The role of the genetic abnormalities, epigenetic and microRNA in the prognosis of chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is increased proliferation of B-cells with peripheral blood and bone marrow involvement, which is usually observed in older people. Genetic mutations, epigenetic changes and miRs play a role in CLL pathogenesis. Del 11q, del l17q, del 6q, trisomy 12, p53 and IgVH mutations are the most important genetic changes in CLL. Deletion of miR-15a and miR-16a can increase bcl2 gene expression, miR-29 and miR-181 deletions decrease the expression of TCL1, and miR-146a deletion prevents tumor metastasis. Epigenetic changes such as hypo- and hypermethylation, ubiquitination, hypo- and hyperacetylation of gene promoters involved in CLL pathogenesis can also play a role in CLL. Expression of CD38 and ZAP70, presence or absence of mutation in IgVH and P53 mutation are among the factors involved in CLL prognosis. Use of monoclonal antibodies against surface markers of B-cells like anti-CD20 as well as tyrosine kinase inhibitors are the most important therapeutic approaches for CLL.

[Intraoperative radiotherapy combined with external beam radiation for prostate cancer without metastasis].

Between 1989 and 1996, 35 patients with prostate cancer without metastasis received intraoperative radiotherapy combined with external beam radiation. 10 of 16 stage B patients and all of 19 stage C patients received additional endocrine therapy for the initial treatment. The radiation therapy included 25-30 Gy of intraoperative radiotherapy for prostate and 30 Gy of external beam radiotherapy for small pelvic region. One patient of stage C was dead for cancer and 4 patient were dead for other causes during 15-99 (mean: 41.6) months follow up period. The overall actuarial survival at 5 years by Kaplan-Meier method were 92.3% for stage B and 87.2% for stage C. Although cystitis, proctitis and anal bleeding were observed as the adverse effects of radiotherapy, both acute and chronic symptoms were not critical. In conclusion, intraoperative radiotherapy combined with external beam radiotherapy was revealed as an effective treatment for prostate cancer without metastasis.

Familial prostate cancer in four brothers.

We identified a family of 4 brothers with prostate cancer. The proband was the second son who was seen at the Department of Urology, Gunma University, Gunma, Japan, in May 1995, with a chief complaint of dysuria. The serum level of PSA was high, and a prostate needle biopsy revealed a moderately-differentiated adenocarcinoma. Subsequently, a total prostatectomy was performed. The family history revealed that the fourth son had been under treatment at the Saitama Cancer Center Hospital for prostate cancer since 1994. Therefore, the other 2 brothers became healthy male family members of the familial prostate cancer line, and their serum PSA levels were examined after obtaining their informed consent. Both had a high serum PSA level and biopsies revealed moderately-differentiated adenocarcinomas in both. Human leukocyte antigen class II gene typing was conducted on 3 of 4 brothers and 4 healthy family members who gave informed consent, and revealed the DRB1*0901-DQB1*0303 haplotype in the first, second and third sons. Familial prostate cancer is well documented in Europe and the US where the incidence of prostate cancer is high, but this is the first report of prostate cancer in 4 brothers in Japan.

Significance of measurement of prostate specific antigen (PSA) in familial prostate cancer lines.

The concentration of prostate specific antigen (PSA) in serum was measured in 20 brothers or sons in 10 families in which the father and son or brothers had prostate cancer using the E test TOSOH IIPA. The patients were between 32 and 70 years old with a mean age of 48.2 years. The PSA value was between 0.4 and 19.5 ng/ml with a mean value of 3.4 ng/ml. Five patients (25%) had PSA values exceeding the cut-off value of 4.0 ng/ml. After obtaining their consent, systematic prostate needle biopsy by transrectal ultrasonography was performed on 3 patients (15%). Prostate cancer was detected in all of them. Among them 2 patients were brothers, and since the other two brothers already had prostate cancer, all four brothers were confirmed to have prostate cancer. This is the first report of a familial prostate cancer in four brothers in Japan. In the western countries where the incidence of prostate cancer is higher than that in Japan, studies have been performed on the risk factors. Family history is one of the most important risk factors. In Japan, the incidence of prostate cancer is increasing rapidly. Moreover, patients with a prostate cancer family history are expected to increase. In such cases, prostate cancer screening should be performed aggressively from a young age.

