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We report a case of gefitinib-induced bilateral upper urinary tract bleeding in an 82-year-old woman administered the drug daily for advanced non-small cell adenocarcinoma of the lung (T4N3M0). Hematuria is an uncommon adverse effect of gefitinib, and in most cases, the bleeding site is unknown. On the 44th day of oral gefitinib administration, the patient noted asymptomatic macroscopic bloody urine. Cystoscopy revealed bleeding from the bilateral ureteric orifices without hemorrhagic inflammation of the bladder. One week later, she was admitted complaining of severe abdominal pain, and her condition was found to be complicated by liver damage and renal dysfunction. We stopped gefitinib administration and started hydration and diuresis. Renal function and urine output soon recovered, and at the request of the patient, we restarted gefitinib, administering it every other day, which was sufficient to maintain antitumor activity and stabilize the disease. On the 41st day after restarting gefitinib, hematuria and proteinuria reappeared. We therefore stopped the gefitinib, and the patient was followed with supportive care. The patient's autopsy findings denied organic urologic diseases. Instead, the reproducibility of the hematuria from the upper urinary system strongly suggests an unexpected gefitinib-related adverse effect.
Ewing sarcoma/primitive neuroectodermal tumor is a rare tumor of soft tissues of thoraco-pulmonary regions, pelvis and lower extremities. Involvement of visceral organs by primitive neuroectodermal tumor is even rarer, with the kidney being the most commonly involved organ. Involvement of the liver has been reported in the form of metastasis from other primary sources presenting as liver abscess. We report a 20-year-old lady presenting with massive hepatomegaly, with computed tomography scan evidence of diffuse hepatomegaly and a normal porta and intrahepatic biliary radicles. She subsequently underwent ultrasonography-guided true-cut needle biopsy of the liver. Histopathology of the liver revealed nests of small round blue tumor cells in the background of hepatocytes infiltrating the liver, which expressed Mic-2 and Fli-1, and were negative for cytokeratin, desmin, hepatocyte-specific antigen (OCHIE5), synaptophysin, chromogranin A and CD-20. Immunohistochemistry revealed CD-99-positive. Extensive search regarding any possible different site of involvement by the tumor was negative. The patient responded to a combination therapy of vincristine, adriamycin and cyclophosphamide alternating with ifosfamide and etoposide 3 weekly over 43 weeks and has been doing well even after 1 year of diagnosis. The clinical presentation, the macroscopic aspect, together with the histological pattern, the cytological characteristic and the cellular immunophenotype lead to the diagnosis of primary primitive neuroectodermal tumor of the liver which responded well to combination chemotherapy.
The role of pelvic lymphadenectomy in patients with lymph node-negative bladder cancer at radical cystectomy (RC) has not yet been examined in detail. We retrospectively reviewed patients who underwent RC with pelvic lymphadenectomy for bladder cancer from January 1987 to March 2008.
We identified consecutive data on 169 patients who underwent RC for bladder cancer. The mean follow-up was 64 months (range: 1–253 months). Node-positive status (pN(+)) was seen in 16 patients and 91 were diagnosed as node-negative (pN(–)). The lymph node status of the remaining 62 patients was unclear (pN(x)). We analysed the association between lymph node status and cancer-specific survival (CSS), and examined the role of the number of retrieved lymph nodes, particularly in pN(–).
The median number of retrieved nodes was 12.9 and 10.2 for stage pN(+) and stage pN(–), respectively. In 91 patients with pN(–), multivariate analysis revealed that pathological T3-4 (P = 0.0276) and less than nine retrieved lymph nodes (P = 0.0108) were independent risk factors for CSS. In a subgroup of 83 patients with pT3-4, Kaplan–Meier curves showed that the 5-year CSS rate in pN(–) patients with less than nine retrieved lymph nodes was 38.8%, which was extremely similar to the 40.8% in pN(+) and 45.1% in pN(x).
Our results demonstrate that at least nine lymph nodes should be removed to improve the survival of pN(–) patients at RC and lymphadenectomy, and would provide information not only on prognosis but also on the therapeutic impact on pT3-4 invasive bladder cancer.
