[A Case of Hormone Receptor-Positive Recurrent Breast Cancer Successfully Treated with Low-Dose Ethinyl Estradiol].

The patient, an 83-year-old woman, was diagnosed with ER- and PgR-positive left breast cancer(T2N0M0, Stage ⅡA) at the age of 68. At the time, she underwent preoperative chemotherapy followed by Bp+Ax and postoperative radiotherapy to the conserved breast. She also received endocrine therapy as adjuvant therapy. At the age of 73, she underwent radiotherapy for multiple bone metastases and left axillary lymphadenectomy due to left axillary lymph node recurrence. After surgery, she received 4 regimens of endocrine therapy over a period of 5 years and 1 month for bone metastases. At the age of 79, S-1 was administered for pulmonary metastasis which continued for the next 2 years and 8 months. At the age of 81, palbociclib+letrozole were administered for 1 year and 8 months owing to the progression of bone metastases. At the age of 83, she developed liver metastases and was administered ethinyl estradiol, starting at 1.5 mg/day and continued at a reduced dose of 0.5 mg/day for 9 months. The reduction in tumor markers after treatment initiation was rapid, and there were no serious adverse events. Ethinyl estradiol was useful for maintaining QOL in this elderly patient with recurrent breast cancer.

Targeting acidic pre-metastatic niche in lungs by pH low insertion peptide and its utility for anti-metastatic therapy.

Dysregulated extracellular pH, the universal feature of tumor, works as an evolutional force to drive dissemination of tumor cells. It is well-established that tumor acidity is associated with tumor growth and metastasis. However, the pH of pre-metastatic niche remains unclear. We hypothesized that primary tumor cells remotely prime acidity in secondary organ to achieve metastatic colonization. Herein, we demonstrated that the pH responsive probe pH Low Insertion Peptide (pHLIP) was notably accumulated in pre-metastatic lungs of 4T1.2 breast tumor-bearing mice. The pHLIP-targeted lungs showed high amounts of lactate and overexpressed glycolysis-related proteins. Pharmacological inhibition of glycolysis suppressed the lung acidification induced by 4T1.2 cancer cell culture supernatant and delayed subsequent metastatic burden of disseminated tumor cells. In the acidic lungs, pHLIP was primarily localized in alveolar type 2 cells which strongly expressed glycolysis-related proteins. 4T1.2-derived extracellular vesicles expressed some of the glycolysis-related proteins, and their administration increased pHLIP accumulation and glycolytic enhancement in lungs. pHLIP-conjugated dexamethasone effectively attenuated lung metastatic burden by disrupting pro-inflammatory response in the acidic lungs. From these results, targeting the metastasis-supporting microenvironment by pHLIP technology creates possibility to identify pre-metastatic organ and prevent metastatic recurrence.

[A Case of Breast Carcinoma That Changed Subtype to Squamous Cell Carcinoma after Chemotherapy].

Metaplastic carcinoma is a rare histological malignancy, often triple-negative, and has a poor prognosis. Here, we report a case of breast cancer in which the primary lesion degenerated into squamous cell carcinoma(triple negative)after drug treatment for invasive ductal carcinoma(Luminal type). The patient was a 41-year-old woman who was diagnosed with Stage Ⅳ left breast cancer T2N2bM1(HEP)(ER 90%, PR 70%, HER2 2+, FISH-)at another hospital and participated in the PATHWAY study(tamoxifen plus goserelin plus palbociclib/placebo). Since the primary lesion and liver metastasis increased in size, the study was discontinued after 8 weeks. She was treated at our hospital thereafter, with capecitabine plus cyclophosphamide, palbociclib plus fulvestrant plus leuprorelin, paclitaxel plus bevacizumab, eribulin, EC therapy, and docetaxel. However, both the primary lesion and liver metastasis increased. In particular, the increase in primary lesion size was remarkable, and the QOL significantly reduced due to bleeding and exudation. Biopsy performed during docetaxel treatment revealed metaplastic/squamous cell carcinoma(ER-, PR-, HER2 0, Ki-67 90-100%)histopathological findings. BRCA and microsatellite instability tests were negative, and PDL1 expression was less than 1%. Although Mohs ointment was used, tumor bleeding, exudate, and stink were poorly controlled, and the patient experienced painful symptoms due to the weight of the tumor. Therefore, left mastectomy plus pectoralis major muscle resection was performed. The patient died one month after the operation.

