A phase I/II study of cancer peptide vaccine S-288310 in patients with advanced urothelial carcinoma of the bladder.

Background: S-288310, a cancer peptide vaccine composed of two HLA-A*24:02-restricted peptides derived from two oncoantigens, DEP domain-containing 1 (DEPDC1) and M-phase phosphoprotein 1 (MPHOSPH1), was investigated in urothelial carcinoma (UC) of the bladder. Patients and methods: Thirty eight HLA-A*24:02-positive patients with progressive UC were enrolled in this study. In the phase I part of the study, three patients each were treated with S-288310 at 1 mg or 2 mg/peptide subcutaneously once a week to evaluate safety and tolerability. In the phase II, 32 patients were randomized to receive either 1 mg or 2 mg to evaluate the difference in cytotoxic T lymphocytes (CTL) induction and safety. Results: S-288310 was safe and well tolerated in the phase I. Of 27 patients evaluable for immune responses in the phase II, there was no difference in CTL induction rate between the 1 mg (100%) and 2 mg (80.0%) groups. Of 32 patients receiving S-288310 in the phase II, the most frequent drug-related AE was the injection site reaction that was observed in 29 patients (90.6%), but none of the patients discontinued administration due to these reactions and no dose relationship in the frequency and severity was observed. The objective response rate of the 32 patients was 6.3% and the disease control rate was 56.3%. The median overall survival (OS) rates for patients vaccinated with S-288310 after one regimen of chemotherapy, 2 regimens, or 3 or more were 14.4, 9.1 and 3.7 months, respectively, and 32.2% of patients post first-line treatment were alive at 2 years. OS of patients who showed CTL induction to both peptides was longer than that of those with CTL induction to no or one peptide. Conclusion: S-288310 was well-tolerated and effectively induced peptide-specific CTLs, which were correlated with longer survival for patients with UC of the bladder. Trial registration ID: JapicCTI-090980.

Therapeutic implication of genetic variants of IL13 and STAT4 in airway remodelling with bronchial asthma.

BACKGROUND: Several gene variants identified in bronchial asthmatic patients are associated with a decrease in pulmonary function. The effects of this intervention on pulmonary function have not been fully researched. OBJECTIVE: We determined the effects of high-dose inhaled corticosteroids (ICSs) on decreased pulmonary function in asthmatic Japanese patients with variants of IL13 and STAT4 during long-term treatments with low to mild doses of ICS. METHODS: In this study, 411 patients with bronchial asthma who were receiving ICSs and living in Japan were recruited, were genotyped, and underwent pulmonary function tests and fibreoptic examinations. The effects of 2 years of high-dose ICSs administered to asthmatic patients who were homozygous for IL13 AA of rs20541 or STAT4 TT of rs925847 and who progressed to airway remodelling were investigated. RESULTS: High-dose ICS treatment increased the pulmonary function of patients homozygous for IL13 AA of rs20541 but not of patients homozygous for STAT4 TT of rs925847. The increased concentrations of the mediators IL23, IL11, GMCSF, hyaluronic acid, IL24, and CCL8 in bronchial lavage fluid (BLF) were diminished after high-dose ICS treatment in patients homozygous for IL13 AA of rs20541. CONCLUSION AND CLINICAL RELEVANCE: IL13 AA of rs20541 and STAT4 TT of rs925847 are potential genomic biomarkers for predicting lower pulmonary function. The administration of high-dose ICSs to asthmatic patients with genetic variants of IL13 AA may inhibit the advancement of airway remodelling. The genetic variants of STAT4 TT did not respond to high-dose ICSs. Therefore, using medications other than ICSs must be considered even during the initial treatment of bronchial asthma. These genetic variants may aid in the realization of personalized and phenotype-specific therapies for bronchial asthma.

Serum prostate specific antigen levels in men with benign prostatic hyperplasia and cancer of prostate.