We present the clinical course of a ureteroiliac arterial fistula in a patient who had been managed by ureteral stenting for 8 years for severe ureteral stricture after abdominoperineal resection with pelvic irradiation for advanced rectal cancer. A multidisciplinary team approach including provocative angiography and an endovascular stent saved the life of the patient. Ureteroarterial fistula is a rare complication of a long-term indwelling ureteral stent that is potentially fatal unless a prompt diagnosis and adequate therapy are provided. Heightened awareness and a high index of suspicion for this condition are required to make an early diagnosis.
Non-muscle-invasive high-grade (T1G3) bladder cancers have high potential for progression. The objective of this study is to clarify the clinicopathological factors affecting the outcome of T1G3 bladder cancer.
We retrospectively reviewed 60 cases of T1G3 bladder cancer between 1994 and 2006. The correlations of both intravesical recurrence and progression with prognostic factors, such as T stage, history of bladder cancer, multiplicity, concomitant carcinoma in situ, tumor size, intravesical instillation of bacillus Calmette–Guérin and intravesical chemotherapy, were evaluated by multivariate analysis with the Cox proportional hazards model.
Median follow-up period was 52 months (4–105 months). Thirty-seven cases of intravesical recurrence (61.7%) were observed during follow-up. Two- and 5-year recurrence-free survival rates were 44.1% and 36.1%, respectively. Tumor multiplicity and instillation of bacillus Calmette–Guérin were significantly correlated with intravesical recurrence on multivariate analysis. Ten cases of progression (16.7%) were observed during the follow-up period. Two- and 5-year progression-free survival rates were 87.7% and 83.4%, respectively. Only tumor multiplicity was significantly correlated with progression on multivariate analysis.
T1G3 cancers with multiple lesions showed high risks of intravesical recurrence and progression. Although bacillus Calmette–Guérin instillation reduced the risk of intravesical recurrence, no effect was observed on disease progression.
A Phase III study was started in Japan to evaluate the non-inferiority in overall survival of segmentectomy compared with lobectomy in patients with small-sized (diameter ≤2 cm) peripheral non-small cell lung cancer, excluding radiologically determined non-invasive cancer. This study began in August 2009, and a total of 1100 patients will be accrued from 71 institutions within 3 years. The primary endpoint is overall survival. The secondary endpoints are post-operative respiratory function, relapse-free survival, proportion of local recurrence, adverse events, proportion of patients who complete segmentectomy, duration of hospitalization, duration of chest tube placement, operation time, blood loss and number of auto-sutures used. This study is one of the first intergroup studies in Japan between the Japan Clinical Oncology Group and the West Japan Oncology Group.
Colorectal adenocarcinoma, the most common tumor that metastasizes to the ovary, is often difficult to distinguish from primary ovarian mucinous adenocarcinoma (POMA). Obtaining the correct diagnosis is difficult but crucial to treatment and prognosis.
We evaluated the immunohistochemical (IHC) expression of cytokeratin 7 (CK7), cytokeratin 20 (CK20), CDX2, CEA, MUC2, MUC5AC and -methylacyl-CoA racemase (AMACR) in 22 POMAs and 41 metastatic colorectal adenocarcinomas (MCAOs) involving ovaries.
MCAOs, in contrast with POMAs, were almost always negative for MUC5 (97.6%), often negative for CK7 (82.9%), focal or diffuse positive for CDX2 (73.2%), diffuse positive for CK20 (65.9%), focal or diffuse positive for MUC2 (51.2%), diffuse positive for CEA (41.5%) and negative for AMACR (41.5%). We therefore considered CK7 (–), CK20 (diffuse +), CDX2 (+) and MUC2 (+) to be colonic markers and regarded cases with expression of more than two colonic markers as MCAO, those with no expression of colonic markers as POMA and those with expression of one colonic marker as indeterminate. Using CK7/CK20/CDX2/MUC2, 82.5% of the cases were correctly classified, 6.3% were misclassified and 6.3% were indeterminate.
