Body mass index and menopausal disorders during menopause affect vasomotor symptoms of postmenopausal Japanese breast cancer patients treated with anastrozole: a prospective multicenter cohort study of patient-reported outcomes.

BACKGROUND: Adverse events related to endocrine therapies have a major impact not only on patients' quality of life but also on treatment discontinuation. Although vasomotor symptoms induced by aromatase inhibitors are frequently recognized, risk factors, especially for Japanese women, are not well reported. To identify risk factors for vasomotor symptoms of Japanese breast cancer patients treated with adjuvant anastrozole, we conducted a prospective cohort study based on patient-reported outcomes (PROs). PATIENTS AND METHODS: For this prospective cohort study (SAVS-JP, UMIN000002455), 391 postmenopausal Japanese estrogen receptor-positive breast cancer patients who were treated with adjuvant anastrozole were recruited from 28 centers. The PRO assessment was obtained from a self-reported questionnaire at baseline, 3, 6, 9 and 12 months between August 2009 and April 2012. Vasomotor symptoms, comprising hot flashes, night sweats, and cold sweats, were categorized into four grades (none, Grade 1: mild, Grade 2: moderate, Grade 3: severe). Pre-existing symptoms were only included if they had become worse than at baseline. RESULTS: Hot flashes, night sweats, and cold sweats at baseline were reported by 20.5, 15.1, and 8.2 % of the patients, respectively, and new appearance or worsening of symptoms in comparison with baseline by 38.4, 29.3, and 28.7 %, respectively. About 80 % of newly occurring symptoms were Grade 1, and less than 5 % were Grade 3. Vasomotor symptoms were reported by 201 out of 362 patients (55.5 %) during the first year and the mean time to onset was 5.6 months. Patients with vasomotor symptoms were significantly younger (mean 62.8 years, range 38-86 vs 64.7 years, range 37-84; p = 0.02), had higher body mass index (BMI) (23.4 kg/m2, range 15.8-39.9 vs 22.4 kg/m2, range 15.8-34.9; p = 0.01), had vasomotor symptoms sooner after menopause (12.4 years, range 0-51 vs 15.1 years, range 1-37; p = 0.002), and had more menopausal disorders during menopause (63.3 vs 36.7 %; p = 0.002). Multivariate analysis showed that BMI [odds ratio (OR) 1.09 per unit of increase, 95 % confidence interval (CI) 1.02-1.16; p = 0.009] and experiencing menopausal disorders (OR 2.11, 95 % CI 1.35-3.30; p = 0.001) were significantly associated with vasomotor symptoms. CONCLUSION: High BMI and experiencing menopausal disorders at menopause were found to be significantly associated with the occurrence of vasomotor symptoms. These findings are expected to prove useful for the management of postmenopausal Japanese women treated with aromatase inhibitors.

Risk factors for joint symptoms in postmenopausal Japanese breast cancer patients treated with anastrozole: a prospective multicenter cohort study of patient-reported outcomes.

BACKGROUND: Endocrine treatment-related adverse events have a strong impact on patients' quality of life and sometimes result in treatment discontinuation. Since joint symptoms are the most frequently recognized side effect of aromatase inhibitors, evaluation of associated risk factors may yield significant findings. PATIENTS AND METHODS: A total of 391 postmenopausal Japanese women with estrogen receptor-positive breast cancer and treated with adjuvant anastrozole were enrolled from 28 centers for assessment of patient-reported outcomes (PROs) in this prospective cohort study (SAVS-JP, UMIN000002455). Patients completed the self-report questionnaire at baseline and after 3, 6, 9, and 12 months of treatment for evaluation of frequency of treatment-related joint symptoms (arthralgia, decrease in range of joint motion, and joint stiffness). RESULTS: We obtained PROs from 362 patients (92.6 %) at baseline and at one or more subsequent points. New or worsening from baseline of joint symptoms were reported by 260 patients (71.8 %). More than 90 % of the symptoms were mild or moderate and nearly 80 % had occurred by 6 months. Multivariate analysis showed that a short time span after menopause [odds ratio (OR) 0.95, 95 % confidence interval (CI) 0.90-0.99; P = 0.02] and adjuvant chemotherapy (OR 2.29, 95 % CI 1.06-4.95; P = 0.03) were significant independent risk factors for joint symptoms. No significant relationships between body mass index (BMI) and joint symptoms were identified. Eighteen patients discontinued treatment during the 1st year and eight of them reported joint symptoms. CONCLUSION: Taking into consideration that PROs may yield higher prevalence rates than physician ratings for symptoms published in pivotal clinical trials, we found that a short time span after menopause and use of adjuvant chemotherapy, but not high BMI, were significantly associated with joint symptoms. These findings might prove useful for counseling before initiating treatment with adjuvant aromatase inhibitors in postmenopausal Japanese women.