[Clinical evaluation of intra-operative radiotherapy combined with subtotal cystectomy for invasive bladder carcinoma].

From 1981 to 1994, intra-operative radiotherapy after subtotal cystectomy was performed on 22 patients with invasive bladder carcinoma on whom radical cystectomy could not be recommended because of old age or condition. All the patients received 25 to 30 Gy of radiotherapy focused on trigonum and internal urethral orifice after subtotal cystectomy with uretero-cutaneostomy. Of 22 patients, 15 patients died. Five patients died of bladder cancer, one died of gastric cancer, one died of rectal cancer and the others died of pneumonia, heart failure, sepsis and senility. The five-year survival rate was 41% and the cause-specific five-year survival rate was 75%. Local recurrence was seen only in one patients, who received second intra-operative radiotherapy and recovered well in complete remission. We believe that intra-operative radiotherapy after subtotal cystectomy is useful for patients with invasive bladder carcinoma on whom radical cystectomy could not be recommended because of old age or condition.

[The clinical usefulness of urinary determinations of cytokeratin 19 fragment (CYFRA 21-1) in urothelial tumor].

The urinary CYFRA 21-1 value corrected for urinary creatinine (ng/ml/creatinine), was studied in the urine of patients with urothelial tumors. To examine its clinical significance we studied urinary CYFRA 21-1 excretion (ng/ml/creatinine), in a total of 22 urine samples from patients with bladder cancer, 7 from patients with renal pelvic and ureteral tumor, 6 from patients with urinary infection 6 from patients with urinary diversion called ileal conduit, and 8 from healthy adult men. The excretion of CYFRA 21-1 in urine was determined by two specific monoclonal antibodies (Ks 19.1 and BW 19.21). The mean value of urinary CYFRA 21-1 in healthy adult men was 1.96 +/- 1.33 (mean +/- SD) ng/ml/creatinine. Urinary CYFRA 21-1 showed a higher value in the urine of urinary infection and urinary diversion. As to bladder cancer, urinary CYFRA 21-1 showed a higher value in a larger volume of tumor than in a smaller volume of tumor in transitional cell carcinoma regardless of the grade and stage. These findings suggest that urinary CYFRA 21-1 may be a non-specific marker in urothelial tumors.

[Single-stomal ureterostomy by extraperitoneal approach].

Single-stomal ureterostomy such as double barreled ureterocutaneostomy and cutaneous transureteroureterostomy have usually been performed by transperitoneal approach. However, extraperitoneal method is preferable since the patients for whom ureterocutaneostomy is indicated usually have a deteriorating general condition. We have reported single-stomal ureterocutaneostomy which can be done extraperitoneally. A total of thirteen patients, one man and twelve women, for whom permanent urinary diversion was indicated, have undergone this extraperitoneal ureterocutaneostomy for February 1988 to June 1994. Those with retroperitoneal lesions or with a history of paraaortic radiotherapy were excluded. The mean age was 61.7 (range: 42-76). The reasons for urinary diversion were vesicovaginal fistula in seven, obstructive nephropathy in four, rectovesical fistula in one and postoperative urine leak from the bladder in one. All patients had been treated for malignant diseases and had undergone transperitoneal surgery. Six patients had colostomy and ten had clinically evident recurrent diseases. In the operation, left ureter was dissected and severed extraperitoneally through left paramedian incision or left lumbotomy. The ureteral end was pushed to the right in a retroperitoneal tunnel created by blunt dissection. Then the ureter was picked up through the contralateral retroperitoneal approach. After both ureters were exposed, ureterocutaneostomy was made in right hypogastrium. Transureteroureterstomy with end-cutaneous ureterostomy, double barreled ureterocutaneostomy and ureteroureterostomy with loop ureterostomy were done in six, four and three patients, respectively. The mean operative time was 119 (range: 75-175) minutes and the mean intraoperative blood loss was 210 (range: 48-682) grams. Arrhythmia developed during retroperitoneal manipulation in one patient for whom the operation was done under spinal anesthesia.(ABSTRACT TRUNCATED AT 250 WORDS)

