Phase III randomised controlled trial of neoadjuvant chemotherapy plus radical surgery vs radical surgery alone for stages IB2, IIA2, and IIB cervical cancer: a Japan Clinical Oncology Group trial (JCOG 0102).

BACKGROUND: A phase III trial was conducted to determine whether neoadjuvant chemotherapy (NACT) before radical surgery (RS) improves overall survival. METHODS: Patients with stage IB2, IIA2, or IIB squamous cell carcinoma of the uterine cervix were randomly assigned to receive either BOMP (bleomycin 7 mg days 1-5, vincristine 0.7 mg m(-2) day 5, mitomycin 7 mg m(-2) day 5, cisplatin 14 mg m(-2) days 1-5, every 3 weeks for 2 to 4 cycles) plus RS (NACT group) or RS alone (RS group). Patients with pathological high-risk factors received postoperative radiotherapy (RT). The primary end point was overall survival. RESULTS: A total of 134 patients were randomly assigned to treatment. This study was prematurely terminated at the first planned interim analysis because overall survival in the NACT group was inferior to that in the RS group. Patients who received postoperative RT were significantly lower in the NACT group (58%) than in the RS group (80%; P=0.015). The 5-year overall survival was 70.0% in the NACT group and 74.4% in the RS group (P=0.85). CONCLUSION: Neoadjuvant chemotherapy with BOMP regimen before RS did not improve overall survival, but reduced the number of patients who received postoperative RT.

Comparison of adjuvant chemotherapy and radiotherapy in patients with cervical adenocarcinoma of the uterus after radical hysterectomy: SGSG/TGCU Intergroup surveillance.

PURPOSE: The authors conducted this retrospective study to evaluate the efficacy of radiotherapy (RT) for high-risk patients with adenocarcinoma (AC) compared with chemotherapy (CT) after radical hysterectomy. MATERIALS AND METHODS: There were 263 patients with AC and 58 with adenosquamous cell carcinoma (ASCC). Of these 321 patients, 151 received adjuvant treatment. Of these 151 patients, 69 received radiotherapy (RT) alone, including concurrent chemoradiotherapy (CCRT) with weekly cisdiamminedichloroplatinum (CDDP), 64 patients received CT alone, and 18 patients received concomitant RT and CT (RT + CT). RESULTS: The five-year overall survival (OS) was 70.9% for patients receiving RT, 79.2% for CT, and 66.2% for RT + CT. Adjuvant treatment did not affect the incidence or the pattern of recurrence. The incidence of lymph node involvement was 9.0% in Stage Ib1, 23.9% in Stage Ib2, 30.8% in Stage IIa, and 41.2% in Stage IIb. CONCLUSIONS: Adjuvant CT may be effective for high-risk patients with cervical adenocarcinoma.

Randomized phase II study comparing docetaxel plus cisplatin, docetaxel plus carboplatin, and paclitaxel plus carboplatin in patients with advanced or recurrent endometrial carcinoma: a Japanese Gynecologic Oncology Group study (JGOG2041).

BACKGROUND: The purpose of this study is to assess the efficacy and safety of treatment with taxane plus platinum in combination therapies for advanced or recurrent endometrial carcinoma. PATIENTS AND METHODS: Patients with measurable disease derived from histologically confirmed stage III/IV or recurrent endometrial carcinoma were randomly assigned to receive docetaxel plus cisplatin (DP), docetaxel plus carboplatin (DC), or paclitaxel plus carboplatin (TC) every 3 weeks until disease progression or adverse events prohibited further therapy. Among these regimens, the study evaluated the tumor response rate as the primary end point as well as toxicity. RESULTS: Ninety patients were enrolled. Of them, 88 were eligible and consequently 29, 29, and 30 patients were randomly assigned to DP, DC, and TC, respectively. Tumor response rates were 51.7%, 48.3%, and 60.0% in DP, DC, and TC, respectively (P = 0.65). The following toxic effects were observed: grade 3/4 neutropenia in 83.3%, 90.0%, and 76.6%; febrile neutropenia in 10.0%, 6.7%, and 3.3%; grade 3/4 thrombocytopenia in 6.7%, 10.0%, and 10.0%; grade 3/4 diarrhea in 13.3%, 3.3%, and 0%, respectively; and grade 3 neurotoxicity in 10.0% of TC. These toxicity profiles were not significantly different. CONCLUSION: The taxane plus platinum combination therapies could be candidates in further phase III trials for endometrial carcinoma.