[Chemo-Resistant Breast Carcinoma with Cartilaginous Differentiation Manifestation after Neoadjuvant Chemotherapy-A Case Report].

A 49-year-old woman was admitted to our hospital because of a tumor in her right breast. The tumor was localized to the C area and was approximately 3 cm in size. A right axillary lymphadenopathy was also found. Histopathological examination and needle biopsy of the breast tumor revealed invasive lobular carcinoma, and she was diagnosed with Stage ⅡB triple-negative breast cancer(cT2N1M0). Paclitaxel plus bevacizumab chemotherapy followed by ddAC chemotherapy was administered as neoadjuvant chemotherapy, but the tumor remained stable. Thus, she underwent mastectomy and lymph node dissection. Pathological findings of the resected specimen showed invasive carcinoma with cartilaginous differentiation. She was then treated with capecitabine 15 days after the surgery; however, multiple lung metastases were found on CT after 6 courses. Therefore, she was transferred to another hospital and received other chemotherapies, but died after 5 months.

[A Case of Gastric Cancer Which Caused Severe Anemia(Hemoglobin 1.8 g/dL)].

A 61-year-old woman, who consulted another doctor with chief complaints of epigastric pain, nausea, anorexia, palpitation, and shortness of breath since a month was referred to our hospital for diagnosis and treatment. She was diagnosed with advanced gastric cancer. She was also found to have severe anemia(hemoglobin 1.8 g/dL)and malnutrition. With adequate precautions to prevent development of heart failure and refeeding syndrome, the patient was treated for anemia with blood transfusion and intravenous iron injection; and for malnutrition with intravenous hyperalimentation and enteral nutrition. The patient underwent distal gastrectomy 17 days after admission. Histological examination revealed a type 3 moderately differentiated tubular adenocarcinoma>solid type of poorly differentiated adenocarcinoma>mucinous adenocarcinoma corresponding to pT4a, pN3a, pStage ⅢB, respectively. The postoperative course was good and adjuvant chemotherapy was started 22 days after surgery. However, the patient died approximately 15 months after surgery due to metastases of gastric cancer to the lymph nodes.

[A Case of Bone Marrow Carcinomatosis Arising from Breast Cancer with a Rapidly Progressive Course].

A 67-year-old woman was diagnosed with Stage ⅡA breast cancer(T2N0M0)in 2003. She underwent mastectomy and lymph node dissection. Oral fluoropyrimidine was administered for 3 years as adjuvant chemotherapy. In 2008, the patient was diagnosed with multiple bone metastases and left supraclavicular lymph node metastasis. Radiotherapy was performed on the left first rib and left supraclavicular lymph node. She was treated with chemotherapy and endocrine therapy and bone metastasis therapeutic agent. In 2013, multiple liver metastases were noted and treated with chemotherapy. Liver metastases were well-controlled. Endocrine therapy was continued for bone metastases without visceral metastasis. In 2016, the patient was diagnosed with bone marrow carcinomatosis and died 2 weeks later due to bone marrow carcinomatosis.

[A Case of Ascending Colon Cancer Probably Arising from a Diverticulum].

A 70's male was admitted to our hospital with complaints of anorexia and abdominal pain. CT showed thickening of the ascending colon. Colonoscopy revealed multiple diverticula of the ascending colon, but no tumor on the mucosa. The patient was diagnosed as a case of diverticulitis of the ascending colon and was advised laparoscopic ileocecal resection. The resected specimen showed wall thickening; however, no remarkable findings were observed, with the exception of multiple diverticula on the mucosal surface. Histological examination showed well-differentiated tubular adenocarcinoma extending into the serosa probably arising from the diverticulum. Chemotherapy was performed after surgery. The patient died due to peritoneal dissemination from the ascending colon cancer 14 months after surgery.