Retroperitoneal malignant mesenchymoma: a case report.

A case of a 37-year-old woman with a retroperitoneal tumor is reported. Angiography revealed that the tumor was partially supplied via an intercostal artery, suggesting that the cause of the tumor might be located in the rib. Histologically the tumor was diagnosed as a malignant mesenchymoma composed of chondrosarcoma and myxoid liposarcoma in addition to fibrosarcoma. The chondrosarcomatous element was predominant, a phenomenon which is extremely rare. Pulmonary metastases developed 8 mo after surgical removal of the tumor and the patient died of the disease 2 yr postoperatively.

Acute pulmonary embolism after conservative surgery for renal cyst: a case report.

A case of acute pulmonary embolism which developed one week after conservative surgery of the renal cyst is reported. He was 41 years old and had a long habit of cigarette smoking. He underwent wedge resection of the renal mass which was proved to be a multilocular renal cyst pathologically. The acute pulmonary embolism which developed on the seventh postoperative day was confirmed by lung scintigraphy. The patient recovered from the disease by thrombolytic therapy. Postoperative bed rest seemed to be closely associated with the incidence in this case. Early ambulation is recommended. In addition, the thromboprophylactic therapy may be justified in patients undergoing kidney-sparing surgery which requires postoperative bed rest.

The aggressive treatment of choriocarcinoma of the testis associated with lung bone, and brain metastases.

A case of metastatic choriocarcinoma of the testis involving the retroperitoneum, lung, bone, and brain was successfully treated by surgery, chemotherapy and radiotherapy.

[Effect of lentinan for advanced prostate carcinoma].

A prospective, randomized multi-center study was conducted to assess the clinical effectiveness of Lentinan, an immunomodulatory agent, in the metastatic prostate cancer. Of seventy-five patients enrolled from July 1987 to June 1992, 69 were eligible. All patients received hormonal therapy and chemotherapy using Tegafur p.o. at a dose of 400-800 mg/day. While 33 patients received Lentinan i.m. for at least three months, the other 36 did not. The dose of Lentinan was 2 mg weekly for inpatients and 4 mg every other week for outpatients. The mean age of treated and control patients was 70 (range; 53-83) and 71 (range; 50-86), respectively. The 50% survival length of treated and control patients was 48 and 35 months, respectively. The five-year survival rate of treated patients was 43% according to the Kaplan-Meier method, while that of control patients was 29% (p < 0.05). We conclude that Lentinan is effective in metastatic prostate cancer when incorporated into hormonochemotherapy.

Extragonadal germ cell tumor of retroperitoneal origin: report of two cases.