[Management of remaining coronary artery dissection after the replacement of the ascending aorta in acute type A aortic dissection].

The authors report a case study of a 54-year-old male admitted to our hospital with severe chest pain and ST depression in II, III and aVf lead on the electrocardiogram. The chest X-ray showed an enlarged superior mediastinum. An enhanced computed tomography (CT) was performed and confirmed the diagnosis of acute type A aortic dissection. The patient underwent emergency surgical repair with the replacement of the ascending aorta. The patient recovered without complication until the fifteenth postoperative day, when another severe chest pain appeared. Emergency coronary angiography revealed a remaining dissection in both the left anterior descending artery (LAD) and the left circumflex artery (LCx). Implantation of Elite stents to the LAD and the LCx was performed. The patient recovered uneventfully after this operation. Remaining coronary artery dissection after the replacement of the ascending aorta is very rare. In this case coronary intervention with Elite stents was effective.

Adenovirus-mediated p16 gene transfer changes the sensitivity to taxanes and Vinca alkaloids of human ovarian cancer cells.

BACKGROUND: Deletions and point mutations of the p16 gene are detectable in more than 50% of ovarian cancer cells. In this study, we examined the effect of p16 gene transduction on the growth of ovarian cancer cells and on the effect of anti-cancer agents. MATERIALS AND METHODS: p16-null human ovarian cancer cell lines, SKOV-3 and OVCAR-5, were used in this study. We transduced the full-length human p16 gene using recombinant adenovirus (AxCA-hp16). RESULTS: The spontaneous growth of these cells was significantly inhibited by hp16 transduction. MTT assay revealed that AxCA-hp16 infection induced chemoresistance in both cell lines. Flow cytometric analysis revealed that only hp16 -transduced SKOV-3, were arrested at the G1-phase for 3 days whereas those infected with AxCA-mock and OVCAR-5 infected with both recombinant viruses did not. Western blot analysis showed increased microtubule-associated proteins 4 (MAP4) in both cell lines. CONCLUSION: These results suggest that in SKOV-3 cells, G1-arrest induced by p16-transduction prevents paclitaxel- and vindesine-induced cell death, and in OVCAR-5 cells, the other unknown mechanisms play a role of chemoresistance.

[Weekly paclitaxel and cisplatin in recurrent ovarian cancer].

This study was performed to assess the feasibility of weekly paclitaxel (TXL) and cisplatin (CDDP) in patients with recurrent ovarian cancer. Ten of eleven patients experienced recurrence after more than 6 months after first line CDDP-based chemotherapy. TXL and CDDP were given at initial doses of 60 mg/m2 and 30 mg/m2 on days 1, 8, and 15 in 2 patients and an increase in the respective dose level was planned to 60/35 in 5 patients, 70/35 in 2 patients, and 70/40 in 2 patients. Toxicities were well tolerated. None of the patients suffered from neurotoxicity or myalgia of more than grade 2. Gastrointestinal disorder was recognized as grade 1-2, and grade 3-4 hematological toxicity included leucocytopenia (64%), anemia (36%), and thrombocytopenia (9%). We set the recommended dose of TXL at 70 mg/m2 and that of CDDP at 35 mg/m2, considering toxicity and performed planned schedule. Of eleven patients, nine were assessable by computed tomographic scan. The overall response rate was 67% (CR: 1, PR: 5, NC: 1, PD: 2). One of two patients with standard TXL/CDDP therapy showed PR by switching to a weekly schedule. The median follow-up duration was 490 days and the median response duration was 371 days. From the results presented here, it is suggested that this regimen with increased DI might be quite effective and well tolerated in patients who experience relapse after CDDP-based chemotherapy.

Conservative therapy for adenocarcinoma and atypical endometrial hyperplasia of the endometrium in young women: central pathologic review and treatment outcome.