2-DOF auto-calibration for a 3D endoscope system based on active stereo.

For endoscopic medical treatment, measuring the size and shape of lesions, such as tumors, is important. We are developing a 3D endoscope system to measure the shape and size of living tissues based on active stereo. In previous works, our group attached a pattern projector outside the endoscope head. Since this increased the diameter of the endoscope, the burden and the risks of the patients would increase. In this paper, we set the pattern projector inside the instrument channel of the endoscope instead of mounting it outside, so that it can be deployed whenever required. This does not increase the size of the endoscope and facilitates the measuring process. However, since the projector is not physically fixed to the endoscope anymore prior to the operation, we propose an "auto-calibration" technique where extrinsic parameters are calibrated intra-operatively from a point marker on the projector observed simultaneously on the target surface. In the experiment, we show that the external parameters were successfully calibrated to obtain 3D reconstructions properly with the overall systems. The accuracy of the auto-calibration was validated by confirming that the epipolar constraints were kept, and a 3D reconstruction of a human tissue was demonstrated.

[A Case of Gastric Cancer with Multiple Liver Metastases Treated with XP Chemotherapy and RFA Resulting in a Complete Response for a Long Time].

A 60-year-old man underwent total gastrectomy with Japanese D2 lymph node dissection for advanced gastric cancer. The resected specimen was diagnosed as well-differentiated tubular carcinoma, pT3, pN1, cM0, and the final stage was considered as ⅡB. During adjuvant chemotherapy with S-1 (120 mg/day, administered for 4 weeks and then stopped for 2 weeks), multiple liver metastases were detected by contrast-enhanced CT images 6 months after the operation. Eight courses of XP therapy (capecitabine 1,600 mg/m2/day: day 1-14, cisplatin 70 mg/m2/day: day 1, then stopped until days 15-21) were administered in consideration of the recurrence during adjuvant chemotherapy with S-1, resulting in a partial response. Adverse events such as grade 1-2 abdominal pain, general fatigue, and the resultant deterioration of ADL led to discontinuation of chemotherapy. The residual liver metastasis was treated with RFA therapy, causing it to disappear completely. Serum CEA level was 5.5 ng/mL postoperatively, elevated to 13.9 ng/mL at the time of recurrence and 2.4 ng/mL after XP and RFA therapy. He is doing well without any recurrence 2 years and 6 months later.

[A Case of Pancreatic Cancer with Multiple Liver Metastases That Developed Postoperatively and Showed a Complete Response with S-1 Monotherapy].

We encountered a case of pancreatic cancer with multiple liver metastases that developed postoperatively and showed a complete response with S-1 monotherapy for a long time. A pancreaticoduodenectomy was successfully performed on an 80- year-old man. Multiple liver metastases developed 6 months postoperatively. Microscopically, the primary lesion was diagnosed as adenosquamous carcinoma with anaplastic carcinoma component, and the final diagnosis was considered to be Stage Ⅲ disease. S-1monotherapy (80 mg/day, administered for 4 weeks and then stopped for 2-weeks) was effective. A partial response was noted after 3 months, and 9 months after the initial administration of S-1, a complete response was achieved, which persisted for more than 12 months, according to contrast-enhanced CT evaluations.Serum CEA and CA19-9 levels, which became slightly elevated at the time of liver metastasis development, normalized promptly and remained within normal limits. Adverse effects of chemotherapy of more than grade 2 severity were not apparent, and the patient tolerated the 11th course of S-1 administration, consistently. A standard therapeutic strategy and its outcomes in cases of pancreatic cancer recurrence are not clearly outlined in the Japanese Guideline for the Treatment of Pancreatic Cancer. A case of pancreatic cancer with multiple liver metastases that developed postoperatively and showed a complete response with S-1 monotherapy is reported in this paper.

