High Frequency of BRCA2 c.5576_5579del Carriers in Kakogawa, Japan.

Background/Aim: Certain germline pathogenic variants (PVs), known as founder mutations, have been frequently observed in specific regions and ethnic groups. In Japan, several pathogenic variants of BRCA1/2 have been identified as founder mutations, with their distribution varying across different regions. This retrospective study aimed to further investigate the detailed distribution and correlation between genotype and clinical features among breast cancer patients. Patients and Methods: This study was conducted at Kobe University Hospital and three collaborating institutions. It included breast cancer patients who underwent BRCA1/2 genetic testing between July 1, 2018, and March 31, 2021, and were found to have germline PVs. Clinical characteristics and breast cancer subtypes were compared between carriers of BRCA2 c.5576_5579del and those with other PVs. Additionally, the detection rate of BRCA2 c.5576_5579del was compared with that observed in a previous report. Results: A total of 38 breast cancer patients were included; PVs in BRCA1 and BRCA2 were detected in 12 and 26 patients, respectively, 12 of whom were BRCA2 c.5576_5579del carriers. BRCA2 c.5576_5579del carriers were more likely to develop triple negative breast cancers among all BRCA2 PV carriers. BRCA2 c.5576_5579del accounted for 30.8% of the PVs detected, with a particularly high frequency of 72.7% at Kakogawa Central City Hospital. Conclusion: BRCA2 c.5576_5579del was detected with a particularly high frequency in Hyogo Prefecture, especially in Kakogawa city. In the future, a survey of the distribution of the BRCA2 c.5576_5579del carriers may provide more clarity regarding their localization.

Investigation of a Novel S-1 Administration Schedule for Treating Metastatic and Recurrent Breast Cancer (KBCOG13).

BACKGROUND/AIM: S-1, a 5-fluorouracil(5-FU) oral anti-cancer drug, has been traditionally used with a schedule of 4-week oral administration followed by 2-week rest for breast cancer treatment. We, herein, aimed to investigate the clinical efficacy and safety of a schedule of 2-week oral administration followed by 1-week rest for patients with metastatic breast cancer. PATIENTS AND METHODS: We enrolled patients with HER2-negative metastatic breast cancer who had not received prior chemotherapy. S-1 was administered consecutively for 2-weeks followed by a 1-week rest. RESULTS: Between September 1, 2013 and August 31, 2016, 32 patients were enrolled. The median follow-up time was 32.1 months. The median progression-free survival (PFS) was 9.4 months. Overall survival (OS) was 41.0 months, time to treatment failure (TTF) was 7.8 months, response rate (RR) was 31.3%, and disease control rate (DCR) was 78.1%. The incidence of grade 3 side-effects was not high. CONCLUSION: The 3-week schedule of S-1 can be considered useful as a treatment for patients with metastatic breast cancer, helping in maintaining a high quality of life.

Risk Analysis for Chemotherapy-induced Nausea and Vomiting (CINV) in Patients Receiving FEC100 Treatment.

BACKGROUND/AIM: Risk factors for chemotherapy-induced nausea and vomiting (CINV) with anthracycline-containing regimen for breast cancer patients remain unknown. The risk factors for CINV with FEC100 were investigated. PATIENTS AND METHODS: Data on CINV events and patient backgrounds of 180 patients were collected from the first cycle of FEC100 treatment. In this regimen, patients were administered various antiemetics (ADs). The combinations of ADs were classified into four categories, while body mass index (BMI) was stratified into three categories. Risk factors were selected based on patient characteristics and combination of ADs. Risks for CINV were analyzed by univariate and multivariate analyses. RESULTS: In the univariate analysis of nausea, BMI was a significant factor, while BMI and combination of ADs were significant in vomiting. In the multivariate analysis concerning nausea, BMI was a significant factor. In the analysis concerning vomiting, the combination of ADs and BMI were significant. CONCLUSION: BMI was the most important risk factor for nausea and vomiting, while the combination of ADs was for vomiting.

[A Case of Primary Lymphoma of the Breast with Hepatic Cirrhosis].

We report a case of primary lymphoma of the breast complicated by heart failure and alcoholic-decompensated hepatic cirrhosis. The patient was a woman in her 60s who noticed a right breast tumor growing 3 months previously. The size of the tumor was approximately 5 cm, and the tumor had infiltrated the skin. There was no metastasis to the axillary lymph node or other organs by CT. We performed right breast mastectomy. Pathology indicated diffuse large B cell lymphoma(DLBCL). We considered chemotherapy, but her general condition was not good because of hepatic cirrhosis, so we administered palliative care. Although chemotherapy is the first choice of treatment for DLBCL, it is necessary to individually consider each patient's circumstances.