Thirty-nine patients with endometrioid adenocarcinoma (EA) and atypical hyperplasia (AH) of the endometrium who received conservative treatment to preserve fertility were collected from member institutions of the Japan Gynecologic Oncology Study Group. Twenty-nine and ten were originally diagnosed with EA without myometrial invasion and AH, respectively. We performed a central pathological review to make definite diagnoses, and the diagnosis of EA in 29 cases was changed to AH in ten, complex hyperplasia in three and atypical polypoid adenomyoma in three, and AH in ten was changed to EA in one and simple hyperplasia in one. Nine of 12 women (75%) with EA and 15 of 18 women (83%) with AH had an initial response to medroxyprogesterone acetate (MPA) treatment. Two of nine responders with EA later developed relapse, and one of them had metastasis to the left obturator lymph node. Two became pregnant, and one delivered one full-term infant. One of the responders with AH had a relapse in the endometrium. Five became pregnant, and four delivered four normal infants. The young women with endometrial carcinoma localized in the endometrium who wish to preserve fertility may be treated as successfully with MPA as those with AH.

A possible relationship between abortions and placental embolism in pregnant rabbits given human granulocyte colony-stimulating factor.

Developmental toxicity studies were conducted in rats and rabbits with a human G-CSF derivative (NTG). As reported for G-CSF, increases in abortions and fetal mortality were observed in rabbits, but not in rats given NTG. Histopathological examination of the rabbit placenta revealed accumulation of neutrophils in vessels and necrosis of the tissues surrounding these vessels. To assess the mechanism of abortion and fetal death in rabbits given G-CSF, 125I-labeled NTG was given intravenously on Day 18 of pregnancy after repeated administration of cold NTG on Days 6 through 17 of pregnancy, and the feto-maternal distribution of radioactivity was examined. In a rabbit given 20 micrograms/kg, high radioactivity was observed in the endometrium, placenta, and some parts of the decidua at 6 hr when the concentration of radioactivity in maternal blood had already decreased. At 24 hr after administration of 200 micrograms/kg NTG, high radioactivity was still detected in parts of the maternal placenta. These patterns of distribution suggest that embolism occurred in parts of the uterus and placenta which might have caused congestion. Radioactivity in the TCA precipitates in the fetus was low, suggesting that NTG does not readily transfer to the fetus. These results strongly suggest that neutrophils accumulated in the vessels of placenta and induced embolism leading to abortions and fetal mortality in the rabbits given G-CSF.

Complete paternal uniparental isodisomy for chromosome 1 revealed by mutation analyses of the TRKA (NTRK1) gene encoding a receptor tyrosine kinase for nerve growth factor in a patient with congenital insensitivity to pain with anhidrosis.

Uniparental disomy (UPD) is defined as the presence of a chromosome pair that derives from only one parent in a diploid individual. The human TRKA gene on chromosome 1q21-q22 encodes a receptor tyrosine kinase for nerve growth factor and is responsible for an autosomal recessive genetic disorder: congenital insensitivity to pain with anhidrosis (CIPA). We report here the second case of paternal UPD for chromosome 1 in a male patient with CIPA who developed normally at term and did not show overt dysmorphisms or malformations. He had only the usual features of CIPA with a homozygous mutation at the TRKA locus and a normal karyotype with no visible deletions or evidence of monosomy 1. Haplotype analysis of the TRKA locus and allelotype analyses of whole chromosome 1 revealed that the chromosome pair was exclusively derived from his father. Non-maternity was excluded by analyses of autosomes other than chromosome 1. Thus, we have identified a complete paternal isodisomy for chromosome 1 as the cause of reduction to homozygosity of the TRKA gene mutation, leading to CIPA. Our findings further support the idea that there are no paternally imprinted genes on chromosome 1 with a major effect on phenotype. UPD must be considered as a rare but possible cause of autosomal recessive disorders when conducting genetic testing.

Multivariate analysis of prognostic determinants after surgery for renal cell carcinoma at Himeji National Hospital.

