimal placement and fixation of the electrode.

Neuromodulación crónica sacra bilateral con una técnica de implantaciónmínimamente invasiva en pacientes con alteraciones funcionales de la vejiga / Bilateral chronic sacral neuromodulation with a minimally invasive implantation technique in patients with bladder dysfunction

OBJETIVO: El porcentaje de fracasos con la técnica descrita por Tanagho y Schmidt para la neuromodulación sacra crónica con estimulación unilateral alcanza hasta el 50 por ciento. Con el objetivo de mejorar la efectividad de la modulación, así como el posicionamiento y fijación de los electrodos, hemos optado por la laminectomía sacra mínima con instalación bilateral de electrodos. MÉTODOS: En un total de 30 pacientes (16 con diagnóstico de inestabilidad del detrusor refractaria a terapia y 14 con hipoactividad del detrusor) se implantó un modulador neurológico con instalación de electrodos sacros bilaterales, previa certificación de la indemnidad de los nervios periféricos con el test de evaluación correspondiente. Con el propósito de asegurar una adecuada instalación y fijación de los electrodos se llevó acabo una laminectomía sacra mínima. RESULTADOS: En los pacientes con inestabilidad del detrusor se observó una reducción del promedio de episodios de incontinencia de 7,2 a 1 por día y la capacidad vesical aumentó de 198 a 348 ml. En los pacientes con hipoactividad del detrusor se constató una disminución en los residuos postmiccionales de 350 a 58 ml. La contracción máxima del detrusor durante la micción aumentó de 12 cm H2O a 34cm H2O. El seguimiento promedio fue de 28 meses. No hubo signos de deterioro en el efecto modulador en ninguno de los pacientes. CONCLUSIÓN: La modulación neurológica sacra bilateral, en conjunto con la técnica de implantación mínimamente invasiva desarrollada por nosotros, permite alcanzar resultados óptimos en pacientes con inestabilidad del detrusor refractaria a terapia así como también en pacientes con detrusor hipoactivo (AU)

Intravenous glycerol therapy should not be used in patients with unrecognized fructose-1,6-bisphosphatase deficiency.

BACKGROUND: In Asian countries, glycerol solution that contains fructose (5%) is often used for management of brain edema. However, glycerol and fructose may cause severe hypoglycemia and metabolic acidosis in patients with fructose-1,6-bisphosphatase (FBPase) deficiency, even under stable conditions. The aim of the present study was to determine whether glycerol solution was used for brain edema during acute metabolic decompensation of hypoglycemia and metabolic acidosis in patients with unrecognized FBPase deficiency in Japan and to examine a long-term prognosis of the patients who had this kind of severe metabolic decompensation with or without glycerol therapy. METHODS: A retrospective study of 20 children with FBPase deficiency was conducted, based on their medical records. RESULTS: Six of the 20 children were given glycerol solution for the presence or possibility of brain edema during acute metabolic decompensation of hypoglycemia and metabolic acidosis; two of the six patients administered with glycerol were given dialysis. In four patients treated with glycerol alone without dialysis, two had no brain edema before glycerol administration but it developed later after the administration. These four patients treated with glycerol alone died or developed severe neurological complications. Fourteen patients who were not treated with glycerol solution had no brain edema and showed good prognosis. CONCLUSIONS: Glycerol solution, which contains fructose in Asian countries including Japan, should not be used as an osmotic agent for treatment of brain edema in patients who have hypoglycemia and retention-type metabolic acidosis, until FBPase deficiency is ruled out by measuring blood concentration of lactate.