[A Case of Rheumatoid Arthritis after Administration of an Aromatase Inhibitor in a Menopausal Patient with Breast Cancer].

Therapy with an aromatase inhibitor(AI)was initiated in a 91-year-old female patient after she had been diagnosed with breast cancer. One week after taking the medicine, she experienced multiple joint pain in her upper extremities. Finally, she was diagnosed with rheumatoid arthritis(RA). Joint pains are frequently recognized as adverse events associated with the administration of an AI; however, the presentation of RA is rare. It has been shown that AI reinforces the activity of osteoclasts. On the other hand, the association between AI and the pathogenesis of RA remains unclear.

Phase III study of long-term prognosis of estrogen receptor-positive early breast cancer treated with neoadjuvant endocrine therapy with/without adjuvant chemotherapy.

PURPOSE: Neoadjuvant endocrine therapy (NET) is a treatment option for estrogen receptor-positive (ER+) postmenopausal early breast cancer (EBC). This phase III trial evaluated the prognosis of EBC patients treated with/without chemotherapy (CT) following NET. METHODS: ER+/HER2-, T1c-2, and clinically node-negative EBC patients were enrolled in 2008-2013 and treated with endocrine therapy (ET) in weeks 24-28. All patients, excluding those with progressive disease (PD) during NET or ≥ 4 positive lymph nodes after surgery, were randomized to ET for 4.5-5 years with/without CT. The primary endpoint was disease-free survival (DFS). Secondary endpoints included distant DFS (DDFS), overall survival (OS), and DFS/DDFS/OS according to clinical response to NET. RESULTS: Of 904 patients, 669 were randomized to CT+ET (n = 333) or ET alone (n = 336). The median follow-up was 7.8 years. DFS (CT+ET, 47 events; ET alone, 70 events) and DDFS did not reach the planned numbers of events. Eight-year DFS/DDFS rates were 86%/93% and 83%/92%, respectively. DFS was significantly better in CT+ET than ET alone in subgroups aged < 60 years (P = 0.016), T2 (P = 0.013), or Ki67 > 20% (P = 0.026). Progesterone receptor and histological grade were predictive markers for clinical responses to NET. CONCLUSION: NET may be used as standard treatment for patients with ER+EBC. Although it is difficult to decide whether to administer adjuvant CT based solely on the effect of NET, the response to NET may help to inform this decision. TRIAL REGISTRATION: This study was registered at the UMIN Clinical Trials Registry under UMIN000001090 (registered 20 March 2008).

Anthracycline-containing regimens or taxane versus S-1 as first-line chemotherapy for metastatic breast cancer.

BACKGROUND: We have previously demonstrated S-1 is non-inferior to taxane with respect to overall survival as first-line chemotherapy for HER2-negative metastatic breast cancer. We aimed to confirm whether S-1 is also non-inferior to anthracycline-containing regimens in the same setting. METHODS: We conducted an open-label, non-inferiority, Phase 3 study. Individuals who had HER2-negative metastatic breast cancer, had received no chemotherapy for advanced disease and had endocrine therapy resistance, were randomly assigned to the anthracycline-containing regimens or S-1. The primary endpoint was overall survival. A pre-planned combined analysis of our two Phase 3 studies was also carried out. RESULTS: We enrolled 230 patients (anthracycline, n = 115; S-1, n = 115). Median overall survival was 30.1 months (95% CI 24.9-35.8) with the S-1 group and 33.7 months (95% CI 25.5-36.9) with the anthracycline group. The HR for the anthracycline group was 1.09 (95% CI 0.80-1.48). The combined analysis constituted 814 patients (395 assigned to standard treatment (anthracycline or taxane); 419 assigned to S-1). Median overall survival was 36.3 months in the standard treatment group and 32.7 months in the S-1 group. S-1 was non-inferior to standard treatment in terms of overall survival (HR 1.06 (95% CI 0.90-1.25); P non-inferiority = 0.0062). CONCLUSIONS: S-1 could be considered a new treatment option for first-line chemotherapy for patients with HER2-negative metastatic breast cancer. CLINICAL TRIAL REGISTRATION: The University Hospital Medical Information Network, Japan: UMIN000005449. This trial was registered on 15 April, 2011.

Ki-67 response-guided preoperative chemotherapy for HER2-positive breast cancer: results of a randomised Phase 2 study.