[Bone Marrow Metastases of Breast Cancer Treated with Endocrine Therapy-A Case Report].

We report a case of bone marrowmetastases of breast cancer treated with endocrine therapy. A 54-year-old woman underwent right partial mastectomy and sentinel lymph node biopsy, followed by adjuvant chemotherapy and radiotherapy. She declined the endocrine therapy and was lost to follow-up after 3 postoperative years. After 9 postoperative years, she visited our hospital because of backache and an axillary lump. FDG-PET scan, incisional biopsy of the axillary lump, and bone marrowbiopsy revealed multiple bone and bone marrowmetastases of the breast cancer. She was treated with endocrine therapy(fulvestrant: FUL), which effectively decreased the FDG uptake in the metastatic lesions after 6 months. However, tumor markers elevated after 1 year and 6 months, and she is currently under combination therapy with aromatase inhibitors and CDK4/6 inhibitors.

[A Case of Chemotherapy with FOLFOXIRI plus Cetuximab for Liver Metastasis of Sigmoid Colon Cancer].

We report a case of chemotherapy with FOLFOXIRI plus cetuximab for liver metastasis of sigmoid colon cancer. The patient was a 40's man who was diagnosed with sigmoid colon cancer with liver metastasis. Colonoscopy revealed a type 2 tumor with stenosis in the sigmoid colon. He underwent sigmoidectomy under laparotomy, and after the operation, received 7 courses of chemotherapy with FOLFOXIRI plus cetuximab. The liver tumor was sufficiently reduced, and laparotomy and liver right lobectomy were performed. Histopathology revealed a modified, Grade 2 tumor regression. He has been followed for 1 year 4months after the operation.

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.

Randomized Controlled Trial of Zoledronic Acid plus Chemotherapy versus Chemotherapy Alone as Neoadjuvant Treatment of HER2-Negative Primary Breast Cancer (JONIE Study).

PURPOSE: Zoledronic acid (ZOL) is a nitrogen-containing bisphosphonate that induces osteoclast apoptosis and inhibits bone resorption by inhibiting the mevalonate pathway. Its benefit for the prevention of skeletal complications due to bone metastases has been established. However, the antitumor efficacy of ZOL, although suggested by multiple preclinical and clinical studies, has not yet been clinically proven. We performed the present randomized Phase 2 trial to investigate the antitumor effect of ZOL with chemotherapy (CT). METHODS: Asian patients with HER2-negative invasive breast cancer were randomly assigned to either the CT or CT+ZOL (CTZ) group. One hundred and eighty-eight patients were randomized to either the CT group (n = 95) or the CTZ group (n = 93) from March 2010 to April 2012, and 180 patients were assessed. All patients received four cycles of FEC100 (fluorouracil 500 mg/m2, epirubicin 100 mg/m2, and cyclophosphamide 500 mg/m2), followed by 12 cycles of paclitaxel at 80 mg/m2 weekly. ZOL (4 mg) was administered three to four times weekly for 7 weeks to the patients in the CTZ group. The primary endpoint was the pathological complete response (pCR) rate, which was defined as no invasive cancer in the breast tissue specimen. Safety was assessed in all patients who received at least one dose of the study drug. RESULTS: This randomized controlled trial indicated that the rates of pCR in CTZ group (14.8%) was doubled to CT group (7.7%), respectively (one-sided chi-square test, p = 0.068), though the additional efficacy of zoledronic acid was not demonstrated statistically. The pCR rate in postmenopausal patients was 18.4% and 5.1% in the CTZ and CT groups, respectively (one-sided Fisher's exact test, p = 0.071), and that in patients with triple-negative breast cancer was 35.3% and 11.8% in the CTZ and CT groups, respectively (one-sided Fisher's exact test, p = 0.112). Thus the addition of ZOL to neoadjuvant CT has potential anticancer benefits in postmenopausal patients and patients with triple-negative breast cancer. Further investigation is warranted. TRIAL REGISTRATION: University Hospital Medical Information Network. UMIN000003261.

[Response to neoadjuvant chemotherapy in breast cancer as assessed by subtype].

The aim of this study was to investigate the responses to neoadjuvant chemotherapy (NAC) in breast cancer according to subtype. The study included 69 women who received NAC at our hospital between January 2004 and January 2013. Complete response( CR) was achieved in 14 patients( 20.3%) and partial response( PR) was achieved in 37 patients (53.6%).CR and PR rates according to subtype were as follows: 0% and 57.1% for the luminal type, 0% and 66.7% for the luminal-human epidermal growth factor receptor (HER)-2 type, 16% and 56% for the triple negative type, and 58.8% and 41.2% for the HER2 type, respectively. The CR rate was the highest among patients with HER2-type breast cancer. Trastuzumab was additionally administered to 12 patients with HER2-type breast cancer, and the CR rate among these patients was significantly higher after trastuzumab treatment( 75%).Thus, it is important to select a treatment strategy for breast cancer on the basis of the subtype diagnosed.

