Neuropathic Pain Features in Patients with Bone Metastases.

AIMS: The results of previous randomised controlled trials suggest that radiation oncologists should consider the presence of neuropathic pain when they prescribe dose fractionations for painful bone metastases. Although validated screening tools for neuropathic pain features are currently available, the prevalence of such features among patients with painful bone metastases is still poorly understood. The purpose of this study was to estimate the prevalence of neuropathic pain features among patients who received palliative radiotherapy for painful bone metastases. MATERIALS AND METHODS: We conducted a cohort survey of consecutive patients who received palliative radiotherapy for painful bone metastases at St Luke's International Hospital between 2013 and 2014. Patients were prospectively assessed before radiotherapy using the validated screening questionnaire to identify neuropathic pain components in Japanese patients. Pain with neuropathic features was prospectively defined using the total score of the seven-item questionnaire and a cut-off score ≥9. The pain response was assessed 2 months after the start of radiotherapy according to the criteria defined by the International Bone Metastases Consensus Working Party. RESULTS: Eighty-seven patients were assessed. Twenty-four per cent of patients (95% confidence interval: 16-35%) were diagnosed as having pain with neuropathic features. On multivariate analysis, no significant correlations were seen between neuropathic pain features and patient characteristics. Sixty-four patients (74%) were assessable 2 months after the start of radiotherapy. Overall response rates were 59% (95% confidence interval: 33-82%) in patients with neuropathic features and 55% (95% confidence interval: 40-70%) in those without such features. CONCLUSIONS: A considerable proportion of the patients were proven to have bone pain with neuropathic features. Further investigations are warranted to validate symptom assessment tools in cooperation with pain distribution and image findings, and to clarify if the presence of neuropathic pain affects the response to palliative radiotherapy.

Occurrence of adverse events caused by valganciclovir as pre-emptive therapy for cytomegalovirus infection after allogeneic stem cell transplantation is reduced by low-dose administration.

BACKGROUND: Pre-emptive therapy with valganciclovir (VGCV) has become the standard therapy for preventing cytomegalovirus (CMV) infection after allogeneic hematopoietic stem cell transplantation (HSCT). The effectiveness of low-dose VGCV (900 mg per day) has been shown to be equal to that of standard-dose VGCV (900 mg twice daily); however, individualized optimal dosing and toxicity of VGCV have not been reported. METHODS: We conducted a retrospective study to evaluate the optimal dose of VGCV as pre-emptive therapy for preventing CMV infection by comparing the frequency of adverse events (AEs) and clinical efficacy in a low-dose VGCV group with those in a standard-dose VGCV group. Thirty-eight patients who were administered VGCV because of CMV antigenemia after HSCT were analyzed. RESULTS: Neutropenia (standard-dose group: 33%, low-dose group: 15%, P = 0.26) and thrombocytopenia (standard-dose group: 39%, low-dose group: 15%, P = 0.14) were frequent AEs of VGCV, and a significantly higher frequency of overall AEs was detected in the standard-dose group than in the low-dose group (P < 0.01). In comparison of dosage based on weight, dosage of VGCV >27 mg/kg was closely related to onset of AEs (P = 0.04). CONCLUSIONS: Low-dose VGCV was not inferior in clinical efficacy, including clearance rate of CMV antigenemia and incidence of consequent CMV disease, to standard-dose VGCV as was previously reported. Initial low-dose VGCV for pre-emptive CMV therapy markedly reduces hematologic toxicity and has clinical efficacy equivalent to that of standard-dose VGCV. It is therefore reasonable for patients, except for noticeably overweight patients, to be given initial low-dose VGCV.

Hepatitis B virus (HBV) reverse seroconversion (RS) can be prevented even in non-responders to hepatitis B vaccine after allogeneic stem cell transplantation: long-term analysis of intervention in RS with vaccine for patients with previous HBV infection.