BACKGROUND: The effectiveness of a therapeutic strategy that switches chemotherapy, based on Ki-67 tumour expression after initial therapy, relative to that of standard chemotherapy, has not been evaluated. METHODS: Patients were randomly assigned to the control arm or the Ki-67 response-guided arm (Ki-67 arm). Primary tumour biopsies were obtained before treatment, and after three once-weekly doses of paclitaxel and trastuzumab to assess the interim Ki-67 index. In the control arm, paclitaxel and trastuzumab were continued for a total of 12 doses, regardless of the interim Ki-67 index. In the Ki-67 arm, subsequent treatment was based on the interim Ki-67 index. Ki-67 early responder is defined as the absolute Ki-67 value that was <10%, and the percentage of Ki-67-positive tumour cells was reduced by >30% compared with before treatment. Early Ki-67 responders continued to receive the same treatment, while early Ki-67 non-responders were switched to epirubicin plus cyclophosphamide. The primary endpoint was the pathological complete response (pCR) rate. RESULTS: A total of 237 patients were randomised. There was almost linear correlation between the Ki-67 reduction rate at interim assessment and the pCR rate. The pCR rate in Ki-67 early non-responders in the Ki-67 arm was inferior to that in the control arm (44.1%; 31.4-56.7; P = 0.025). CONCLUSIONS: The standard chemotherapy protocol remains as the recommended strategy for patients with HER2-positive breast cancer. CLINICAL TRIAL REGISTRATION: Clinical Trial Registration: UMIN-CTR as UMIN000007074.

Factors affecting enrollment in randomized controlled trials conducted for patients with metastatic breast cancer.

BACKGROUND: It is critical to obtain informed consent from eligible patients to complete clinical trials. We investigated the factors that affect the participation rates of eligible patients. PATIENTS AND METHODS: Patients with metastatic breast cancer who were eligible for SELECT BC or SELECT BC-CONFIRM trials, randomized controlled trials conducted for patients with chemotherapy-naive metastatic breast cancer were recruited to prospective studies, SELECT BC-FEEL and SELECT BC-FEEL II, respectively. SELECT BC FEEL and SELECT BC-FEEL II were conducted to identify the factors affecting the rates at which informed consent was obtained, using a self-administered questionnaire we developed. RESULTS: In total, 232 patients participated in the studies. The patients who agreed to take part in the randomized trials were more likely than the refusers to answer that they decided to participate because: 'My doctor wanted me to participate in this trial' (P = 0.00000), ' My family or friends wanted me to participate in this trial' (P = 0.00000), 'Both treatment regimens used in the trial are suitable to me' (P = 0.00383), 'I know that the trial is conducted to determine which is a better treatment' (P = 0.01196), and ' I think that my participation in the trial will contribute to the benefit to future patients with the same disease' (P = 0.00756). CONCLUSIONS: To enhance the consent rate in randomized trials of metastatic breast cancer patients, concepts of the trials must be considered important and acceptable not only by patients but also by doctors and their families.

Validation of the 21-gene test as a predictor of clinical response to neoadjuvant hormonal therapy for ER+, HER2-negative breast cancer: the TransNEOS study.

PURPOSE: The Recurrence Score test is validated to predict benefit of adjuvant chemotherapy. TransNEOS, a translational study of New Primary Endocrine-therapy Origination Study (NEOS), evaluated whether Recurrence Score results can predict clinical response to neoadjuvant letrozole. METHODS: NEOS is a phase 3 clinical trial of hormonal therapy ± adjuvant chemotherapy for postmenopausal patients with ER+, HER2-negative, clinically node-negative breast cancer, after six months of neoadjuvant letrozole and breast surgery. TransNEOS patients had tumors ≥ 2 cm and archived core-biopsy samples taken before neoadjuvant letrozole and subsequently sent for Recurrence Score testing. The primary endpoint was to evaluate clinical (complete or partial) response to neoadjuvant letrozole for RS < 18 versus RS ≥ 31. Secondary endpoints included evaluation of clinical response and rate of breast-conserving surgery (BCS) by continuous Recurrence Score result, ESR1 and PGR single-gene scores, and ER gene-group score. RESULTS: Of 295 TransNEOS patients (median age 63 years; median tumor size 25 mm; 66% grade 1), 53.2% had RS < 18, 28.5% had RS18-30, and 18.3% had RS ≥ 31. Clinical response rates were 54% (RS < 18), 42% (RS18-30), and 22% (RS ≥ 31). A higher proportion of patients with RS < 18 had clinical responses (p < 0.001 vs. RS ≥ 31). In multivariable analyses, continuous Recurrence Score result (p < 0.001), ESR1 score (p = 0.049), PGR score (p < 0.001), and ER gene-group score (p < 0.001) were associated with clinical response. Recurrence Score group was significantly associated with rate of BCS after neoadjuvant treatment (RS < 18 vs. RS ≥ 31, p = 0.010). CONCLUSION: The Recurrence Score test is validated to predict clinical response to neoadjuvant letrozole in postmenopausal patients with ER+, HER2-negative, clinically node-negative breast cancer.

[A Case of Rectal Gastrointestinal Stromal Tumor(GIST)Treated with Imatinib Mesylate Neoadjuvant Therapy to Preserve the Anus].