[Clinical significance of neutrophil to lymphocyte ratio in colorectal cancer patients receiving adjuvant chemotherapy combined with polysaccharide-K].

The neutrophil to lymphocyte ratio (N/L ratio) has been reported to be related to the prognosis of various types of cancer. In particular, a high N/L ratio has been suggested to be associated with poor outcome. We investigated the changes in N/L ratio during treatment in 12 patients who had undergone surgery for colorectal cancer and were receiving postoperative adjuvant therapy with a combination of chemotherapy and polysaccharide-K (PSK). The patients were stratified into 2 groups according to the preoperative N/L ratio (cut-off ratio was 2.5): high N/L (≥2.5) and low N/L (<2.5). The changes in N/L ratio and other clinical parameters over time were investigated. In patients with a high preoperative N/L ratio, the use of postoperative PSK-chemotherapy controlled the N/L ratio at low levels. The N/L ratio tended to remain low in patients with low preoperative N/L ratios. No difference in outcome was observed between patients with high and low N/L ratios. In patients who underwent colorectal cancer surgery, postoperative adjuvant therapy with a combination of chemotherapy and PSK succeeded in controlling the N/L ratio at low levels. Further studies with more patients are required to explore the outcomes associated with changing N/L ratios.

[Two long-term survival cases of Stage IV colon cancer through multidisciplinary treatment].

We report the long-term survival in two cases of colon cancer through multidisciplinary treatment, including surgery. Case 1: A 67-year-old male patient underwent anterior rectal resection, partial hepatectomy(S4, S5, S5/8) and cholecystectomy for rectal cancer with liver metastasis in July 2006(pSS, pN0, sH1, sP0, sM0, Stage IV, Cur B). Liver metastasis, lung metastasis, and metastatic colon cancer occurred 5 times during the 59 months following the first operation. We performed surgery and adjuvant chemotherapy to treat each recurrence. Case 2: A 42-year-old male patient underwent sigmoidectomy for sigmoid colon cancer with multiple liver metastasis in May 2007 (pSS, pN0, sH2, sP0, sM0, Stage IV, Cur C). Recurrence occurred 7 times at the liver and lung during the 58 months after the first operation. We performed surgery and adjuvant chemotherapy to treat each recurrence.

[Three cases of sigmoid colon cancer accompanied by invagination].

Invagination in adults is rare compared to children. We experienced 3 sigmoid colon cancers in which symptoms of invagination were discovered. Because the tumors in 2 of the 3 cases could be reduced, operations were electively performed. The tumor in the remaining case could not be reduced and an urgent operation was required. Because all cases responded in the early stage, their postoperative progress was good. Invagination in adults is typically caused by an organic disease, particularly cancer. It is necessary to consider not only reduction of the invagination but also treatment of the primary disease causing invagination. It is important that the malignant symptoms be detected promptly in order to develop a suitable treatment strategy.

[A case of severe subcutaneous emphysema during laparoscopic right-hemicolectomy].

A 76-year-old woman, weighing 40 kg, was scheduled for laparoscopic right-hemicolectomy. Forty minutes after starting the laparoscopic procedure, PaCO2 increased to 64.3 mmHg. Massive subcutaneous emphysema from the anterior thorax to the abdomen was noted and we stopped the laparoscopic procedure. In the laparoscopic procedure for the treatment of colectomy, it is important to discover abnormalities such as snowball crepitation and arrhythmia, and to monitor ETCO2 continuously in order to avoid massive subcutaneous emphysema and hypercapnia. During a laparoscopic procedure, hypercapnia might cause acidosis, arrhythmia, hypotension, myocardial ischemia, and cardiac arrest.

[A resected case of signet-ring cell carcinoma of the rectum].

Here, we present the case of a 76-year-old woman who consulted us in April 2010, following a positive fecal occult blood test, and was diagnosed with lower rectal cancer. Signet-ring cell carcinoma was diagnosed by histology. Because hydronephrosis of both sides was considered the cause of dissemination of the tumor, only chemotherapy was performed. After the eighth course of XELOX+bevacizumab treatment, hydronephrosis of both sides improved and the tumor marker level became normal. An abdominoperineal rectal resection was performed in February 2011. The results of pathological examination of the resected specimen showed complete response. After the operation, the tumor marker level was elevated, and recurrence in the pelvic cavity and multiple bone metastases were detected by positron emission tomography/ computed tomography. Chemotherapy has now been resumed. Signet-ring cell carcinoma is rare in colorectal cancer. The frequency of multiple organ metastases is high, and the growth rate of the tumor is also high. Poor prognosis compared to the usual colorectal cancer has been reported.

