Factors associated with response to compression-based physical therapy for secondary lower limb lymphedema after gynecologic cancer treatment: a multicenter retrospective study.

BACKGROUND: Lower limb lymphedema (LLL) is one of the most refractory and debilitating complications related to gynecological cancer treatment. We investigated factors associated with response to compression-based physical therapy (CPT) for secondary LLL after gynecologic cancer treatment. METHODS: We performed a multicenter retrospective study using the records of seven medical institutions from 2002 and 2014. Patients who developed LLL after gynecological cancer treatment were included. Limb volumes were calculated from the lengths of the limb circumferences at four points. All participants underwent compression-based physical therapy for LLL. Factors, including MLD, indicative of circumference reductions in LLL were determined. RESULTS: In total, 1,034 LLL met the required criteria of for the study. A multivariate linear regression analysis identified age; body mass index (BMI); endometrial cancer; radiotherapy; and initial limb circumference as significant independent prognostic factors related to improvement in LLL. In analysis of covariance for improvement in LLL adjusted by the initial limb circumference and stratified by BMI and radiotherapy, patients with BMI 28 kg/m2 or higher and receiving radiation rarely responded to CPT. CONCLUSIONS: Improvements in the lower limb circumference correlated with clinical histories and physical characteristics, which may be used as independent prognostic factors for successful CPT for LLL after gynecological cancer treatment.

Evidence-Based Practice Guideline for the Management of Lymphedema Proposed by the Japanese Lymphedema Society.

Background: Secondary lymphedema mostly occurs as an aftereffect of cancer treatment, and it is estimated that 100,000-150,000 patients are affected in Japan. An estimated 3500 patients, develop lymphedema of the lower and upper extremities each year secondary to uterine and breast cancer treatment. Medical reimbursement was first instituted in April 2008 by the Ministry of Health, Labour and Welfare in Japan. Since 2008, we have developed guidelines regarding treatment options for patients with lymphedema based on scientific evidence. This is the third edition of the guidelines established by the Japanese Lymphedema Society (JLES), published in 2018. The JLES Practice Guideline-Making Committee (PGMC) developed 21 clinical questions (CQs). Methods and Results: A review of these 15 CQs was performed in accordance with the methodology for establishing clinical guidelines. The 15 recommendations for each of these CQs were developed and discussed until consensus by the PGMC was reached. Moreover, outside members who had no involvement in these guidelines evaluated the contents using the Appraisal of Guidelines for Research and Evaluation (AGREE) II reporting checklist. Conclusion: These guidelines have been produced for the adequate management of lymphedema by doctors and other medical staff on the lymphedema management team of medical institutes, including nurses, physical technicians, and occupational therapists.

Current Status of Endoscopic Surgery in Japan: The 15th National Survey of Endoscopic Surgery by the Japan Society for Endoscopic Surgery.

In Japan, the first endoscopic surgery, a laparoscopic cholecystectomy, was performed in 1990. Since then, operative procedures have been standardized, and the safety and efficacy of endoscopic surgery have been evaluated. In accordance with the social acceptance of endoscopic surgery as a less invasive type of surgery, the number of endoscopic procedures performed has increased in all surgical domains. The Japan Society for Endoscopic Surgery (JSES) has played an important role in the development of endoscopic surgery in Japan. Notably, a technical skills certification system for surgeons was established by the JSES to train instructors on how to teach safe endoscopic surgery. Furthermore, the JSES has conducted a national survey every 2 years. In 2019, 291,792 patients underwent endoscopic surgery in all surgical domains, such as abdominal, thoracic, mammary and thyroid gland, cardiovascular, obstetrics and gynecology, urologic, orthopedic, and plastic surgery. The 15th National Survey of Endoscopic Surgery conducted by the JSES demonstrated the status of laparoscopic surgery in Japan in 2018-2019.

Risk factors for late-onset lower limb lymphedema after gynecological cancer treatment: A multi-institutional retrospective study.