Two cases of primary extragonadal germ cell tumor of retroperitoneal origin are reported. One was a 26-year-old man complaining of back pain. He had a large retroperitoneal tumor with lung, liver and supraclavicular lymph node metastases. He was referred to us after being treated for malignant lymphoma. The serum AFP, beta-subunit of human chorionic gonadotropin (hCG-beta), CEA and CA-19-9 were elevated. The retroperitoneal disease was treated surgically and with radiotherapy. The pathological diagnosis was that of embryonal carcinoma and teratoma. The lung, liver and supraclavicular lymph node metastases disappeared completely after two courses of cisplatin-based chemotherapy. While further chemotherapy was postponed due to myelosuppression, the disease relapsed and was resistant to subsequent therapy. The patient died twelve months after he first saw us. The second case was that of a 36-year-old man complaining of edematous legs and external genitalia. He had an extensive retroperitoneal tumor with multiple pulmonary metastases. The serum AFP level was high. Suspected of having an extragonadal germ cell tumor, he was referred to us promptly. Cisplatin-based chemotherapy coupled with resection of residual retroperitoneal and pulmonary disease resulted in complete remission. The pathological diagnosis was that of possible embryonal carcinoma. Further chemotherapy was given as scheduled, using granulocyte colony-stimulating factor. The patient has been in complete remission for two years. The chemotherapeutic regimen and surgical policy in the treatment of the two patients were essentially same. Early diagnosis, adequate initial therapy and the use of granulocyte colony-stimulating factor may be relevant to the favorable prognosis in the latter case.

Feasibility and pharmacokinetics of continuous subcutaneous infusion of low-dose interferon-gamma: a pilot study.

Continuous subcutaneous infusion of interferon-gamma was carried out in an attempt to improve the therapeutic efficacy of the agent, one of the most potent immunomodulatory cytokines. Seven patients with renal cell carcinoma underwent the therapy using battery-powered micro-infusion pumps. In four patients, recombinant human interferon-gamma, 15 x 10(6) JRU (Japan Reference Unit)/body, was administered subcutaneously and continuously for five days. The therapy was repeated without interruption up to three times in four patients, including one for whom a single course of five-day therapy had been given three months previously. The major side effects were fever, anorexia, general malaise and local skin reaction. Discontinuation of the therapy was necessary in two patients, one in single five-day therapy and the other in repeated therapy, due to generalized skin eruption and general malaise, respectively. Serum interferon-gamma levels, as determined by radioimmunoassay, increased gradually and reached 20-30 IU/ml on day 4 or 5. Among patients who received two or three courses of therapy, the interferon-gamma levels showed high inter-individual differences after day 6. The levels gradually fell after the therapy terminated with a half-life of about 2 days. No clinical response was observed. Our data suggest that interferon-gamma can be administered by continuous subcutaneous infusion, and warrants further study.

[Adjuvant chemotherapy for invasive bladder cancer. Multicenter study].

During 2 years and 10 months from November 1985 to September 1988, 50 patients with invasive bladder cancer (pT2-4, pN0-2, M0) were treated with total cystectomy followed by adjuvant combination chemotherapy including cis-platinum. In addition, so-called immunopotentiator (OK-432) and Kanpo (Juzentaihoto: TJ-48) were given to the patients in a random fashion to evaluate whether or not these agents had any significant effect on patients' prognosis. The 3- and 5-year survival rates for 48 evaluable patients were 71% and 67%, respectively. Histologic grade of primary tumors and number of cycles of adjuvant chemotherapy administered had a significant correlation to patients' survival: patients with grade 2 anaplasia had a better 3- and 5-year survival rates than those with grade 3 anaplasia, and patients receiving 3 or more cycles of chemotherapy had a better 3-year survival rate than those with 2 or less cycles. pT and pN categories also affected patients' survival, though not statistically significant. Administration of OK-432 or TJ-48 and pre-operative treatment such as irradiation and intra-arterial chemotherapy had no favourable effects on the survival. Side effects of the adjuvant chemotherapy were minimal to moderate and more than 70% of the patients tolerated at least 3 cycles of chemotherapy. It is likely that adjuvant chemotherapy, when given in a post-operative setting, should be repeated at least 3 cycles or more.

[Intraoperative radiotherapy for local recurrence of intrapelvic malignancies].