CK7, CK20, CDX2 and MUC2 IHC staining is a useful adjunctive diagnostic tool to differentiate MCAOs from POMAs, in addition to clinical history and gross and microscopic findings.
To evaluate the effectiveness of vaginal misoprostol in overcoming an unsatisfactory colposcopy in the patients who had abnormal cervical cytology and to evaluate side effects of vaginal misoprostol.
Sixty patients with an unsatisfactory colposcopy during the period of September 2007–November 2008 were recruited and randomly allocated to receive either two tablets of 200 µg misoprostol (400 µg) or two tablets of similar-looking placebo vaginally. Colposcopic re-examination was performed ~6 h later. The results and side effects before and 2 weeks after the colposcopic re-examination were recorded.
Six out of 30 patients in the misoprostol group (20.0%) had a satisfactory colposcopic re-examination compared with 2 out of 27 patients (7.4%) in the placebo group without statistically significant difference (P = 0.172). Three patients in the placebo group dropped out due to not present at the appointment time. Six out of 30 patients (20.0%) and 1 out of 30 patients (3.3%) in the misoprostol group had side effects before and 2 weeks after the colposcopic re-examination orderly. Twenty-seven patients in the placebo group did not have any side effects before and 2 weeks after the colposcopic re-examination. All side effects occurred were minimal and well tolerated.
Four hundred micrograms of vaginal misoprostol were not proved to be effective in converting an unsatisfactory to a satisfactory colposcopy.
The objectives of this study were to determine the maximum tolerated dose (MTD) and recommended dose (RD) of S-1 plus cisplatin (CDDP) and to evaluate safety and efficacy using the defined RD in advanced/recurrent head and neck cancer (HNC).
S-1 was administered orally at 40 mg/m2 twice daily for 14 consecutive days, and CDDP was infused on day 8 at a dose of 60 and 70 mg/m2. Each course was repeated every 4 weeks.
A total of 38 patients were registered, 10 patients for the Phase I study and an additional 28 patients for the Phase II study. Although no dose-limiting toxicity (DLT) was observed in the CDDP 60 mg/m2 (Level 1) group, two of six patients in the CDDP 70 mg/m2 (Level 2) group exhibited DLT (fatigue/diarrhea). The MTD was not achieved in the Phase I study. Level 2 was therefore determined as the RD. In the Phase II study, 34 patients, including 6 patients from the Phase I study, were evaluated. At the termination of treatment, the confirmed response rate was 44.1% (15/34, 95% CI: 27.4–60.8). The best response rate without an adequate duration time was 67.6% (95% CI: 51.9–83.4). The median survival period was 16.7 months, and the 1-year survival rate was 60.1%. The main toxicities of Grade 3 or above were anorexia (26.5%), nausea (14.7%), neutropenia/thrombocytopenia (11.8%) and anemia/fatigue (8.8%).
This is considered to be an effective regimen with acceptable toxicities for HNC.
This study aims to assess the efficacy and safety of sunitinib in Japanese patients with metastatic renal cell carcinoma (RCC).
Fifty-one Japanese patients with prior nephrectomy, 25 treatment-naive patients (first-line group) and 26 cytokine-refractory patients (pretreated group) were enrolled in this phase II trial. Patients received sunitinib 50 mg orally, once daily, in repeated 6-week cycles (4 weeks on treatment, 2 weeks off). The primary endpoint was RECIST-defined objective response rate (ORR) with tumour assessments every 6 weeks via computed tomography or magnetic resonance imaging. Toxicity was assessed regularly. In the primary efficacy analysis of the intent-to-treat (ITT) population, ORR and 95% confidence interval were calculated based on independent review. Secondary time-to-event endpoints, such as progression-free survival (PFS), were estimated using the Kaplan–Meier method.
In the ITT population, ORR was 48.0% in the first-line group (after a median 4 cycles), 46.2% in the pretreated group (5 cycles) and 47.1% overall, with median times to tumour response of 7.1, 10.7 and 10.0 weeks, respectively. Median PFS was 46.0, 33.6 and 46.0 weeks, respectively. The most common treatment-related grade 3/4 adverse events and laboratory abnormalities were fatigue (20%), hand-foot syndrome (14%) and hypertension (12%), decreased platelet count (55%), decreased neutrophil count (51%), increased lipase (39%) and decreased lymphocyte count (33%).