BACKGROUND: Reactivation of hepatitis B virus (HBV) infection, reverse seroconversion (RS), is a serious complication after allogeneic stem cell transplantation (alloHSCT). We previously conducted a post-transplant hepatitis B vaccine intervention trial and demonstrated the vaccine efficacy in preventing HBV-RS. This report is an update of the hepatitis B vaccine study. METHODS: In this trial, 21 patients were enrolled and received a standard 3-dose regimen of hepatitis B vaccine after discontinuation of immunosuppressants, whereas 25 transplant recipients with previous HBV infection did not receive the vaccine and served as controls. RESULTS: None of the 21 patients in the vaccine group developed HBV-RS and 12 controls developed HBV-RS in median follow-up periods of 60 months (range 13-245). HBV vaccine resulted in a positive value of hepatitis B surface antibody (HBsAb) titer in 9 patients, while HBsAb remained negative in 12 patients. Presence of a high titer of HBsAb before vaccination was associated with conversion into HBsAb positivity after vaccination. CONCLUSION: These results demonstrated the long-term effects of HBV vaccine for preventing HBV-RS after alloHSCT. Of note, no HBV-RS occurred, even in patients who did not achieve conversion into HBsAb positivity after vaccination.

Clinical impact of cycling the administration of antibiotics for febrile neutropenia in Japanese patients with hematological malignancy.

Despite the availability of newer classes of antibiotics, infection with multi-drug-resistant bacteria is a serious problem. To suppress the appearance of multi-drug-resistant bacteria and to avoid severe infection derived from febrile neutropenia (FN), we conducted cycling the administration of antibiotics for FN in patients with hematological malignancy. The treatment protocol consisted of the administration of four antibiotics each for 3 months in 1 year. The above regimen was repeated for 4 years. A total of 193 patients were registered in the protocol. The mean duration of the administration of cycling antibiotics was 5.9 days (range: 1-16 days). The frequency of FN before the study and during the study was unchanged until the third year, but decreased significantly in the fourth year. The frequency of detection of multi-drug-resistant bacteria in the first year was the same as that before the study was started, but dramatically decreased after the second year. Bacteriological treatment success rates were similar in each trimester and each year. The effective rate was not statistically different in each trimester and each year. We conclude that cycling the administration of antibiotics in patients with FN is useful for suppressing the appearance of multi-drug-resistant bacteria and for obtaining excellent clinical efficacy.

Long-term results of salvage photodynamic therapy for patients with local failure after chemoradiotherapy for esophageal squamous cell carcinoma.

BACKGROUND AND STUDY AIMS: Local failure after chemoradiotherapy (CRT) remains a major problem for patients with esophageal squamous cell carcinoma (ESCC). The aim of this study was to clarify the long-term results of salvage photodynamic therapy (PDT) for local failure. PATIENTS AND METHODS: Patients were treated with CRT, consisting of more than 50 Gy irradiation and concurrent chemotherapy. The indications for salvage PDT were as follows: 1) absence of lymph-node or distant metastasis after CRT; 2) failure lesion limited to T2; 3) refusal by patient to undergo salvage esophagectomy; 4) written informed consent. PDT was performed using an excimer dye laser at 48 and 72 hours after administration of Photofrin. RESULTS: A total of 37 consecutive patients underwent salvage PDT. The baseline stage before CRT was as follows: T1/T2/T3/T4 in 3/4/24/6 and N0/1 in 13/24 patients, respectively. Prior to PDT, 20 patients had a uT1 lesion, and 17 had a uT2 lesion; 24 patients had histologically proven local failure. A complete response was achieved in 22 patients (59.5%) following PDT. Esophageal fistulae, stenosis, and phototoxicity occurred in 4 (10.8%), 20 (54.1%), and 2 (5.4%) patients, respectively. Over a median follow-up period of 55 months, the 5-year progression-free (PFS) and overall survival rates of 37 patients following PDT were 20.7% and 36.1%, respectively. The 5-year PFS and overall survival of 24 patients with proven local failure were 17.6% and 34.6%, respectively. CONCLUSION: Salvage PDT is a curative treatment option for patients with local failure after CRT for ESCC.

Submucosal tumor appearance is a useful endoscopic predictor of early primary-site recurrence after definitive chemoradiotherapy for esophageal squamous cell carcinoma.

