Analysis of acute-phase toxicities of intensity-modulated proton therapy using a model-based approach in pharyngeal cancer patients

Pharyngeal cancer patients treated with intensity-modulated proton therapy (IMPT) using a model-based approach were retrospectively reviewed, and acute toxicities were analyzed. From June 2016 to March 2019, 15 pharyngeal (7 naso-, 5 oro- and 3 hypo-pharyngeal) cancer patients received IMPT with robust optimization. Simulation plans for IMPT and intensity-modulated X-ray therapy (IMXT) were generated before treatment. We also reviewed 127 pharyngeal cancer patients with IMXT in the same treatment period. In the simulation planning comparison, all of the normal-tissue complication probability values for dysphagia, dysgeusia, tube-feeding dependence and xerostomia were lower for IMPT than for IMXT in the 15 patients. After completing IMPT, 13 patients completed the evaluation, and 12 of these patients had a complete response. The proportions of patients who experienced grade 2 or worse acute toxicities in the IMPT and IMXT cohorts were 21.4 and 56.5% for dysphagia (P < 0.05), 46.7 and 76.3% for dysgeusia (P < 0.05), 73.3 and 62.8% for xerostomia (P = 0.43), 73.3 and 90.6% for mucositis (P = 0.08) and 66.7 and 76.4% for dermatitis (P = 0.42), respectively. Multivariate analysis revealed that IMPT was independently associated with a lower rate of grade 2 or worse dysphagia and dysgeusia. After propensity score matching, 12 pairs of IMPT and IMXT patients were selected. Dysphagia was also statistically lower in IMPT than in IMXT (P < 0.05). IMPT using a model-based approach may have clinical benefits for acute dysphagia.     

Are bladder washing samples suitable for investigation of HPV infection in urinary bladder? Comparison in HPV prevalence between urine and washing samples

Although urine and bladder washing samples are commonly used for the cytological evaluation of the bladder mucosa, it has been unknown whether these samples are likely suitable to investigate human papillomavirus (HPV) prevalence in the urinary bladder. The present study aimed to elucidate the appropriateness of spontaneously voided urine or bladder washing in screening HPV infection in the urinary bladder. Urine and bladder washing samples were obtained from 201 patients who underwent transurethral bladder tumor resection. After extracting DNA from both samples, HPV-DNA was examined using a nested polymerase chain reaction with GP5+/6+ and MY09/11 primers. HPV genotyping was performed in the HPV-positive samples. In situ hybridization (ISH) was performed to observe the HPV-DNA localization in urothelial cells among cytological samples and paraffin-embedded tumor tissues in HPV-positive washing samples. HPV prevalence in urine and washing samples were 9.5% and 7.0%, respectively. High-risk HPV prevalence in urine and washing samples was 7.5% and 4.0%, respectively. The most common HPV type was HPV 16, followed by HPV 52 and HPV 18 in both samples. HPV type distribution in both samples was not in agreement (κ = −0.431). The ISH analysis revealed that HPV-DNA signal was observed in urothelial cells of five (55.7%) of nine detectable HPV-positive cytological samples. Six (66.7%) of nine HPV-positive cases had HPV-DNA signals in tumor tissue. The use of washing samples was likely applicable for investigating HPV prevalence in the urinary bladder. HPV-DNA detected in washing samples might be frequently derived from the urinary bladder.     

Efficacy of postoperative adjuvant therapy for stage ilia breast cancer: Futraful vs futraful+tamoxifen for er-positive patients and futraful vs futraful + adriamycin for er-negative breast cancer

A multi-center, randomized controlled collaborative study was conducted in 310 institutions located throughout Japan for 3 years and 9 months from February 1985 until October 1988 to evaluate the efficacy of post-operative adjuvant therapy for patients who had previously undergone curative surgery for treatment of Stage IIIa breast cancer. Patients with estrogen receptor-positive [ER( + )] breast cancer were treated with two types of regimens, ie, cyclophosphamide + adriamycin + fluorouracil (CAF; 2 cycles) + Futraful (FT) or CAF (2 cycles) + FT + tamoxifen (TAM), and the clinical benefit of additional use of TAM was evaluated. Of the 509 ER( + ) patients registered for the trial, 473 patients (92.9%) were eligible for evaluation. The 5-year survival rate was 77.2% for the CAF + FT group and 74.6% for the CAF + FT+TAM group, and the 5-year disease-free survival rate was 56.7% for the CAF+FT group and 59.2% for the CAF + FT + TAM group. Neither the survival rate nor the disease-free survival rate differed significantly between the groups. Analyses by factor revealed that the 5-year disease-free rate for lymph node-negative patients in the CAF + FT + TAM group was significantly higher than that for the corresponding patients in the CAF + FT group. No differences were noted in the incidence of adverse reactions between the two treatment groups, other than an increase in LDH (the frequency of which was higher in the CAF + FT+TAM group than in the CAF + FT group). Patients with estrogen receptor-negative [ER( -)] breast cancer were treated with two types of regimens, ie, CAF + FT or CAF + FT + adriamycin (ADR), and the clinical benefit of the combined use of intermittent doses of ADR was evaluated. Of the 514 ER(-) patients registered in the trial, 478 (93.0%) were eligible for evaluation. The 5-year survival rate was 64.9% for the CAF + FT group and 63.0% for the CAF + FT + ADR group, and the 5-year disease-free survival rate was 59.2% for both CAF + FT and CAF + FT + ADR groups. Neither the survival rate nor the disease-free survival rate differed significantly between the groups. There were no significant differences between these groups in analyses by nodal or menopausal status. The incidences of adverse reactions including anorexia, nausea/vomiting and alopecia were higher in the CAF + FT+ADR group than in the CAF + FT group.     