[A Case of Unresectable Rectal Cancer Associated with Hemorrhage of the Primary Tumor after Chemotherapy].

A 47-year-old man visited our hospital with complaints of abdominal pain and hematuria.He was diagnosed with unresectable rectal cancer invading the urinary bladder with multiple liver metastases. Systemic chemotherapy with mFOLFOX6 and panitumumab was started soon after sigmoid colostomy. Three months later, both the primary tumor and the liver metastases had partially responded. Another 2 months later, he complained of terrible abdominal pain. CT images revealed a huge primary tumor and hemorrhage in the sigmoid mesocolon occupying the pelvic cavity. A salvage operation was performed and the primary tumor was palliatively resected. Soon after the operation, a local recurrence appeared and grew rapidly. He died 8 months after diagnosis. Rapid growth of the primary tumor seemed a limiting factor for the prognosis.

[A Case of Recurrence of Rectal Cancer with Para-Aortic Lymph Node Metastases Successfully Resected Resulting in Long Term Survival].

Laparoscopy-assisted low anterior resection (Japanese D3 lymph node dissection) was performed to treat a 68-year-old man for rectal cancer. Microscopically, the resected specimen was diagnosed as a moderately differentiated adenocarcinoma and the final stage was considered as pT3, pN1, cM0, pStage Ⅲa. He was administered capecitabine for 6 months as adjuvant chemotherapy. Then, enlarged para-aortic lymph nodes, indicated by follow up CT at 1 year and 11 months postoperatively developed behind the left renal artery. FDG accumulated in it, consistent with the CT images. Para-aortic lymph node dissection was performed after the diagnosis of solitary lymph node metastases. Microscopically, the resected lymph nodes showed features similar to the primary lesion. He is doing well without recurrence for 4 year and 6 months, without any adjuvant chemotherapy. Para-aortic lymph node metastases are frequently associated with other distant metastases; if not, a complete cure may be possible by curative resection for solitary metastases.

[A case of locally advanced rectal carcinoma treated with preoperative chemoradiotherapy resulting in pathologically complete response].

An 84-year-old woman presented with the chief complaint of melena. Colonoscopy revealed a type 2 tumor that circumferentially occupied the lumen of the lower rectum about 6 cm from the anal verge. A biopsy specimen was obtained from the tumor and the patient was diagnosed with moderately differentiated adenocarcinoma. Computed tomography revealed that the rectal cancer had invaded the marginal fatty tissue, accompanied by several regional lymph node metastases with no distant metastasis. On the basis of this evidence, the tumor was staged as cT4a, cN2b, cM0 according to the TNM Classification of Malignant Tumors (7th Edition, UICC). Preoperative radiotherapy combined with an oral chemopreventive agent (RT 1.8 Gy × 25 frames; total 45 Gy, S-1 80 mg/day) was administered with trivial adverse effects. Laparoscopy-assisted low anterior resection with Japanese D3 dissection was performed successfully. The patient is doing well without recurrence after 14 months of surgery. Histological examination revealed that both the primary lesion and regional lymph nodes had no residual cancer; that is, the histological effect of the preoperative chemoradiotherapy was a pathologically complete response (pCR).

[A case of colon cancer with multiple liver metastases showing a long-term response following first-line therapy].

A 71-year-old man presented with sigmoid colon cancer and multiple unresectable liver metastases. As the sigmoid colon cancer caused anemia, we performed laparoscopic-assisted sigmoidectomy prior to the administration of systemic chemotherapy. Bevacizumab (Bv) plus modified Leucovorin, 5-fluorouracil, and oxaliplatin (mFOLFOX6) was administered as first line therapy.At 3 months from the start of chemotherapy, computed tomography revealed that the size of the liver metastases reduced by 49.45%, as evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines (version 1.1). The only adverse event observed was Grade 1 peripheral neuropathy after the eighth dose of oxaliplatin.As the progression of peripheral neuropathy was observed at the ninth dose of oxaliplatin, oxaliplatin was omitted from further therapy; the patient was converted to maintenance therapy with simplified biweekly Leucovorin and fluorouracil (sLV5FU2). Bv plus mFOLFOX6 followed by sLV5FU2 for first-line therapy was effective for disease management over 23 months, but a partial response (PR) was the best overall response achieved.