Chemoradiotherapy (CRT) for esophageal cancer is disadvantageous because of a high locoregional failure rate. Detecting early small recurrent cancers at the primary site is necessary for potential salvage treatment. However, most endoscopists are inexperienced and therefore, a role for surveillance endoscopy after complete remission (CR) has not been established. We retrospectively evaluated serial surveillance endoscopic images from patients eventually proved to have primary-site recurrence in order to identify useful endoscopic features for early diagnosis. From January 2000 to December 2004, 303 patients with esophageal squamous cell carcinoma underwent definitive CRT, and 133 of them achieved CR. The surveillance endoscopic images stored at intervals of 1-3 months for the 16 patients with recurrence only at the primary tumor site and the 61 patients with no recurrence were collected for reexamination. Among 133 patients who achieved CR, 16 (12%) developed only local recurrence at the primary site. Thirteen of the 16 primary-site recurrent tumors (81%) appeared as submucosal tumors (SMT), with the remaining appearing as erosions or mild strictures. Of biopsy-proven recurrences, 81% were preceded by newly developed lesions such as SMT, erosions, or mild strictures detected by earlier surveillance endoscopies. For all 77 patients achieving CR with no metastasis, 86% of the evolving SMT with negative biopsies were eventually confirmed as cancer at later endoscopies. Thirteen of the 21 evolving lesions were subsequently confirmed as recurrent cancer. Early primary-site recurrence of esophageal cancer after a complete response to CRT is detectable with frequent endoscopic surveillance. SMT appearance is a useful endoscopic sign of early recurrence, as well as a predictor of subsequent diagnosis of recurrence.

Increased risk of bacterial infection after engraftment in patients treated with allogeneic bone marrow transplantation following reduced-intensity conditioning regimen.

Although bacterial infection is a major cause of death even after reduced-intensity conditioning (RIC) for allogeneic stem cell transplantation (SCT), little is known about the epidemiology and risk factors. The incidence of bacterial infection in 43 patients who received allogeneic bone marrow transplantation (BMT) using a RIC regimen was compared with that in 68 patients who received BMT using a myeloablative conditioning regimen, and risk factors for bacterial infection were identified. Before engraftment, incidences of febrile neutropenia (FN) and documented infections (DI) were significantly decreased in RIC patients (FN: 59.5% vs. 89.6%, P<0.01, DI: 4.8% vs. 17.9%, P<0.01). However, incidence of bacterial infection was significantly increased in RIC patients in the post-engraftment phase (53.8% vs. 11.1%, log-rank, P<0.01). Blood stream was the most frequent focus of infection in both groups. In multivariate analysis, RIC and acute graft-versus-host disease were revealed to be significant risk factors for bacterial infection in this phase. In summary, risk of bacterial infection after engraftment was significantly higher in RIC patients, although infection was decreased before engraftment, and we need to develop a RIC-specific strategy against bacterial infection after RIC SCT.

Long-term results of salvage endoscopic mucosal resection in patients with local failure after definitive chemoradiotherapy for esophageal squamous cell carcinoma.

BACKGROUND AND STUDY AIMS: Local failure after definitive chemoradiotherapy (CRT) in patients with esophageal cancer remains one of the major problems in finding a cure. Endoscopic mucosal resection (EMR) is one treatment option when failure lesions are superficial. However, there are no relevant long-term survival data. The aim of this study was to clarify the long-term survival of salvage EMR. PATIENTS AND METHODS: Between January 1998 and March 2004, 289 patients with esophageal squamous cell carcinoma were treated with definitive CRT at the National Cancer Center Hospital East, Japan. Of these 289 patients, 21 patients with local failure without lymph-node or distant metastases were treated with salvage EMR. The technique of salvage EMR involved a strip biopsy method. We retrospectively analyzed the long-term survival data for the patients who underwent salvage EMR. RESULTS: At a median follow-up period of 54 months (range, 16-108 months), eight of 21 patients (38%) were alive with no recurrence and two patients had died from another disease but with no recurrence of esophageal cancer. Local recurrence after EMR was detected in four patients, with local and lymph-node recurrence in two patients, and lymph-node and/or distant metastases in five patients. The 5-year survival rate from the initiation of salvage EMR was 49.1%. There were no severe complications associated with EMR. CONCLUSION: EMR is one of the curative salvage treatment options for local failure after definitive CRT, if the failure lesion is superficial and there are no lymph-node or distant metastases.

Cost benefit and clinical efficacy of low-dose granulocyte colony-stimulating factor after standard chemotherapy in patients with non-Hodgkin's lymphoma.