OBJECTIVE: To determine the sensitivity, specificity and positive predictive value of the PSA test at the conventional cut-off value of 4 ng/ml. DESIGN: Retrospective study. SETTING: Nairobi Hospital Laboratory, Nairobi. DATA SOURCE: Results of serum Prostate specific Antigen (PSA), estimation and prostate histology specimens at the Nairobi Hospital Laboratory between January 1997 and December 1999. RESULTS: A total of 3309 PSA tests and 524 prostate biopsies were processed during the study period. One hundred cases had both PSA test and histology, where the PSA test was done before the surgical procedure. Forty nine of them had histological diagnosis of cancer of prostate (CAP) while 71 had benign prostate hyperplasia (BPH). There was considerable overlap in the PSA concentrations between the two groups, the ranges being 0.34-36 ng/ml and 1.78-4339 ng/ml for BPH and CAP respectively. 63.4% of BPH subjects had PSA concentrations above the 4 ng/ml threshold value; 29.6% being in the diagnostic gray zone of 4-10 ng/ml. In contrast only 6% of CAP subjects had PSA values in the gray zone. Using the 4 ng/ml cut-off, the sensitivity, specificity and positive predictive value of the PSA test were 89.8, 37 and 49% respectively. CONCLUSION: Although PSA is a sensitive test, it is not sufficiently specific to discriminate between BPH and CAP at intermediate values. Additional approaches are required to enhance its specificity for CAP screening without reducing the sensitivity.

[A case of squamous cell carcinoma arising in the urinary bladder diverticulum].

A 49-year-old man was admitted to our hospital with the chief compliant of difficulty of urination, lower abdominal pain and macrohematuria. On cystoscopy, a non-papillary tumor was seen in the diverticulum on the right side of the urinary bladder. Having made the diagnosis of urinary bladder cancer, we performed total cystectomy, retroperitoneal node dissection and construction of an ileal neobladder. Histologically, it was squamous cell carcinoma, pT3a, pN0. Seven months after the operation, the patient died of recurrent disease.

[A case of emphysematous cystitis].

Emphysematous cystitis is a rare lower urinary tract infection. Patients with diabetes mellitus, neurogenic bladder, and recurrent urinary tract infection are generally at higher risk of this disease. A 71-year-old woman with neurogenic bladder was referred from the internal medicine department because of urinary retention. Abdominal radiography and computed tomographic (CT) scanning revealed a characteristic accumulation of air in the wall and lumen of the urinary bladder. Emphysematous cystitis was improved by antibiotic therapy and urinary drainage. CT scan was a sensitive method for detecting early signs and confirming the diagnosis.

[Transurethral removal of the ureter by the intussusception method in the treatment of renal pelvic and ureteral tumors].

Between August 1986 and December 1998, 19 patients who had renal pelvic and upper ureteral tumors were treated with nephrectomy and transurethral removal of the ureter using the intussusception method. Removal of the ureter failed in 5 patients because of excessive ablasion of the ureter or insufficient electro-resection around the ipsilateral ureteral orifice. Excluding those patients, the safety of the operation and the intravesical recurrence were compared with the outcome in 12 patients undergoing partial cystectomy for similar tumors. The mean operating time was not significantly shorter with the intussusception method compared with partial cystectomy (190.4 versus 251.3 minutes), but the mean blood loss was significantly smaller (187.5 versus 460.2 ml) and the intussusception method did not require a blood transfusion. The mean term of hospitalization was 20.3 days for patients treated by the intussusception method which was significantly shorter than that for patient undergoing partial cystectomy (25.4 days). Intravesical recurrence was found in seven patients (50%) treated by the intussusception method and the 1- and 5-year recurrence-free rates were 69.2% and 30.8% respectively. There was no significant difference in the recurrence-free rates between the two surgical techniques. These results suggest that the intussusception method is superior to partial cystectomy in decreasing the operating time, blood loss and term of hospitalization. It can be an attractive option in selected cases, without increasing the risk of intravesical recurrence.

[Metastatic renal tumor originating from esophageal carcinoma: a case report].

We report a case of renal metastasis from esophageal carcinoma. The patient was a 74-year-old man, who had undergone an operation for esophageal carcinoma thirteen months previously. He was admitted to our clinic for examination of a right renal mass. Computed tomography (CT) revealed an irregular low density area in the right kidney and angiography showed a hypovascular tumor. Partial nephrectomy was performed. Histological examination revealed squamous cell carcinoma and the diagnosis was metastasis of esophageal carcinoma. Metastatic renal tumors are rarely encountered clinically and, to our knowledge, the present case is only the 16th clinical report of the renal metastasis of esophageal carcinoma in Japan. However, metastasis to the kidney is relatively common at autopsy. It is the fifth most common site of metastasis following the lungs, liver, bones and adrenals. Consequently, patients with malignancy should be followed up while keeping renal metastasis in mind.