Cathepsin B-dependent motor neuron death after nerve injury in the adult mouse.

There are significant differences in the rate of neuronal death after peripheral nerve injury between species. The rate of neuronal death of motor neurons after nerve injury in the adult rats is very low, whereas that in adult mice is relatively high. However, the understanding of the mechanism underlying axotomy-induced motor neuron death in adult mice is limited. Cathepsin B (CB), a typical cysteine lysosomal protease, has been implicated in three major morphologically distinct pathways of cell death; apoptosis, necrosis and autophagic cell death. The possible involvement of CB in the neuronal death of hypogrossal nucleus (HGN) neurons after nerve injury in adult mice was thus examined. Quantitative analyses showed the mean survival ratio of HGN neurons in CB-deficient (CB-/-) adult mice after nerve injury was significantly greater than that in the wild-type mice. At the same time, proliferation of microglia in the injured side of the HGN of CB-/- adult mice was markedly reduced compared with that in the wild-type mice. On the injured side of the HGN in the wild-type adult mice, both pro- and mature forms of CB markedly increased in accordance with the increase in the membrane-bound form of LC3 (LC3-II), a marker protein of autophagy. Furthermore, the increase in CB preceded an increase in the expression of Noxa, a major executor for axotomy-induced motor neuron death in the adult mouse. Conversely, expression of neither Noxa or LC3-II was observed in the HGN of adult CB-/- mice after nerve injury. These observations strongly suggest that CB plays a critical role in axotomy-induced mortor neuron death in adult mice.

Overlap/switch to adefovir monotherapy for lamivudine-resistant patients who responded to combination therapy: a pilot controlled study.

OBJECTIVE: The aim of this study was to investigate the outcome of overlap/switch to adefovir dipivoxil (ADV) monotherapy for chronic hepatitis B (CHB) patients with lamivudine (LAM)-resistant HBV, who responded to LAM plus ADV combination therapy. METHODS: In 29 of 35 LAM-resistant CHB patients, serum HBV-DNA levels decreased to <3.7 log genome equivalent (LGE)/mL at 12 months after LAM plus ADV combination therapy, defined as complete virological response (CVR). The 29 CVR patients were randomly allocated to continuation of combination therapy or switch to ADV monotherapy within 12 months. The cumulative rates of sustained CVR were compared between the two groups. RESULTS: The follow-up duration after randomization was 19.3-36.7 months (median, 28.2 months) for the combination group and 21.0-36.4 months (29.0 months) for the overlap/switch group. The cumulative rate of sustained CVR during the follow-up period was 100% in all patients of both groups. The total medical expenses during follow-up after randomization were median US$20,949 for the combination group and US$16,107 for the overlap/switch group (p=0.012). Overlap/switch to ADV monotherapy sufficiently repressed the replication of LAM-resistant mutants without the development of ADV-resistant mutants. The rate of sustained CVR was not influenced by treatment regimen (continuation of combination therapy or switching to ADV monotherapy), the duration of the overlap period, or patient and virological characteristics. CONCLUSION: In LAM-resistant CHB patients who achieved CVR to LAM plus ADV combination therapy, CVR was maintained after overlap/switch to ADV monotherapy, suggesting that it could be a useful regimen for such patients.

[A case of Cronkhite-Canada syndrome in which contrast radiologic examinations of the digestive tract were performed at the time of development of the clinical symptoms].

We encountered a case of Cronkhite-Canada syndrome in which contrast radiologic examinations of the upper and lower digestive tract were performed immediately before and after the development of the clinical symptoms. These contrast radiologic images showed mainly mucosal coarseness and no polyposis of the stomach and colon. The endoscopy, performed 3 months later from the development of the clinical symptoms, revealed polyposis of the stomach and colon. So we recognized that the clinical symptoms developed before appearance of the polyposis of the digestive tract and the polyposis progressed rapidly.