Effect of 2-Hydroxypropyl-β-cyclodextrin on Crystallization and Polymorphic Transition of Nifedipine in Solid State

The glassy state of nifedipine (NP) was prepared in the absence and presence of 2-hydroxypropyl--cyclodextrin (HP--CyD), and its crystallization and polymorphic transition behavior was investigated by differential scanning calorimetry (DSC) and powder X-ray diffractometry. In DSC thermograms, the glassy NP exhibited an en-dothermic peak at 48°C representing the glass transition of NP, an exothermic peak at 105°C for the crystallization to a metastable form of NP (Form B), an exothermic peak at 125°C for the polymorphic transition of Form B to a stable form of NP (Form A), and an endothermic peak at 171°C for the melting of Form A. The powder X-ray diffractogram of Form B was apparently different from that of Form A. In the presence of HP--CyD, the exothermic peak at 125°C for the Form B to A transition disappeared and a new en-dothermic peak appeared at 163°C. This new peak was ascribed to the melting of Form B, and the conversion of Form B to Form A was significantly suppressed in HP--CyD matrix. Upon storage at 60°C, the glassy NP was converted to Form A with an activation energy of 18 kcal/mol. The apparent dissolution rate of the NP/HP--CyD (molar ratio 1:1) increased in the order of glassy NP < Form A < Form B, because the glassy NP was readily converted to Form A upon contact with water, resulting in a lower dissolution rate. The present data suggest that HP--CyD is useful for the preparation of a fast dissolving form of metastable NP through glassy NP.     

Low grade amplification of MDM2 gene in a subset of human breast cancers without p53 alterations

MDM2 protein is thought to bind to p53 tumor suppressor protein leading to inhibition of p53-mediated transactivation. Amplification of the MDM2 gene has been frequently observed in human sarcoma, and relevant overexpression of the MDM2 protein is assumed to contribute to tumorigenesis through inactivation of the p53 function. In order to determine whether MDM2 amplification plays a role in the development of human breast cancer without genetic alteration of p53, we analyzed, MDM2 gene amplification by quantitative hybridization and genetic alteration of p53, in 32 primary tumors and 26 metastatic lymph nodes. Low grade amplification of the MDM2 gene (2-6 fold) was observed in four cases, none of which showed even subtle genetic alterations of p53 or loss of alleles on 17p. Moreover, in three of the four cases with MDM2 gene amplification, the level of gene amplification in the metastatic lymph nodes was slightly higher than that in the primary tumors. These results, taken together with previous findings, suggest that a subset of breast cancers without genetic alteration of p53 may also arise by inactivation of the p53 function through interaction with the overexpressed MDM2 protein induced by gene amplification.     

Evaluation of a screening program on reduction of gastric cancer mortality in Japan: preliminary results from a cohort study.

BACKGROUND: Systematic population-based screening for gastric cancer is widely spread in Japan. However, the case-control study method has been the main method used to evaluate the effectiveness of the screen ing to reduce gastric cancer mortality in Japan. METHODS: This article presents a population-based cohort study. A questionnaire about lifestyles and dietary habits was distributed to 36,990 residents in a city of Japan. The response rate to the questionnaire was 92.0%. After ineligible responders had been excluded, 24,134 subjects were classified into screened and un screened groups according to their self-reports of participation in the screening the previous year. We followed them up for 40 months and linked resident death records in the city. We compared mortality from gastric cancer and all other causes between the groups by us ing the Cox proportional hazard model. RESULTS: The follow-up period was 78,156.6 person-years from September 1992 to December 1995. The multivariate relative risks for gastric cancer death of the screened group in comparison with the unscreened group were 0.72 (95% CI 0.31-1.66) among males and 1.46 (95% CI 0.43-4.90) among females. CONCLUSION: Although our data are preliminary, we were unable to demonstrate a large contribution of the present screening program to decreasing gastric cancer mortality. Further follow-up is needed to in crease the precision.     