In Japanese patients with RCC, sunitinib is consistently effective and tolerable with similar risk/benefit as that in Western patients, though there was a trend toward greater antitumour efficacy and higher incidence of haematological adverse events in Japanese patients.
The sensitivity of cytologic examination of pleural effusions is variable and not predictive of prognosis. Survivin is an inhibitor of apoptosis that may be a novel diagnostic/prognostic marker of cancers. This study aimed to determine the diagnostic and prognostic value of measuring survivin mRNA levels in pleural effusions.
Eighty-eight consecutive pleural effusion samples were examined for both cytology and survivin mRNA level. The accuracy of diagnosis and the correlation between survivin mRNA level and survival in malignant pleural effusion (MPE) were determined. Pleural effusions were divided into three groups: Group I, malignancy-associated (n = 44); Group II, inflammatory (n = 27); and Group III, transudative (n = 17).
Survivin mRNA levels in Group I (1.03 ± 0.61, range 0–2.96) were significantly higher than those in Groups II (0.45 ± 0.69, range 0–3.30) and III (0.08 ± 0.22, range 0–0.71) (P < 0.001). Survivin mRNA level was significantly higher in MPE than in non-MPE. The cut-off value for survivin mRNA levels in pleural effusions was 0.074 for the diagnosis of malignancies, with sensitivity, specificity, and positive and negative predictive values of 96%, 45%, 45% and 96%, respectively. Survivin mRNA level in pleural effusions of cancer patients significantly correlated with poor survival.
Survivin mRNA level is significantly higher in MPEs. Over-expression of survivin mRNA correlates with poor prognosis in cancer patients.
In this study, we assessed the clinical and pathological characteristics of urothelial cancers of the upper urinary tract (UUT) in patient under dialysis and evaluated the efficacy and complications of surgical management of the disease.
A total of 70 dialysis patients with primary urothelial carcinoma (UC) of the UUT were identified with 5-year follow-up after surgery (61–122 months). Potential factors were analysed to determine the risk factors of subsequent tumours and unfavourable prognostic factors of overall survival. Incidence of urothelial tumours and overall survival of 7503 dialysis patients were also evaluated.
The incidence of primary UC of the UUT in dialysis patients in Taiwan was 0.93%. The 2-year and 5-year overall survival rates of dialysis patients with primary UC of the UUT were 74.3% and 42.9%, respectively. Subsequent bladder tumours and contralateral UUT tumours developed in 52.6% and 37.9% patients, respectively. No significant risk factor could be identified to predict subsequent tumours in dialysis patients. Pathological stage (P = 0.021) and grade (P < 0.001) were the unfavourable prognostic factors in the log-rank test. No significant difference was observed in perioperative mortality and overall survival between patients receiving one-stage nephroureterectomy and those receiving two-stage bilateral nephroureterectomy; however, the cystectomy procedure increased perioperative mortality according to the 2 test (P = 0.042).
Closely monitoring the residual urinary tracts after nephroureterectomy in dialysis patients with primary UC of the UUT should be performed. There is no statistical difference for overall survival between one-stage and two-stage bilateral nephroureterectomy.
We analyzed information surveyed from a community-based sample of Korean women older than 40 years of age to understand the relationships between health status and screening behavior.
In a cross-sectional population-based study, a two-stage, geographically stratified household-based sampling design was used for assembly of a probability sample of women aged 40–69 years living in Gunpo in Korea, resulting in a total sample size of 503 women. The primary outcome variable for this analysis was the respondent's intention to obtain a mammogram. Predictor variables included health status and other factors known to influence the use of cancer screening, such as age, education, income, marital status and the presence of co-morbid illnesses. Health status was assessed by using the EuroQol (EQ-5D).