[A Case of a Breast Cancer Patient with Cardiac Metastasis].

The patient was a 65-year-old woman who was diagnosed with Stage III A triple-negative breast cancer(T2N2aM0)at the age of 63. AC chemotherapy(3 months)followed by paclitaxel plus bevacizumab(4 months)was administered as neoadjuvant chemotherapy. After chemotherapy, she underwent mastectomy and lymph node dissection. Pathological examination revealed a partial response. After surgery, radiotherapy with a radiation dose of 50 Gy was applied to the chest wall and supraclavicular lymph node. Multiple pulmonary metastases and mediastinal lymph node metastases were diagnosed 23 months after initial treatment, and she was treated with S-1 administration. Two months after S-1 treatment, the PET-CT showed metastasis in the right atrium. Since there were no cardiac symptoms, S-1 treatment was continued without cardiovascular treatment. However, the mediastinal lymph node metastasis progressed; and therefore, S-1 administration was stopped and chemotherapy with eribulin was initiated. Brain metastasis was diagnosed at the same time and treated with a gamma knife. Although chemotherapy with eribulin was continued, the patient died 33 months after initial treatment owing to the brain metastasis. The cardiac metastasis did not progress during chemotherapy with eribulin. There was no sign of heart failure or arrhythmia during the treatment.

[A case of premenopausal stage IV breast cancer responding to neoadjuvant endocrine therapy after chemotherapy with FEC].

A 33-year-old woman was referred to our hospital with a complaint of left breast tumor. After examinations, she was diagnosed as invasive ductal carcinoma with sternum metastasis (T2N0M1(OSS), Stage IV). The tumor was hormone receptor- positive and HER2-negative. Primary systemic chemotherapy with FEC was performed. After four courses, the efficacy was judged as a partial response (PR). After chemotherapy, endocrine therapy with goserelin and tamoxifen was performed. The efficacy of endocrine therapy was as good as that of chemotherapy. After endocrine therapy for 13 months, breast conserving-surgery was performed. After surgery, radiotherapy for left breast and sternum was performed. She continues to undergo outpatient endocrine therapy with no detectable tumor. It is suggested that neoadjuvant endocrine therapy may be useful with consideration for treatment effectiveness and the patient's quality of life.

[Two cases of breast cancer responding to primary systemic chemotherapy containing trastuzumab without surgery].

The first case was a 40-year-old woman who was referred to our hospital with a complaint of left breast tumor. She was diagnosed as invasive ductal carcinoma (T2N0M0, Stage IIA). The tumor was ER-negative, PR-negative and HER2-positive. After primary systemic chemotherapy with 6 courses of 5-fluorouracil+epirubicin+cyclophosphamide(FEC)and 3 courses of weekly paclitaxel (PTX)+trastuzumab, the efficacy of chemotherapy was judged as a complete response (CR). After chemotherapy, radiotherapy for her left breast was performed without surgery. At 21 months after CR, local efficacy was judged as CR, but liver and bone metastases appeared, and were treated by capecitabine and trastuzumab. The efficacy of chemotherapy was judged as a partial response (PR). The second case was a 26-year-old woman referred to our hospital with a complaint of right breast tumor. She was diagnosed as invasive lobular carcinoma (T2N0M0, Stage IIA). The tumor was ER-positive, PR-negative and HER2-positive. After primary systemic chemotherapy with 4 courses of FEC and 6 courses of docetaxel+trastuzumab, the efficacy of chemotherapy was judged as CR. Then, 4 courses of weekly PTX+trastuzumab were performed. After chemotherapy, radiotherapy for her right breast was performed without surgery. The efficacy of treatment was judged as CR for 15 months.