INTRODUCTION: Late-onset lower limb lymphedema (LLL) is a significant clinical challenge for physicians dealing with patients that undergo treatment involving the pelvic cavity. We aimed to clarify the prevalence of and risk factors for late-onset LLL after treatment for gynecological cancer. METHODS: We conducted a multicenter retrospective study using records of cases in which LLL diagnosed by physical findings and measurement of limbs girths. Patients with LLL after treatment for uterine cervical, endometrial, and ovarian cancer were sequentially enrolled. We examined the timing of LLL onset and the associations between the time to onset and clinical characteristics, including age, type of cancer, lymphadenectomy sites, and performance of radiotherapy. We also investigated the risk factors for late-onset LLL and their effects on the cumulative incidence of late-onset LLL. RESULTS: In total, 711 patients fulfilled the required criteria. Mean age of was 50.2 years old and median follow-up period was 5.05 years. More than half of them (50.5%) presented with LLL ≥5 years after undergoing treatment for gynecological cancer. A substantial number of patients (29.4%) developed LLL ≥10 years after undergoing treatment for gynecological cancer. Being aged <50 years [(odds ratio (OR): 1.919, P = 0.001), cervical cancer (OR: 1.912, P = 0.001), and radiotherapy (OR: 1.664, P = 0.017) were identified as significant risk factors for late-onset LLL in multivariate logistic regression analysis. CONCLUSIONS: A substantial number of patients present with LLL ≥5 years after receiving treatment for gynecological malignancies. Clinicians are required to identify high-risk patients and inform them of the risk of late-onset LLL.

Current status of endoscopic surgery in Japan: The 14th National Survey of Endoscopic Surgery by the Japan Society for Endoscopic Surgery.

In Japan, the first endoscopic surgery, a laparoscopic cholecystectomy, was performed in 1990. Since then, operative procedures have been standardized, and the safety and efficacy of endoscopic surgery have been evaluated. In accordance with the social acceptance of endoscopic surgery as a less invasive type of surgery, the number of endoscopic procedures performed has increased in all surgical domains. The Japan Society for Endoscopic Surgery (JSES) has played an important role in the development of endoscopic surgery in Japan. Notably, a technical skills certification system for surgeons was established by the JSES to train instructors on how to teach safe endoscopic surgery. Furthermore, the JSES has conducted a national survey every two years to evaluate the status of endoscopic surgery over time. In 2017, 248 743 patients underwent endoscopic surgery in all surgical domains, such as abdominal, thoracic, mammary and thyroid gland, cardiovascular, obstetrics and gynecology, urologic, orthopedic, and plastic surgery. The 14th National Survey of Endoscopic Surgery conducted by the JSES demonstrated the status of laparoscopic surgery in Japan in 2016-2017.

Efficacy and safety of an amino acid jelly containing coenzyme Q10 and L-carnitine in controlling fatigue in breast cancer patients receiving chemotherapy: a multi-institutional, randomized, exploratory trial (JORTC-CAM01).

PURPOSE: Cancer-related fatigue (CRF) is one of the most common symptoms reported by cancer patients. This randomized trial investigated the efficacy of the amino acid jelly Inner Power(®) (IP), a semi-solid, orally administrable dietary supplement containing coenzyme Q10 and L-carnitine, in controlling CRF in breast cancer patients in Japan. METHODS: Breast cancer patients with CRF undergoing chemotherapy were randomly assigned to receive IP once daily or regular care for 21 days. The primary endpoint was the change in the worst level of fatigue during the past 24 h (Brief Fatigue Inventory [BFI] item 3 score) from day 1 (baseline) to day 22. Secondary endpoints were change in global fatigue score (GFS; the average of all BFI items), anxiety and depression assessed by the Hospital Anxiety and Depression Scale (HADS), quality of life assessed by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and EORTC Breast Cancer-Specific QLQ (EORTC QLQ-BR23), and adverse events. RESULTS: Fifty-nine patients were enrolled in the study, of whom 57 were included in the efficacy analysis. Median patient age was 50 years. Changes in the worst level of fatigue, GFS, and current feeling of fatigue were significantly different between the intervention and control groups, whereas the change in the average feeling of fatigue was not significantly different between groups. HADS, EORTC QLQ-C30, and EORTC QLQ-BR23 scores were not significantly different between the two groups. No severe adverse events were observed. CONCLUSION: IP may control moderate-severe CRF in breast cancer patients. TRIAL REGISTRATION: The registration number of this study in the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) is UMIN000008646.