[A case of refractory pancreatic fistula following pancreaticoduodenectomy treated successfully by intestinal decompression catheter insertion to jejunum under local anesthesia].

The case was an 80-year-old woman with inferior bile duct cancer. The patient had undergone subtotal stomach-preserving pancreaticoduodenectomy with end-to-side pancreaticojejunostomy. Postoperative pancreatic fistula was observed in a short period and was treated by somatostatin analog administration and abscess drainage. Despite these conservative therapies, pancreatic fistula resulted in abdominal bleeding from the branch of dorsal pancreatic artery, which stopped by emergent transcatheter arterial embolization. Because pancreatic fistula had become refractory, the intestinal decompression catheter insertion was performed under local anesthesia to the jejunum located directly below abdominal wall. After this surgery, pancreatic fistula was resolved over a few weeks. This technique could be safely performed and avoided the injury of drainage fistula, and was considered to be an option for treating refractory pancreatic fistula.

[Two cases of ovarian metastasis of colon cancer].

CASE 1: A 45-year-old female underwent sigmoidectomy, simple total hysterectomy and bilateral adnexotomy for sigmoid colon cancer and a right ovarian metastasis in December 2007. As adjuvant chemotherapy, S-1 was conducted for six months. She remains disease-free for 38 months after the surgery. CASE 2: A 61-year-old female underwent simple total hysterectomy and bilateral adnexotomy for bilateral ovarian tumors following the surgery for colon cancer, metastatic liver cancer and gastric cancer in January 2010. As adjuvant chemotherapy, capecitabine was administered seven times. Five months after the last surgery, para-aortic lymph node recurrence was diagnosed. FOLFIRI/panitumumab therapy was maintained. For both of the two cases in immune-staining, CK20 staining was positive, and CK7 staining was negative. Ovarian tumors were diagnosed as metastasis from colon cancer. Ovarian metastasis of colon cancer is a relatively rare event, but a long-term survival case has been reported by multimodality therapy including surgery.

[Two cases of recurrence at anastomosis site with leakage after operation for rectal cancer].

We report two cases of recurrence at an anastomosis site with leakage after operation for rectal cancer. In these cases, we thought that an implantation on leakage sites should be occurring by remaining stool with cancer cell. Colorectal cancer with ileus owing to obstacle by tumor, such as our cases, has a high risk of leakage at the anastomosis site and developed a complication that increased the risk of local recurrence. In our case of colorectal cancer with ileus owing to stenosis by tumor, a treatment method including the selection of operation should be contemplated how to prevent a local recurrence.

[A case of ovarian metastasis from colon cancer successfully treated with multidisciplinary therapy].

An 80-year-old female patient was undergone sigmoidectomy with D2 lymph node dissection for type 2 sigmoid colon cancer in February 2007. A post operative pathological finding of cancer was SS, N0, P0, H0, M0 (Stage II), curative A. Twelve months after the operation, elevated CEA level was observed. CT scan and MRI revealed a mass of 10 cm in diameter with multiple cysts in the pelvic cavity, which was diagnosed a malignant ovarian tumor. In May 2008, total hysterectomy, bilateral oophorectomy, and partial omentectomy were performed and its pathological finding was metastatic ovarian tumor originating from colon cancer. Adjuvant chemotherapy was administered, as cancer cells were detected in the ascites. The patient has been in good health without recurrence for 25 months after the second operation.

[A case report of primary adenocarcinoma of small intestine].

This is an account of a case of primary adenocarcinoma of the small intestine with peritoneal dissemination successfully treated with chemotherapy. A 64-year-old woman was admitted with a complaint of severe abdominal distension. Abdominal computerized tomography revealed a bowel obstruction with tumor and the remarkable small bowel dilation of oral side of tumor. The tumor was found at surgery to be at the ileum 15 cm proximal from the ileocecal region. Peritoneal dissemination was recognized around the ileocecal region, so ileum partial resection was performed for the primary cancer lesion and dissemination region. Pathological diagnosis of the resected specimen was adenocarcinoma with lymph nodes metastasis. The peritoneal dissemination consisted of metastatic adenocarcinoma from small intestine. After an operation, internal use of S-1 was performed as adjuvant chemotherapy. But a recurrent lesion at the ovarium was detected 6 months after surgery. The patient was subsequently treated with resection of the ovarium. For lung metastasis, the combination chemotherapy with mFOLFOX6 + bevacizumab was administered. Primary small intestinal adenocarcinoma is a rare disease, and it is often diagnosed as advanced cancer because of few characteristic symptoms. So carcinoma of the small intestine usually has a poor prognosis.