[A case of stage IV breast cancer with large cancer ulcer responding to combination therapy of capecitabine and medroxyprogesterone acetate and cyclophosphamide].

A 53-year-old woman suffering from nausea and vomiting was admitted to our hospital. There was a large ulcer from her left anterior chest to her right side chest. After pathological examination from the ulcer, she was diagnosed as breast cancer, scirrhous carcinoma. The estrogen and progesterone receptors were positive in the tumor. HER2 score was 1+ in the tumor. The stage was T4bNxM1(OTH). Uterine metastases of the breast cancer caused obstructive nephropathy. Ureteral obstruction was treated by urinary tract catheter. After improvement of renal failure, chemotherapy with 5-FU+epirubicin+cyclophosphamide (FEC) and docetaxel was performed. The efficacy was judged as stable disease (SD). For third-line chemotherapy, she was then treated with oral combination chemoendocrine therapy with capecitabine and medroxyprogesterone acetate. After the combination chemoendocrine therapy, the local tumor was remarkably reduced. With added cyclophosphamide, the partial response (PR) continued for 19 months. She died of peritonitis carcinomatosa and pleuritis carcinomatosa. No adverse reactions occurred with the combination chemoendocrine therapy. It is suggested that this oral combination chemoendocrine therapy may be useful with consideration for treatment effectiveness and the quality of life of the patient.

[A case of bilateral T4 breast cancer with different responses to chemotherapy].

It is recognized that hormone receptors and HER2 are important as prognostic factors in breast cancer. Moreover, it seems likely that hormone receptors and HER2 are important predictive factors for response to chemotherapy in breast cancer. We report a case of bilateral T4 breast cancer with different expression for hormone receptors and HER2. The patient was a 67-year-old woman. The Stage was T4bN2aM0, respectively. The right tumor was negative for hormone receptors and positive for HER2, while the left tumor was positive for hormone receptors and negative for HER2. After primary chemotherapy with FEC, paclitaxel and docetaxel, the efficacy for the right local tumor was judged as cCR. However, brain metastases appeared and were treated by resection and radiation. The efficacy for the left tumor was judged as PR. Modified radical mastectomy with axillary lymph node dissection was performed. The patient has survived with no recurrence.

[A case of recurrent breast cancer with multiple liver metastases responding to combination therapy of capecitabine and MPA].

The patient was a 68-year-old woman who underwent left partial mastectomy on February 1999. The stage was T2N1. There were positive for estrogen and progesterone receptors in the tumor. After operation, adjuvant therapy consisting of oral administration of tamoxifen and radiation was performed. On February 2005, she felt dyspnea and right femoral pain. After examinations, she was diagnosed as recurrent breast cancer with pleuritis carcinomatosa and bone metastasis. The patient was treated with oral administration of anastrozole and pamidronate disodium 90 mg intravenously every 4 weeks, radiation of her right femur, and OK-432 injection into the intrapleural cavity. On November 2005, she felt general fatigue and anorexia. CT examination revealed multiple liver metastases. She was treated with oral combination chemoendocrine therapy with capecitabine (2,400 mg/day) and MPA (600 mg/day). After the four courses, multiple liver metastases were remarkably reduced in the CT findings. After twelve courses, the partial response continued. No adverse reactions occurred except for gain in weight of grade 1. It is suggested that this oral combination chemoendocrine therapy may be useful for recurrent breast cancer with consideration for treatment effectiveness and the quality of life of the patient.

[A case of rectal cancer with multiple liver metastases responding to TS-1].