[Team medical care for lymphedema management from evidence-based medicine].

Lymphedema is divided into primary lymphedema due to inherited conditions, and secondary lymphedema arising from damage to the lymph nodes or vessels. The main cause of secondary lymphedema in Japan is cancer treatment such as lymph node dissection and/or irradiation. However, surgeons are not often interested in this non-fatal aftereffect of surgery. Therefore, there has been little research with a high level of evidence to reach a better evidence-based medicine(EBM)or understanding of the real incidence of lymphedema. Because of the delay of standardization of management, prophylactic instruction against lymphedema and the use of elastic garments and bandaging for the treatment of lymphedema have been covered by medical reimbursement since 2008. Doctors must now pay attention to the management of postoperative lymphedema. Prophylactic instructions are given to doctors, nurses, and physical therapists so that they may teach the prescribed points to patients independently. These medical staff are also supposed to be in charge of the treatment of lymphedema patients; however, only the costs of compression materials have been reimbursed as of 2013. A standard strategy based on the EBM should be performed as a team practice. A comprehensive program including lymphedema management is also introduced.

Bevacizumab in the treatment of five patients with breast cancer and brain metastases: Japan Breast Cancer Research Network-07 trial.

BACKGROUND: Brain metastases from breast cancer occur in 20%-40% of patients, and the frequency has increased over time. New radiosensitizers and cytotoxic or cytostatic agents, and innovative techniques of drug delivery are still under investigation. METHODS: Five patients with brain metastases who did not respond to whole-brain radiotherapy and then received bevacizumab combined with paclitaxel were identified using our database of records between 2011 and 2012. The clinicopathological data and outcomes for these patients were then reviewed. RESULTS: The median time to disease progression was 86 days. Of five patients, two (40%) achieved a partial response, two had stable disease, and one had progressive disease. In addition, one patient with brain metastases had ptosis and diplopia due to metastases of the right extraocular muscles. However, not only the brain metastases, but also the ptosis and diplopia began to disappear after 1 month of treatment. The most common treatment-related adverse events (all grades) were hypertension (60%), neuropathy (40%), and proteinuria (20%). No grade 3 toxicity was seen. No intracranial hemorrhage was observed. CONCLUSION: We present five patients with breast cancer and brain metastases, with benefits from systemic chemotherapy when combined with bevacizumab.

Efficacy of meloxicam in combination with preoperative chemotherapy for breast cancer - Japan Breast Cancer Research Network (JBCRN) 02-1 trial.