A clinico-pathological study was performed retrospectively on 62 patients who underwent surgery for renal cell carcinoma between January 1992 and October 1998 at Himeji National Hospital to clarify the prognostic determinants for survival. The median follow-up period was 32 months and the cause-specific survival rates at 1, 3 and 5 years were 86.7, 81.3, 81.3%, respectively. Of the 62 patients, 11 (17.7%) patients died of renal cell carcinoma and 2 (3.2%) patients died of unrelated causes. Of the variables related to survival, presenting symptoms, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), alkaline phosphatase (ALP), tumor size, pathological tumor grade, infiltration pattern, pathological tumor stage, N classification and M classification were significant risk factors for survival by univariate analysis. However, ALP, N classification and M classification were significant for survival as determined by the step-wise procedure and M classification was the most significant factor according to Cox's proportional hazard model analysis.

[A pilot trial of high dose CEP (cyclophosphamide, epirubicin, cis-platinum) therapy in patients with advanced and recurrent ovarian cancer].

We evaluated the feasibility of high-dose CEP (cyclophosphamide 750 mg/m2, epirubicin 90 mg/m2, cis-platinum 70 mg/m2) therapy, with granulocyte colony-stimulating factor support every 21 days, in 18 patients with advanced and recurrent ovarian cancer. Ten patients (56%) received 6 cycles of this regimen as planned. Toxicities more than grade 3/4 on' the WHO scale of neutropenia and thrombocytopenia were observed in all cases. Nausea, vomiting, mucositis, malaise, alopecia, hepatotoxicity, and fever were common adverse effects. The average relative dose intensity of cyclophosphamide, epirubicin, cis-platinum was 0.77, 0.77, 0.79 respectively, and each RDI decreased in the last two cycles. These data suggest that this regimen could be performed safely with careful consideration on hepatotoxicity and thrombocytopenia.

Influence of emission from rice straw burning on bronchial asthma in children.

BACKGROUND: Emission from rice straw burning (ERSB) is observed everywhere after harvest of rice in Niigata Prefecture every year. Pediatricians and many guardians in this district have had the impression that ERSB may induce asthma attack. Recent studies have suggested that particulate air pollution plays a role in the exacerbation of asthma. The authors investigated relationship of ERSB to asthma attack in children. METHODS: A questionnaire on rice straw burning (RSB) was circulated to guardians and pediatric institutions. Change in the monthly number of children with asthma attack (CAA) for 5 years from January 1994 to December 1998 was investigated. In addition, change in the number of CAA from the meteorologic conditions and RSB was investigated from the fourth week of August to the third week of September in 1996, 1997 and 1998. Challenge test exposure to ERSB was tried on a volunteer adult with chronic asthma. The situation of air pollution was examined by measuring suspended particulate matter (PM10). The relationship between PM10 and the number of CAA was studied. RESULTS: A majority of the guardians had the impression that ERSB induces asthma attack. Pediatricians replied similarly to the questionnaire. The number of CAA visiting our emergency room and admitted to our ward increased in the season of RSB. The PM10 had a significant correlation with the number of CAA. It was suggested that the increase in CAA may be not due to the meteorologic conditions, but to the influence of ERSB. CONCLUSION: The ERSB has made an issue of air pollution. Furthermore, the possibility that ERSB induces or exacerbates asthma attack has become clear in the present study. Therefore, it is recommended that RSB should be abolished for the health of inhabitants, especially children with asthma.

Phase II study of irinotecan and cisplatin as first-line chemotherapy in advanced or recurrent cervical cancer.

Irinotecan (CPT-11) and cisplatin are singly active against cervical cancer. We evaluated the efficacy and toxicity of CPT-11 plus cisplatin as first-line chemotherapy in patients with advanced or recurrent cervical cancer. Twenty-nine chemotherapy-naive patients with advanced or recurrent cervical cancer were treated with CPT-11 (60 mg/m(2)) on days 1, 8, and 15 by intravenous infusion over 90 min, followed by cisplatin (60 mg/m(2) i.v.) on day 1 over 90 min. The patients' median age was 57 years (range 35-75). Nineteen patients (66%) had advanced primary disease. Six patients with recurrent disease (21%) had been treated with prior radiotherapy. The remaining 4 patients (14%) had residual or recurrent disease after radical surgery. The histologic diagnoses were squamous cell carcinoma in 25 patients (87%), adenocarcinoma in 3, and adenosquamous cell carcinoma in 1. All eligible patients were included in the toxicity and response analysis based on the intent to treat. Two patients (7%) achieved a complete response and 15 (52%) a partial response (overall response rate: 59%, 95% confidence interval; 41-74%). Stable disease was recorded in 6 patients (21%) and progressive disease in 3 patients (10%). In 3 patients, image-guided evaluation of response was judged to be unfeasible at the time of independent extramural review (10%). The median time to response was 32 days (range 16-62 days). The median survival was 27. 7+ months (range, 6.4-52.8+ months). Two dose-limiting side effects were observed: grade 3 (28%) or 4 (45%) neutropenia and grade 3 (7%) or 4 (7%) diarrhea. Other severe toxicities included anemia (45%), thrombocytopenia (3%), nausea/vomiting (31%), and alopecia (7%). The combination of CPT-11 with cisplatin is an active regimen for treatment of advanced or recurrent cervical cancer albeit with a significant degree of myelosuppression.