Gastrointestinal stromal tumor arising from anorectum: correlation of imprint cytology and radiologic imaging.

The diagnosis of gastrointestinal stromal tumor (GIST) is generally established on histopathologic examination of surgical specimens. Gastrointestinal stromal tumor comprises a heterogenous group of neoplasms of the gastrointestinal tract previously referred to as leiomyomas, leiomyosarcomas, or schwannomas. Gastrointestinal stromal tumor arising from anorectum is a rare instance. We report a case of GIST for the correlation of imaging and cytologic features with immunocytochemical staining. A computed tomography and magnetic resonance imaging confirmed a 2-cm tumor growing into the rectal lumen. The central portion of the tumor showed T1-weighted imaging of low signal and suspected central necrosis by the T2-weighted imaging of high signal. Imprint cytology from excised tumors showed isolated or loosely aggregated spindle cells with scanty and fibrillary cytoplasmic processes, nuclear pleomorphism, fine granular chromatin, and irregular nuclear margins. Epithelioid tumor cells showed grooves with abundant cytoplasm and several round nucleoli. Both c-kit and CD34 antigen were positive with strong and diffuse stainability in smears as well as paraffin sections by immunoperoxidase staining. We suggest that the combined use of imaging diagnosis and cytology with immunocytochemical staining are useful initial diagnosis of GIST.

A male patient with metachronous triple cancers of small cell lung, prostate and breast.

We present a very rare case of metachronous triple cancers, including small cell carcinoma of the lung, as well as prostate and male breast cancer. To our knowledge, this is the first documented case of its kind. A 64-year-old man was referred to our hospital with left nipple retraction. He had previously undergone lobectomy of the right lung as treatment for small cell lung cancer at 57 years of age, and at 61 years of age, he had undergone prostatectomy and bilateral orchiectomy for prostate cancer, histologically determined to be moderately or poorly differentiated adenocarcinoma. Physical examination identified a painless irregular hard tumor in the left breast. Ultrasonography and magnetic resonance imaging (MRI) showed a nodular mass, and fine needle aspiration cytology of the mass revealed adenocarcinoma. Modified radical mastectomy was performed. Histological examination revealed that the breast tumor was scirrhous carcinoma, t1, n0, m0, stage T. Immunohistochemistry demonstrated that the prostate tumor was positive for prostatic specific antigen (PSA) and negative for estrogen receptor (ER), while the breast tumor was positive for ER and negative for PSA. Primary breast cancer was diagnosed. At present, 1 year and 8 months after surgical removal of the breast cancer, the patient has had no recurrence of breast cancer, small cell lung cancer, or prostate cancer. We discuss the possible causes of the triple cancers in this case with reference to the literature.

[A case of unresectable advanced gastric cancer with peritoneal dissemination responding to UET/low-dose CDDP combination chemotherapy].

We report the case of a 69-year-old female with unresectable gastric cancer (T3, N2, P3, H0, Stage IVb) accompanied by peritoneal dissemination, diagnosed on laparotomy. UFT/low-dose cisplatin (CDDP) combination chemotherapy was performed after surgery. UFT 300 mg/day was administered orally every day, and CDDP 10 mg was injected intravenously every week. Chemotherapy was continued for ten months with a total dose of CDDP of 380 mg, but was stopped after oral mucositis developed as a side effect. Seven months after the chemotherapy was started, endoscopy revealed that the gastric cancer tumors had disappeared and the gastric mucosa was intact. Gastric cancer recurrence occurred 2 years and 2 months after chemotherapy was started. Low-dose CDDP/5-FU chemotherapy and TS-1 chemotherapy were performed, but no effects were observed. The patient died 3 years and 6 months after the start of initial chemotherapy, and was treated as an outpatient for 3 years while maintaining a good quality of life. UFT/low-dose CDDP combination chemotherapy offers promise as an effective tool in the clinical management of advanced gastric cancer with peritoneal dissemination.