High costs of molecule-targeted drugs, such as rituximab, ibritumomab, and tositumomab have given rise to an economical issue for treating patients with non-Hodgkin's lymphoma (NHL). Granulocyte colony-stimulating factors (G-CSFs), which are also expensive, are widely used for treating neutropenia after chemotherapy. In Japan, lenograstim at 2 microg/kg (about 100 microg/body) or filgrastim at 50 microg/m(2) (about 75 microg/body) is commonly administered for patients with NHL after chemotherapy. Therefore, cost-effectiveness is an important issue in treatment for NHL. Patients with advanced-stage NHL who needed chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or a CHOP-like regimen with or without rituximab were enrolled in this randomized cross-over trial to investigate the efficacy and safety of low-dose G-CSF. Half of the patients were administered 75 microg filgrastim in the first course after neutropenia and 50 microg lenograstim in the second course, and the other half were crossed over. Forty-seven patients were enrolled in this cross-over trial, and 24 patients completed the trial. Frequencies and durations of grade 4 leukocytopenia and neutropenia were similar in the two groups. Severe infection was rare and was observed at similar frequency. Frequencies of antibiotics use were also similar. The total cost of G-CSF (cost/drug x duration of administration) was significantly lower in patients who received 50 microg lenograstim. Hence, a low dose of lenograstim might be safe, effective and pharmaco-economically beneficial in patients with advanced-stage NHL.

Successful treatment with allogeneic peripheral blood stem cell transplantation and granulocyte transfusion for severe aplastic anemia with sinusitis.

A 43-year-old woman with severe aplastic anemia (SAA) received anti-thymocyte globulin and cyclosporin A (CyA) and achieved hematological remission. Although she had maintained hematological remission, the disease relapsed 10 months after arbitrary discontinuance of maintenance therapy with CyA. Resumption of CyA therapy was not effective, and her condition became complicated with progressive sinusitis with bone destruction, which was refractory to antibiotics, antifungal agents, granulocyte colony-stimulating factor, and surgical drainage. Because of the necessity for early neutrophil recovery (to resolve the infection), we proceeded with a combination therapy using allogeneic peripheral blood stem cell transplantation (PBSCT) promptly followed by granulocyte transfusion (GTX) from the same human leukocyte antigen-identical donor rather than carrying out a second immunosuppressive therapy. The patient showed temporal resolution of infection on the second day after a single GTX. Although the patient had pneumonia on day 11, it was resolved promptly after engraftment on day 16. This report suggests the clinical utility of a salvage therapy with allogeneic PBSCT followed by GTX in a particular case of recurrent SAA with refractory infections.

Detection and cloning of a protein recognized by anti-human prostate-specific antigen (PSA) antibody in the rat ventral prostate.

Prostate-specific antigen (PSA), a 33 kDa glycoprotein produced in the epithelium of the human prostate, has become established as a useful tumor marker for prostate cancer in man. Since reports of homologous proteins in animals other than primates have been lacking, the present investigation was carried out to identify any PSA-like protein in rats. Immunoblot analysis using a specific monoclonal anti-human PSA antibody detected a 32 kDa immunoreactive protein in the ventral lobe of the rat prostate, but not in other lobes or in other tissues. Positive immunostaining was observed only for the luminal surface of the glandular epithelium and the intraductal fluid in the ventral prostate. Sequence analysis of a cDNA for the rat PSA-like protein, cloned by immunoscreening of an expression cDNA library prepared from the ventral lobe, revealed identity to the rat submaxillary gland S3 kallikrein. Human PSA also belongs to the kallikrein family. Thus, this protein produced in the rat ventral prostate was suggested to be a possible counterpart of human PSA.

Promoting effects of antiandrogenic agents on rat ventral prostate carcinogenesis induced by 3,2'-dimethyl-4-aminobiphenyl (DMAB).