Combination therapy with irinotecan and cisplatin as neoadjuvant chemotherapy in locally advanced cervical cancer.

To evaluate the response rate and toxicity of the combination of irinotecan (CPT-11) and cisplatin in a neoadjuvant setting, a phase II study was conducted regarding the regimen of this combination in patients with locally advanced cervical cancer. Eligibility included patients with previously untreated stage Ib2, IIb, or IIIb squamous cell carcinoma with good performance status. CPT-11 (60 mg m(-2)) was administered intravenously on days 1, 8 and 15, followed by cisplatin (60 mg m(-2)) given intravenously on day 1. Treatment was repeated every 4 weeks for a total of two or three cycles. Among 23 eligible patients (median age: 59 years), three showed complete response (13%), 15 showed partial response (65%), for an overall response rate of 78% (95% confidence interval 58-90%). Stable disease was observed in four cases (17%) and progressive disease in one (4%). The median time to failure and median survival time have not yet been reached. Of the 52 treatment cycles administered, diarrhoea and grade 3 or 4 neutropenia were observed in 10% and 75% respectively. There were no therapy-related deaths. The combination of CPT-11 with cisplatin is a promising regimen for neoadjuvant chemotherapy in locally advanced cervical cancer. The toxicities of this regimen are well tolerated.

Contingent negative variation in children with anorexia nervosa.

BACKGROUND: Central catecholamines, particularly dopaminergic and noradrenergic systems, have affected the appetitive behavior in patients with anorexia nervosa (AN). The purpose of this study is to distinguish the characteristics of contingent negative variation (CNV) and postimperative negative variation (PINV), which may reflect the level of catecholamine in children with AN. METHODS: Eight children with AN aged 10 to 15 years and 23 age-matched healthy children were recruited. Contingent negative variation was recorded from the frontal midline (Fz), central midline (Cz) and parietal midline (Pz) referenced to linked earlobes during 30 trials consisting of a warning stimulus and an imperative stimulus with an interstimulus interval of 2 s and an intertrial interval of 10 s. The imperative stimulus of each trial required a button press. RESULTS: Children with AN had a diminished amplitude of the CNV. They had a significantly more attenuated early CNV and late CNV amplitude at Cz than normal children. No significant differences were observed between AN children and normal children in the amplitude of PINV at all three electrode sites. No difference could be found between the two groups in the frequencies of normal and abnormal duration of PINV. CONCLUSION: These findings suggest that early CNV may be diminished by norepinephrine deficiency and late CNV may be attenuated by dopaminergic deficiency in children with AN. Reduced CNV may represent impaired cognitive processes which reflect impaired appetitive behavior in AN children.

Sympathetic skin response in diabetic children: do diabetic children have diabetic neuropathy?