A 63-year-old woman was referred to our hospital with complaints of anal pain, constipation and abdominal distention caused by a rectal tumor. After examinations, she was diagnosed as rectal cancer with multiple liver metastases. The CEA level was 70.0 ng/ml and the CA19-9 level was more than 5,000 U/ml at admission. To prevent bowel obstruction, low anterior resection of the rectum was performed. At 34 days after operation, TS-1 chemotherapy was started as outpatient treatment (each course consisted of daily oral administration of 100 mg TS-1 for 4 weeks followed by 2 drug-free weeks). After the first course, the CEA level was reduced to 3.3 ng/ml and the CA19-9 level to 15 U/ml, both under the normal value. After the second course, administration was discontinued due to diarrhea, and restarted as a daily oral administration of 80 mg TS-1. After the five courses, the CEA level was 4.0 ng/ml and the CA19-9 level was 4 U/ml, both under the normal value. Multiple liver metastases had remarkably reduced in the CT findings. The patient continues to undergo outpatient treatment with good QOL.

Successful laparoscopic right gastroepiploic aneurysmectomy: report of a case.

A 75-year-old woman presented with a pulsatile, movable mass, about 5 cm in diameter, in her lower abdomen. Abdominal ultrasonography revealed a circular mass with a variable hypo- and isoechoic border and a hypoechoic center. Color Doppler echography showed blood flow in the hypoechoic center, which was strongly enhanced on contrast-enhanced computed tomography. Based on these findings, we diagnosed a splanchnic artery aneurysm; however, celiac arteriography, performed twice, could not definitively identify it. An operation was performed under the tentative diagnosis of an aneurysm of the superior mesenteric artery or the gastroepiploic artery. On laparoscopic exploration, a globe-shaped mass, about 5 cm in diameter, was found in the right side of the greater omentum, which was diagnosed as an aneurysm of the right gastroepiploic artery. We resected the aneurysm laparoscopically and the patient had an uneventful postoperative course. Thus, laparoscopic surgery was effective for this patient who required no vascular reconstruction.

A case of lung cancer with hypercalcemia which was incidentally complicated with primary hyperparathyroidism due to parathyroid adenoma.

In lung cancer patients, hypercalcemia is a fairly common metabolic problem associated with malignancy. However, the occurrence of hypercalcemia in lung cancer patients means an ominous prognostic sign. As hypercalcemia often causes early death, quick diagnosis and treatment for hypercalcemia are required. A 69-year-old woman was admitted to our hospital with anorexia caused by hypercalcemia. On admission, serum level of PTH was elevated and PTHrP was normal. From the results of CT findings and transbronchial lung biopsy, the cause of the hypercalcemia was determined as lung cancer incidentally complicated with primary hyperparathyroidism. First, serum calcium level was returned to normal through hydration with saline and bisphosphonates. Next, left hemithyroidectomy for primary hyperparathyroidism was performed. Histologically, the tumor was diagnosed as parathyroid adenoma. Fifteen days later, left lower lobectomy for primary lung cancer was performed under a video-assisted thoracoscopic approach. Histologically, the tumor was diagnosed as a moderately differentiated adenocarcinoma. Four years and three months after the operation, the patient is alive and well with no sign of recurrence. When a lung cancer patient is complicated with hypercalcemia, we need to consider that primary hyperparathyroidism is a possible cause of the hypercalcemia.

Role of Epstein-Barr virus-encoded latent membrane protein 2A on virus-induced immortalization and virus activation.

To quantitatively evaluate the role of Epstein-Barr virus (EBV)-encoded latent membrane protein 2A (LMP2A) in immortalization of peripheral B-lymphocytes, we used the Akata cell system to generate an EBV recombinant in which the first exon of the LMP2A gene was disrupted. The results indicated that deletion of the LMP2A gene did not affect the immortalization efficiency of EBV in B-lymphocytes. Deletion of the LMP2A gene made EBV-transformed lymphocytes more permissive for virus replication in response to surface immunoglobulin cross-linking. On the other hand Akata cells, in which LMP2A expression was much lower than in EBV-transformed lymphocytes, were equally permissive for virus replication whether they were infected with wild EBV or LMP2A-knockout EBV. The results raise a question as to the role of LMP2A in inhibition of disruption of virus latency in vivo, where LMP2A expression has been expected to be low as in Akata cells.