The median EQ visual analogue scale score was 75.0, ranging from 20 to 100. In bivariate analyses, the percentage of women reporting to have intention toward mammography use decreased with worsening health status. Women who had problems with mobility or anxiety/depression showed lower intention to undergo future screening mammography. Multivariate logistic regression confirmed that health status was significantly associated with intention toward mammography use. Anxiety or depression was an independent predictor of future screening mammography use.
Health status is significantly associated with intention regarding screening mammography use. Physicians or other health professionals should be aware that health status is an important component for health promotion, and should pay more attention to clients' possible vulnerability in screening mammography use due to their poor health status.
Hormonal imbalance characterized by excessive production of growth hormone (GH) and a low circulating concentration of insulin-like growth factor (IGF)-1 has been demonstrated in individuals with various serious conditions. However, little is known about changes in the GH–IGF-1 axis in cancer patients.
We prospectively examined the circulating levels of several hormones in 58 patients with solid tumors who were classified according to Eastern Cooperative Oncology Group performance status (PS): PS 0–1, n = 15; PS 2, n = 15; PS 3, n = 15; and PS 4, n = 13. The relations of hormone concentrations, with a focus on the GH–IGF-1 system, to PS were evaluated by Spearman's rank correlation test and regression analysis.
The circulating levels of IGF-1, IGF-binding protein-3 and thyroid hormones (total T3 and T4) were inversely correlated with PS score. The concentration of GH was increased irrespective of PS but not statistically significant. The ratio of IGF-I to GH was inversely correlated with PS. The levels of GH and IGF-1 in all patients were also inversely correlated.
The present study suggests that the GH–IGF-1 axis is disturbed in patients with cancer.
Capecitabine is effective and well tolerated in patients with anthracycline- and/or taxane-pre-treated metastatic breast cancer. We compared the efficacy and safety of capecitabine monotherapy between 1st, 2nd, 3rd and ≥4th line settings for advanced and metastatic breast cancer pre-treated with/without anthracycline and taxanes.
Subjects comprised 84 patients with histologically confirmed advanced or metastatic breast cancer and at least one measurable metastatic lesion. We evaluated time to disease progression (TTP), response rate (RR) and clinical benefit rate (CBR) for 1st (n = 17), 2nd (n = 28), 3rd (n = 23) and ≥4th (n = 16) line setting treatments of capecitabine monotherapy.
Median number of cycles of capecitabine monotherapy was 12 cycles in 1st line, 11 cycles in 2nd line, 9 cycles in 3rd line and 11 cycles in ≥4th line. RR and CBR were 23.5% and 58.8% in 1st line, 21.4% and 53.6% in 2nd line, 21.7% and 52.2% in 3rd line, and 18.8% and 50.0% in ≥4th line, respectively. No significant differences in TTP were seen between each line setting (P = 0.843).
Capecitabine monotherapy is effective and well tolerated in all line settings of chemotherapy in patients with metastatic or advanced breast cancer, and is suitable for outpatient therapy.
Since late 1990s, many molecular target agents have been introduced to clinical trials for various kinds of tumors, and some of them showing significant benefits have been approved. However, these global trials were mainly conducted outside Japan, and the ‘drag lag’ has been a serious problem in Japan recently. Nowadays, Japanese institutions have been participating in some global trials, and the drug lags are getting shorter. For colorectal cancer, molecular target agents such as bevacizumab and cetuximab have been approved in Japan, resulting in improved clinical outcomes. For gastric cancer, Japanese institutions not only contribute to the global Phase III trials of trastuzumab and bevacizumab but also show leadership in the early development of other new agents. For pancreatic cancer, only erlotinib has shown a survival benefit in these 10 years. Worldwide approach including Japan is warranted to achieve better clinical outcomes. For liver cancer, although Japanese institutions did not participate even in the Asian trial of sorafenib, it has been approved in Japan. For esophageal cancer, because there has been no new molecular target agents developed by pharmaceutical companies, investigator-initiated registration trial will play an important role. For all gastrointestinal malignancies, molecular target agents have made a progress in their treatments. In the near future, Japanese institutions will participate in more and more global trials and should play a specific role in worldwide drug development. Furthermore, the optimal use of these new drugs, molecular target agents, based on the daily practice should also be explored in Japan.