BACKGROUND: Abnormal sympathetic skin response (SSR) has been reported in adult patients with diabetic neuropathy. In addition, other studies have revealed abnormal SSR in diabetic patients not having autonomic symptoms and autonomic dysfunctions. These findings have been only obtained from adult patients. There have been few reports on the autonomic functions in diabetic children. Accordingly, it is not clear whether the autonomic neuropathy occurs in diabetic children. The aim of the present study is to clear autonomic function in children with insulin-dependent diabetes mellitus by SSR. METHODS: The SSR was measured in 28 normal healthy children and in eight patients with IDDM not having symptoms of dysautonomia. The SSR was elicited using 10 stimuli on programmed Nihonkoden Neuropack Sigma model machine. Following a single electrical stimulation, four SSR were recorded in both the palms and the soles simultaneously. RESULTS: The SSR were simultaneously obtained in 100% of the two groups. The amplitudes in the palms and soles were not significantly different between the two groups. The mean and shortest latency in the soles were significantly longer in the IDDM group than in the control group (P < 0.01). None of the measurements of SSR revealed correlation with duration of diabetes and onset of illness. CONCLUSIONS: Diabetic neuropathy may not have occurred in young patients having shorter duration of illness. Conversely, assuming that prolonged latency is abnormal, it may even have occurred in them. Follow up on these patients with prolonged latencies would be required.

[CDDP-resistant early recurrent uterine cervical cancer successfully treated with low-dose oral etoposide: a case report].

A 36-year-old woman with early recurrence of uterine cervical cancer had received radiotherapy and a CDDP-containing chemotherapy regimen. She was treated with oral etoposide by administration of 50 mg/day for 21 consecutive days at 14-day intervals. After two courses, complete remission was demonstrated by disappearance of the cervical tumor mass and pelvic lymph node enlargement on MRI. Leukopenia (grade 3) occurred after five courses, as well as alopecia (grade 2) and gastrointestinal discomfort (grade 1) after two courses. The patient has shown no sign of recurrence for 1.5 years. This method might be quite effective for patients with recurrent cervical cancer as well as allowing outpatient treatment and improving the quality of life.

[Intravesical bacillus Calmette-Guerin instillation for patients over 80 years old].

To study the efficacy and the safety of intravesical bacillus Calmette-Guerin (BCG) therapy for very elderly patients with superficial bladder cancer, we retrospectively compared patients over 80 years old who had received BCG therapy at our department between 1991 and 1996 (Group A; 10 patients 11 courses), with those below 80 years old (Group B, 17 patients 18 courses). In these patients, skin test reactivity to purified protein derivative showed a significant negative correlation with age (p = 0.016). No irreversible complications were observed in any patient. Persistence of acid-fast bacilli for more than one month after the termination of the course was observed in two patients in group A, and one in group B. A comparison of the cases undergoing eradicational BCG therapy in the two groups, grade 2 transitional cell carcinoma (TCC) was significantly more predominant than grade 3 TCC in group A (p = 0.004). (None of the tumors in group A were of grade 3) The disease-free rate was significantly lower in group A (p < 0.05), but 5 of the 10 patients in this group were finally disease-free. From these results, we conclude that intravesical BCG instillation therapy can be performed in patients over 80 years old, although a relatively lower disease-free rate is expected and special attention should be taken with regard to persistent BCG infection. The lower disease-free rate could be attributable to either diminished cellular immunity or a difference in tumor grade, although a definite conclusion could not be obtained here.

[Combination therapy of daily intramuscular injection of interferon-alpha and oral administration of fluorouracil for advanced renal cell carcinoma].

BACKGROUND: To achieve optimum drug delivery of Interferon-alpha in treatment of renal cell carcinoma, a regimen consisting of its daily intramuscular administration, in combination with oral fluorouracil, was designed and carried out. Its efficacy is examined retrospectively. METHODS: In our department 7 patients with disseminated renal cell carcinoma were treated with daily intramuscular injection of interferon-alpha (3 x 10(6) IU) and daily oral administration of fluorouracil. All patient was nehprectomized before initiation of the regimen. RESULTS: Two patients achieved complete, and three patients achieved partial response radiographically (Overall response rate 71%). Metastatic sites of responders were lung (4) and pleura (2). The time required until response was 3.9 (median 5.4) months. In two responders, new lesions appeared in other organs despite durable response in initial pulmonary metastatic sites. There were two no-responders, one patient is alive with stable disease and the other patient died for progression of the disease. In all, two patients died of disease, one died for other cause, one surviving without evidence of disease, and three are surviving with disease. No significant side effect was noted in these seven patients. CONCLUSIONS: This regimen can be carried out on outpatient basis and considerable response can be expected for pulmonary and pleural lesions.