BACKGROUND: We reported that doxorubicin and cyclophosphamide (DC) followed by weekly paclitaxel is an active and manageable preoperative regimen for breast cancer patients. However, as one of the side effects of paclitaxel, neuropathy was noted in up to 30% of patients. Cyclooxygenase-2 (COX-2) and its derived prostaglandins play a role in stimulating angiogenesis, inhibiting apoptosis, and suppressing the immune response. Some recent studies showed that COX-2 inhibitors, such as meloxicam, have the potential to enhance tumor suppression and reduce the severity of paclitaxel-induced neuropathy. PATIENTS AND METHODS: Four cycles of DC (doxorubicin: 60 mg/m(2) and cyclophosphamide: 600 mg/m(2)) administered intravenously (i.v.) on day 1 every 21 days were followed by 12 cycles of paclitaxel i.v. (80 mg/m(2)) every 7 days, prior to surgery. During paclitaxel therapy, breast cancer patients were administered meloxicam (10 mg per day) daily, when experiencing symptoms of grade 2 neuropathy (motor or sensory). The primary endpoint was the pCR rate achieved with the treatment. RESULTS: Forty-three patients received preoperative chemotherapy between April 2004 and March 2007 at six centers. The patient population was identified from a database of the Japan Breast Cancer Research Network. Clinical responses were rated as clinically complete response (cCR) in 9 patients (22%), clinically partial response (cPR) in 25 patients (59%), and clinically stable disease (cSD) in 9 patients (19%). pCR was seen in 25.6%. In addition, we identified 15 patients, who developed grade 2 neuropathy during paclitaxel therapy and subsequently received meloxicam. Meloxicam application had a marked effect within 28 days of initiation. The sensory neuropathy of the patients was reduced gradually, but their motor neuropathy did not improve. Five out of the 15 patients with neuropathy experienced symptom improvement after meloxicam treatment (p<0.05; before versus after 2 months of meloxicam administration). Furthermore, among the 15 patients, who received meloxicam, clinical responses were rated as cCR in 2 patients, cPR in 4 patients, and cSD in 9 patients. The pCR was seen in 4 patients (26.7%). CONCLUSION: Although meloxicam in combination with DC and weekly paclitaxel chemotherapy did not show promising therapeutic activity, it may provide some relief for neuropathy.

[Pharmaceutical services for patients receiving AC chemotherapy].

General treatments for breast cancer patients, such as surgery, chemotherapy, radiotherapy and lymphatic edema drainage, are performed at the Department of Breast Surgery in Kyushu Central Hospital. In those treatments, pharmacists provide the pharmaceutical treatment. Combination chemotherapy of doxorubicin and cyclophosphamide (AC therapy) is one of the standard regimens for breast cancer. In breast cancer patients who received AC therapy, we carried out investigations on side effects, and prepared pamphlets to support patients' self-management in their daily lives. In the process of preparing pamphlets, we made check sheets to monitor the severity and incidence of side effects. Based on the results of analysis and patients' opinions as well as staff remarks, we prepared pamphlets. According to the evaluation survey, pamphlets are regarded as useful. To meet the needs of patients, we intend to periodically revise pamphlets by continuing investigations on side effects, and provide up-to-date information.

Clinical characteristics of small cell carcinoma of the breast.

Primary small cell carcinoma of the breast is a rare tumor of which less than 40 cases have been reported in the literature. Because of its rarity, its biological and clinical characteristics are still not fully understood and, to date, no standard therapy has been developed. Here, we present a case and a review of the literature regarding this cancer, focusing on clinicopathological findings and treatment. Primary small cell carcinoma of the breast differs from more common types of breast cancer in its biological features. It is anticipated that an improved understanding of the clinical characteristics of this tumor will result in the development of new therapeutic modalities, which would improve its prognosis.

A phase II study of trastuzumab and capecitabine for patients with HER2-overexpressing metastatic breast cancer: Japan Breast Cancer Research Network (JBCRN) 00 Trial.