A case of ABO-incompatible renal transplant patient with non-insulin-dependent diabetes mellitus; long-standing observation of serial glomerular change by protocol biopsy

A 41-yr-old patient with non-insulin-dependent diabetes mellitus (NIDDM), before and after ABO-incompatible renal transplant, is reviewed using serial protocol biopsy. Although she recovered from delayed hyperacute rejection (DHAR) immediately post-transplantation, her graft function deteriorated gradually. A mild acute transplant glomerulitis, noted at the 155th day post-transplantation, progressed to pronounced chronic transplant glomerulopathy over 5 yr. In the specimen of the last biopsy, at 5 yr post-transplantation, glomeruli demonstrated an exudative hyaline lesion, which was characteristic of diabetic nephropathy in addition to chronic transplant glomerulopathy. Therefore, we made a diagnosis of this glomerular lesion as chronic transplant glomerulopathy complicated by diabetic glomerulopathy. Considering the result of this case, the protocol biopsy is a useful procedure to diagnose an accurate cause of graft dysfunction in individual cases. It is concluded that the protocol biopsy is apparently useful for the detection of various pathological processes occurring in allograft and may contribute to a strategy for improvement of graft survival.     

Auditory brainstem responses in patients with autonomic failure with Parkinson's disease and multiple system atrophy

Auditory brainstem responses (ABRs) were examined in six patients with autonomic failure with Parkinson's disease (AF with PD) and 10 patients with autonomic failure with multiple system atrophy (AF with MSA), all of which showed marked parkinsonian features as a principal sign. We designated the central abnormalities of ABRs as prolongation of latencies (wave III or V) and interpeak latencies (IPLs; I-III, I-V, and III-V IPL) or decreased amplitude ratios of wave III or V to those of wave I (less than 1.0). None of the patients with AF with PD showed abnormalities in ABRs. In contrast, in those with AF with MSA, the peak latencies or IPLs were prolonged in two of the 10 patients, and the amplitude ratios of wave III or V to those of wave I were decreased in other two of these patients. Moreover, both prolongation of latencies and a decreased ratio were observed in other one. Overall, five of the 10 patients with AF with MSA showed central abnormalities in ABRs. It is clinically difficult to differentiate AF with PD from AF with MSA, particularly when no cerebellar signs are apparent in AF with MSA patients. When central abnormalities of ABRs are observed in AF patients, AF with MSA should be suspected rather than AF with PD. In conclusion, ABRs provide useful information for the differential diagnosis of AF with PD and AF with MSA.     

Total Esophagectomy versus Proximal Esophagectomy for Esophageal Cancer at the Cervicothoracic Junction

To investigate the adequate extent of esophagectomy and lymphadenectomy for an esophageal cancer localized at the cervicothoracic junction, the mortality and morbidity rates, survival rates, and patterns of recurrence were retrospectively analyzed in two groups—14 patients who underwent total esophagectomy with or without laryngectomy and 15 patients who underwent proximal esophagectomy with or without laryngectomy—at Kurume University Hospital from 1981 to 1996. Proximal esophagectomy with or without laryngectomy resulted in a lower hospital mortality rate and better overall survival for patients who underwent curative esophagectomy compared with total esophagectomy with or without laryngectomy. Multivariate analysis indicated that the extent of esophagectomy (total esophagectomy versus proximal esophagectomy) was not a prognostic factor. The incidence of recurrence was not different between the two groups. Lymph node metastasis or recurrence from such esophageal cancers was localized to the neck and upper mediastinum. For an esophageal cancer localized at the cervicothoracic junction, therefore, proximal esophagectomy with or without laryngectomy and with cervical and upper mediastinal lymphadenectomy could be better indicated for preselected patients.     

Comparative epidemiology of cancer between the United States and Japan. A second look

Vital statistics were examined for the years 1955 through 1985 for Japanese natives and United States whites to elucidate changes in cancer mortality and related antecedent patterns of life-style in these two populations. Results show that lung cancer rates are rapidly accelerating among Japanese males as a consequence of their prior history of heavy cigarette smoking. Oropharyngeal cancer rates are also rising in Japan paralleling increases in alcohol and tobacco utilization. As the Japanese life-style and diet continue to become more "westernized," the rates of malignancies of the breast, ovary, corpus uteri, prostate, pancreas, and colon also continue to rise. Nevertheless, the mortality patterns of certain malignancies, viz., laryngeal, esophageal, and urinary bladder cancer, are discrepant with their established risk factor associations, suggesting the existence of other differences in risk factor exposure between the two countries. Epidemiologists and health educators need to develop innovative international programs of investigation and health promotion with preventive impact on common malignancies associated with risk factors of life-style.