The objective of this study was to determine the effects of androgen depletion by 5alpha-reductase inhibitor (eg epristeride), pure antiandrogen (eg casodex) or C17-20 lyase inhibitor (eg YM116) on rat prostate carcinogenesis induced by administration of 3,2'-dimethyl-4-aminobiphenyl (DMAB). DMAB was subcutaneously administered on male F344 rats for the first 20 weeks. Epristeride (10 and 50 mg/kg, three times per week), casodex (15 and 30 mg/kg, three times per week) or YM116 (15 and 30 mg/kg, three times per week) were administered orally for 40 consecutive. Then, all accessory sex organs were studied for the formation of neoplastic lesions by histological examination. All carcinoma lesions were produced only in the ventral lobe of the prostate. The incidence of carcinoma developing in the ventral lobe of the prostate was 9.5% in the control group on which DMAB alone was administered, whereas it was 31.6% in the epristeride 10 mg/kg group. 45.0% in the epristeride 50 mg/kg group, 47.8% in the casodex 15 mg/kg group, 63.2% in the casodex 30 mg/kg group, 10.5% in the YM116 15 mg/kg group and 5.0% in the YM116 30 mg/kg group. The incidences of carcinoma in the epristeride 10 mg/kg group, casodex 15 mg/kg group and casodex 30 mg/kg group were significantly higher than that of the control group. In this experimental model, all ventral prostate carcinomas were in situ adenocarcinomas that did not form palpable nodules or distant metastasis. Epristeride and casodex showed a dose-dependent promoting effect on rat ventral prostate carcinogenesis. These results were contradictory to the results of our previous studies; exogenous testosterone in combination with DMAB produced palpable, and metastatic tumors in other portions of accessory sex organs of F344 rats but no carcinoma in ventral prostate, and those invasive carcinomas were significantly inhibited by 5alpha-reductase inhibitor and nonsteroidal anti-androgen. The action mechanisms of androgen and the effects of androgen-regulatory drugs on prostate carcinogenesis should be further studied. Prostate Cancer and Prostatic Diseases (2000) 3, 115-119

[A case of synchronous multifocal urothelial tumors in a patient with phenacetin abuse].

A 79-year-old male with phenacetin abuse was admitted to our University Hospital for treatment of asymptomatic gross hematuria. Intravenous urograpdy and computed tomography revealed synchronous right renal pelvic carcinoma and bladder carcinoma. Right nephroureterectomy and transurethral resection of bladder tumor (TUR-Bt) were performed. Histologically, right renal pelvic tumor and bladder tumor were both transitional cell carcinomas of grade 2, pT1, and grade 1 = 2, Ta, respectively. Additionally, pathological examination revealed two distal ureteral tumors, which were transitional cell carcinomas of grade 2, pTa. He also had a history of heavy tobacco-smoking (20 cigarettes per day for 50 years). We discuss the relationship between transitional cell carcinoma and phenacetin abuse as well as the influence of tobacco-smoking, and review the literature.

Effects of a soybean isoflavone mixture on carcinogenesis in prostate and seminal vesicles of F344 rats.

Several epidemiological studies have suggested an inverse association between the risk of prostate cancer and intake of soybeans and their products. In vitro data pointing to possible anti-carcinogenic properties of the soybean isoflavone, genistein, led us to investigate the chemopreventive potential of soybean isoflavones in a rat carcinogenesis model induced by 3,2'-dimethyl-4-aminobiphenyl (DMAB) and testosterone propionate (TP). Animals received DMAB s.c. injections at 2-week intervals for the first 20 weeks and implanted silicon tubes containing 40 mg of TP, replaced at 6-week intervals throughout the experiment. The soybean isoflavone mixture consisting of 74% genistein and 21% daidzein was mixed in basal diet (AIN-76A) at concentrations of 100 and 400 ppm and fed to F344 male rats throughout the experiment. Rats treated with carcinogens and administered isoflavone mixture at 100 and 400 ppm developed adenocarcinomas at incidences of 35% and 29%, respectively, in the prostate and seminal vesicles, whereas the figure was 60% for those maintained on control diet. Feeding of the isoflavone mixture at 100 and 400 ppm significantly inhibited the number of argyrophilic nucleolar organizer regions (AgNORs) in adenocarcinomas of the accessory sex glands as compared to those of rats fed control diet. No influence on the development of neoplastic lesions originating in other organs was noted. The results of this study provide evidence that soybean isoflavones may have potential as chemopreventive agents against carcinogenesis in the prostate.

Effects of soybean isoflavones on cell growth and apoptosis of the human prostatic cancer cell line LNCaP.