PURPOSE: To determine the response rate and toxicity profile of trastuzumab and capecitabine in women with HER2-overexpressing advanced breast cancer. PATIENTS AND METHODS: A total of 59 patients from 6 participating centers in Japan entered onto the study of trastuzumab and capecitabine. Eighty six percent of women had received prior chemotherapy as part of adjuvant (21.4%) or metastatic treatment (48.2%), or both (16.1%), including substantial portions of patients who had previously received either CMF (7.1%), anthracyclines (28.6%), taxanes (25.0%), or both types (25.0%) of chemotherapy. RESULTS: Responses were observed in 28 of 56 patients (overall response rate, 50%). The response rate was 65.0% in patients treated with trastuzumab and capecitabine as first-line therapy for metastatic disease, and 62.5% among HER2 +3 positive patients, while high response rates were also seen in women treated with second- or third-line therapy. Patients receiving trastuzumab and capecitabine as first-line therapy had a longer TTP than did patients receiving this treatment as second- or third-line therapy (median TTP, 280 vs. 130 days, P < 0.05). Further, patients receiving trastuzumab and capecitabine as first-line therapy had longer OS than did patients receiving this treatment as second- or third-line therapy (median OS, 780 days vs. 480 weeks, P < 0.05). The treatment-related adverse events were hand-foot syndrome (30.4%), nausea (25%), diarrhea (10.7%), stomatitis (10.7%), fatigue (7.1%), and vomiting (5.4%). However, the majority were Grade 1-2 adverse events and only six patients experienced Grade 3 adverse events. Further Grade 1 cardiac toxicity was observed in one patient, while there were no cases of alopecia and treatment-related death. CONCLUSION: Trastuzumab in combination with capecitabine is highly active in women with HER2-overexpressing metastatic breast cancer and is well tolerated.

Considerable multiple esophageal carcinoma. Implications of a new clinical entity.

BACKGROUND/AIMS: The multiple occurrence of primary squamous cell carcinoma of the esophagus is often observed, and most such occurrences are double cancers. There have also been some cases with three or more intra-esophageal cancers, however, no detailed clinicopathologic study has yet been performed in the literature. METHODOLOGY: Two hundred and fifty patients of primary esophageal squamous cell carcinoma without preoperative treatment that underwent esophageal resection were re-evaluated by serial histopathologic investigations and we analyzed the data of ten patients with three or more intraesophageal cancers. RESULTS: The clinical and histopathologic characteristics were as follows; 1) all but one of the cases were male, 2) all patients had a history of both heavy smoking and drinking but only one case had a family history of esophageal cancers among their siblings, 3) the depth of invasion in the carcinomas was restricted to within the submucosal layer of the esophageal wall, which was defined as superficial esophageal carcinoma, almost all (90%) of the cases accompanied esophageal squamous epithelial dysplasia. CONCLUSIONS: Based on these prominent characteristics of considerable multiple intra-esophageal cancers, a new clinical entity of "esophageal field cancers" could thus be suggested.

Early report of correlation between the thermal dosage and the treatment effect of hyperthermia in combination with chemoradiotherapy for esophageal cancer patients.

BACKGROUND/AIMS: It is known to be difficult to determine thermal dosage in clinical tumor treatment. The aim of this study is to examine whether the quantitative heating dose reflects the treatment effect in esophageal cancer. METHODOLOGY: Hyperthermo-chemoradiotherapy was performed on 14 patients with advanced esophageal cancer. The heating dosage was calculated as an integration of the isoeffective dose at 43 degrees C using the following formulas: delta teq(T) = 2(T-43).delta t (second)--(a) (> or = 42.5 degrees C) delta teq(T) = 2(42.5-43).6(T-42.5).delta t (second)--(b) (< 42.5 degrees C) When hyperthermia continued at the same temperature for 2 seconds or more, the temperature was regarded as the heating temperature, and the cumulative time was defined as the thermal dose which was administered during the heating period. RESULTS: Nine patients were resectable and the remaining 5 patients were categorized as non-resectable. The treatment effect was evaluated by an esophagram and an endoscopic examination both pre- and post-hyperthermo-chemoradiotherapy. Five patients were regarded to demonstrate a complete response, while 2 showed a partial response and 8 demonstrated no change, respectively. The maximal cumulative heating time was 2,312 seconds in the complete response group, 1,811 seconds in the partial response group and 1,260 seconds in the no change group (p = 0.038). The minimal and average cumulative heating time did not show any correlation with the treatment effect. CONCLUSIONS: Our results indicate that the thermal doses calculated by those formulas were adequate for clinical hyperthermia in esophageal cancer patients.