From 1986 to 1992, seventeen patients with recurrent intrapelvic malignancies have been treated with intraoperative radiotherapy (IOR) in Saitama Cancer Center. They were 8 males and 9 females. The age ranged 44 to 83 (mean:61.6). The primary organs involved were rectum in 7, urinary bladder in 5, uterine cervix in 3 and ovary in 2. Invasion of recurrent disease into bony pelvis was noted in all but one patient. A total of 27 IORs were done on 18 occasions for 17 patients. The mean radiation dose was 25.6 Gy (range: 12-30). The cones used were 4 to 7 (mean: 5.4) cm in diameter. Debulking surgery was performed in 13 patients just before IOR. Chemotherapy and/or external radiotherapy were done in addition to IOR in most of the cases. As of May 1992, 14 patients had died with a mean survival time of 10 months (range:0.5-29.8). IOR seems to be useful in controlling the intrapelvic recurrent disease and may warrant further investigation.

[Clinical efficacy of tosufloxacin on the patients with urinary tract infections].

We evaluated a newly developed quinolone agent, tosurofloxacin (TFLX), for its safety and clinical efficacy on patients with urinary tract infections (UTI). Among 138 cases satisfying the UTI criteria, 75 cases were acute simple UTI and 63 cases were chronic complicated UTI. In principle, a daily dose of 450 mg of TFLX was administered for 3 days and for 5 days for acute simple UTI and for chronic complicated UTI, respectively. Clinical efficacy of TFLX in these cases was evaluated according to the criteria of Japanese UTI committee. Bacteriologically, all 80 strains isolated from acute simple UTI were eradicated following TFLX administration. However, 2 gram positive strains and 1 gram negative strain, appeared following the treatment. In cases of chronic complicated UTI, 29 out of 32 gram positive strains and 29 out of 44 gram negative strains were eradicated. Among the isolated strains, P. aeruginosa and S. marcescens persisted, which suggests that they were less sensitive to TFLX. Overall clinical effectiveness rate of TFLX on acute simple UTI was 100%, while that on chronic complicated UTI was 73%. Adverse drug side effects were minimum, stomach discomfort and constipation was observed in one case each. These findings indicate that TFLX is a useful agent for the treatment of both simple and complicated UTI.

[Effect of tegafur administration combined with hormonal therapy in patients with newly diagnosed stage D prostatic cancer].

To study the effect of tegafur administration combined with hormonal therapy on the survival rate of newly diagnosed patients with stage D prostatic cancer, 66 patients, 70.9 years old in mean age, were treated from 1979 to 1986. The cancer was proven by the histological or cytological examination of the specimen which was obtained by the needle biopsy and/or aspiration biopsy of the prostate. The histopathological diagnosis of 59 patients was as follows: well differentiated type of adenocarcinoma was observed in 13 patients, moderately differentiated type in 19 cases, poorly differentiated type in 24 cases and mixed type in 3 cases. Daily 600 mg tegafur was administered orally as long as possible from the beginning of the treatment combined with hormonal therapy. Actual and relative 5 year survival rates calculated with Kaplan-Meier's method were 31.2% and 39.2%, respectively. When deaths other than prostatic cancer death were counted as lost cases, the actual survival rate was 47.5%. The present study also demonstrated that there were some factors affecting the patients' prognosis. They were the age of onset of the disease (patients under 64 years old were worse than those over 65 years old; p less than 0.05), performance status (patients with PS from 0 to 2 at the first admission were better than those with PS 3 to 4; p less than 0.025), differentiation of the tumor (well differentiated type was better than moderately; p less than 0.025 or poorly differentiated type; p less than 0.005).

[Multiple malignant schwannoma treated with a multidisciplinary therapy--a case report].

A 32-year-old man, complaining of an abdominal mass, was admitted to hospital where, on undergoing examination, the mass, which had spread widely through the abdominal cavity and the retroperitoneal space, was diagnosed as a malignant schwannoma with a liver metastasis. Thus, a multidisciplinary treatment was initiated and a remission was achieved. Later, however, he developed a multiple, local recurrence and died forty months after onset of his clinical symptoms. Since the prognosis of patients with a malignant schwannoma that do not undergo radical surgery is extremely poor, the authors emphasize the necessity of research for an effective adjuvant therapy.