BACKGROUND: Epidemiological studies have suggested that soybean isoflavones are associated with a lower risk of prostate cancer. However, the mechanisms of prostate cancer prevention by soybean isoflavones have yet to be fully clarified. METHODS: Two soybean isoflavones (genistein and daidzein) and their glucosides (genistin and daidzin) were tested for their effects on cell growth and apoptosis of the LNCaP human prostatic cancer cell line. RESULTS: Among these isoflavones, genistein was found to inhibit the growth of LNCaP most effectively, with an IC50 value of 40 microM. The inhibition of cell growth by genistein was accompanied by the suppression of DNA synthesis and the induction of apoptosis. Expression of prostate-specific antigen (PSA) in LNCaP was also significantly reduced by the treatment with genistein. CONCLUSIONS: The results suggest that genistein might primarily influence human prostate cancer development by reducing tumor growth.

p53 and p21(WAF1) expression in lymphocytic thyroiditis and thyroid tumors.

To clarify the roles of increased apoptosis and cell proliferation in chronic autoimmune lymphocytic thyroiditis and thyroid tumorigenesis, expression of p53 and p21(WAF1) proteins was immunohistochemically investigated in a series of 158 cases. Positive epithelial cells were quantified to give numbers per unit square and to score for distribution. They were found scattered in nontumorous thyroid tissue, their numbers increasing with the severity of thyroiditis and the correlation between expression of the two proteins, regardless of the presence or absence of thyroid neoplasms. Simultaneous expression of both proteins was occasionally found in the same cells by analysis of serial histologic sections. In thyroid tumors, increased expression was found to be diffuse, focal, or scattered for the distribution of p53- or p21(WAF1)-immunopositive cells in accordance with tumor cell dedifferentiation, showing significant correlation between expression of the two proteins. Correlated with these findings, enhanced apoptosis along with decreased Bcl-2 expression and increased Ki-67 labeling in lymphocytic thyroiditis and thyroid tumors was also confirmed in the same series, using in situ DNA nick-end labeling and immunohistochemical methods. Increased expression of p53 and/or p21(WAF1) proteins was thus suggestive of possible DNA damage and increased apoptosis in autoimmune thyroiditis. In addition, a significant correlation between protein overexpression and dedifferentiation of thyroid tumor cells was apparent.

A five-alpha reductase inhibitor or an antiandrogen prevents the progression of microscopic prostate carcinoma to macroscopic carcinoma in rats.

BACKGROUND: The objective of this study was to elucidate the prophylactic effects of 5-alpha reductase inhibitor (e.g., finasteride) and a pure antiandrogen (e.g., casodex) on rat prostate carcinogenesis and to determine whether latent prostate carcinoma can be prevented to develop to clinically significant cancer by use of these drugs. METHODS: F344 rats were subcutaneously administered 3,2'-dimethyl-4-aminobiphenyl (DMAB) for the first 20 weeks and testosterone propionate throughout the 60-week study. Finasteride (5 mg/kg and 15 mg/kg, 2 times per week) and casodex (15 mg/kg, 30 mg/kg, and 60 mg/kg, 3 times per week) were administered orally during the last 40 weeks of the study. Tumors were classified as visible prostate carcinoma when they could be recognized with the naked eye and as microscopic prostate carcinoma when detectable only with a microscope. RESULTS: The incidence of visible prostate carcinoma was 51% (18 of 35 rats) in the positive control group, whereas it was 40% (4 of 10 rats) in the finasteride 5 mg/kg group, 16.7% (2 of 12 rats, P = 0.0091) in the finasteride 15 mg/kg group, 20% (4 of 20 rats, P = 0.05) in the casodex 15 mg/kg group, 14.3% (3 of 21 rats, P = 0.0008) in the casodex 30 mg/kg group, and 0% (0 of 11 rats, P = 0.0002) in the casodex 60 mg/kg group. On the other hand, when visible carcinomas and microscopic carcinomas were handled together, only casodex 60 mg/kg significantly inhibited the carcinogenesis rate. CONCLUSIONS: Finasteride achieved dose-dependent inhibition of macroscopic rat prostate carcinogenesis, and casodex also inhibited macroscopic prostate carcinogenesis. However, both drugs showed insufficient prevention of carcinogenesis at the microscopic level. These findings indicate that, in clinical medicine as well, such drugs may also be able to prevent the progression of latent prostate carcinoma to life-threatening disease.