[The efficacy and safety of terazosin and tamsulosin in patients with urinary disturbance accompanying prostatic hypertrophy].

Terazosin (TE) and tamsulosin (TA) were allocated randomly to 38 patients who had urinary disturbance accompanying prostatic hypertrophy, and the efficacy and safety of the drugs were examined. Subjective symptoms due to I-PSS were improved significantly in both TE and TA groups. On the other hand, objective symptoms such as the maximum urinary flow and mean urinary flow were improved more in the TE group. TE showed hypotensive and cholesterol-decreasing effects in patients who also had hypertension and hyperlipemia. No unknown adverse reactions were observed in either groups, and the drugs were shown to be highly safe. TE was considered to be useful as the first choice drug for the patients with hypertension and or hyperlipemia and those with severe objective symptoms. TA was considered to be useful for the patients with impaired drug compliance or those with severe subjective symptoms though objective symptoms were not so severe.

[A case of congenital hydronephrosis suffering from rupture of the renal pelvis due to trauma].

A 19-year-old male patient was admitted with the chief complaint of left abdominal pain. After receiving a mild punch in the abdomen during boxing exercises, he had severe abdominal pain and was brought to an emergency room. Since abdominal CT scanning revealed the retention of massive fluid in the retroperitoneum, hydronephrotic rupture due to the trauma was diagnosed and nephrectomy was performed. The removed kidney was filled as a result of urinary retention, and congenital hydronephrosis accompanied by the ureteropelvic junction obstruction was macroscopically and pathohistologically diagnosed. Postoperative course was favorable and the patient was discharged on the 10th hospital day.

[A case of ureterovesical malacoplakia that manifested hydronephrosis].

A 70-year-old woman visited a nearby physician with a chief complaint of fever and was admitted to a hospital with a diagnosis of acute pyelonephritis. After discharge, pyuria persisted and examination revealed an intravesical solid tumor. The patient was referred to this department for close examination and treatment. The right kidney was hydronephrotic. The intravesical tumor that was resected was solid yellowish-white and ranged from the neck of the uterus to both ureteral orifices. In addition, a grain-sized tumoral lesion, was found in the lower part of the ureter and was also resected. There was sclerotic thickening localized to the right intramural ureter, which had a slightly edematous interior. This was considered to be the cause of the hydronephrosis and a ureteral stent was put in place. Pathological diagnosis was given as malacoplakia. With this case, placement of a ureteral stent was chosen based on the findings of a minimal ureteral lesion, a narrow area of scarring in the intramural ureter as a probable cause of hydronephrosis, and a judgement of mild obstruction. A stent is less invasive for patients, but consideration should be given to urinary infection due to long-term placement recurrence of malacoplakia due to the increased risk of infection, and trouble with periodical exchanging of catheters due to aggravated scarring. Absence of pyuria or signs of recurrence after seven months' placement suggests that use of the stent was the best method.

Study of the prediction system for clinical response to M-VAC neoadjuvant chemotherapy for bladder cancer.

Neoadjuvant chemotherapy for invasive bladder cancer, involving a regimen of M-VAC, can manage micrometastasis and improve the prognosis. However, some patients suffer from severe adverse drug reactions without any effect, and no method yet exists for predicting the response of an individual patient to chemotherapy. Our purpose in this study is to establish a method for predicting the response to the M-VAC therapy. We analyzed gene-expression profiles of biopsy materials from 40 invasive bladder cancers using a cDNA microarray consisting of 27 648 genes, after populations of cancer cells had been purified by laser-microbeam microdissection. We identified 14 predictive genes that were expressed differently between nine responder and nine non-responder tumors and devised a prediction-scoring system that clearly separated the responder group from the non-responder group. This system accurately predicted the clinical response for 19 of the 22 additional test cases. The group of patients with positive predictive scores had significantly longer survival times than that with negative scores. As real-time RT-PCR data were highly concordant with the cDNA microarray data for those 14 genes, we developed a quantitative RT-PCR-based prediction system that could be feasible for routine clinical use. Taken together, our results suggest that the sensitivity of an invasive bladder cancer to the M-VAC neoadjuvant chemotherapy can be predicted by expression patterns in this set of genes, a step toward achievement of "personalized therapy" for treatment of this disease.