A woman in her 40's who initially presented with anal pain was diagnosed with rectal GIST. A 9 cm tumor extended to near the anus, and curative abdominoperineal tumor resection was required. The patient initially received neoadjuvant therapy with imatinib mesylate. Neoadjuvant chemotherapy for 6 months reduced the tumor to approximately 47% of its original size and permitted anus-preserving surgery. The present case suggests that neoadjuvant therapy with imatinib mesylate is useful for large rectal GISTs, from the standpoint of anal function preservation.

[A Case of Advanced Colon Cancer with Long-Term and Re-Administration of Regorafenib].

A 54-year-old woman diagnosed with sigmoid colon cancer and multiple liver metastases underwent sigmoidectomy, partial hepatectomy, and RFA in September 2009. Because of postoperative liver and lung recurrence, 5 regimens with combinations of L-OHP/CPT-11 plus anti-VEGF antibody/anti-EGFR antibody was performed. Following these treatments, she underwent hepatic arterial infusion therapy with UFT/Krestin for progressive liver metastases. Starting in November 2014, regorafenib was administered, with an immediate decrease in tumor marker levels; tumor reduction demonstrated enhanced effect against liver metastases. After 8 months of administration, we stopped regorafenib and changed to TAS-102 due to diarrhea and eating disorders. However, TAS-102 was not effective; there were significant increases in tumor markers, liver function tests, and tumor size on computed tomography, and worsening of abdominal pain. After re-administration of regorafenib, a rapid decrease in tumor marker levels and improvement of liver dysfunction and abdominal pain were observed. Re-administration continued for 8 months until best supportive care was instituted. In cases with observed therapeutic effect of regorafenib, long-term or re-administration is possible, with extension of the prognosis depending on the adjustment, and without size reduction of metastatic tumors.

[A Case of Pseudomyxoma Peritonei Derived from Cecum Colon Cancer with Long-Term Recurrence-Free Survival].

A 29-year-old woman was diagnosed with advanced cecum colon cancer, and right hemicolectomy was performed. The pathological findings showed stage Ⅲa disease, including moderately differentiated tubular adenocarcinoma>mucinous adenocarcinoma, pT3, pN1, cM0, and Cur A resection. The patient was treated with 5-FU plus l-LV adjuvant chemotherapy. Fourteen months after surgery, bilateral ovarian metastasis and ascites were found, and another surgery was performed, revealing that the abdominal cavity was filled with a gelatinous ascites. Under the diagnosis of pseudomyxoma peritonei, resection of both ovaries, abdominal lavage, and intraperitoneal administration of CDDP were performed, followed by S-1 plus CDDP treatment. Two years after the recurrence, peritoneal re-recurrence on the vaginal fornix was detected. A total hysterectomy, partial vaginectomy, and resection of disseminated peritoneal nodules were performed. The patient received mFOLFOX6 treatment postoperatively. To date, 8 years and 9 months after her re-recurrence, the patient is alive and without signs of a third recurrence.

Robot-assisted distal gastrectomy and local resection for gastric cancer and gastrointestinal stromal tumor.

Gastrointestinal stromal tumors surrounding the esophagogastric junction are often challenging to resect, with no consensus regarding the optimal surgical technique. Here in, we present a case of concurrent gastric cancer in the antrum and gastrointestinal stromal tumors adjacent to the esophagogastric junction. The patient underwent simultaneous distal gastrectomy and local resection assisted by a surgical robot, avoiding the need for total gastrectomy. The utilization of robot-assisted surgery has become an increasingly popular technique, holding promise for simplifying complex surgical procedures across diverse medical settings.

[Prognostic factors affecting the surgical treatment of metastatic lung tumor from colorectal cancer].

For aging, people having malignant disease are increasing. And surgical resection is an important part in the treatment of pulmonary metastasis from colorectal cancer. We analyzed the treatment outcome and prognostic factors affecting survival in our subset of patients. We have experienced 64 operations of metastatic lung tumors from colorectal cancer for 23 years since January 1988. Various factors affecting prognosis are studied based on 5-year survival in this report. Overall 5-year survival rate was 38.7%. The disease-free intervals more than 2 years, a solitary metastatic pulmonary lesion and the serum level of prethoracotomy carcinoembryonic antigen (CEA) were significantly affecting factors on the prognosis. Furthermore, sequential study for 23 years couldn't demonstrate the prognostic improvement by the advance of the thoracoscopic technology or the development of the new anti-cancer drugs, though the treatment of patients with pulmonary metastases from colorectal cancer continues to evolve. The role of pulmonary metastasectomy is very important to reduce the volume of metastatic lesions for the better prognosis.

Hyaline-vascular type unicentric Castleman disease with dysplastic follicular dendritic cell proliferative lesions: a case report.

Castleman disease (CD) is a rare lymphoproliferative disease. Hyaline-vascular type unicentric CD has a good prognosis if completely resected during surgery. However, follicular dendritic cell proliferative lesions have the potential for recurrence and metastasis. A 22-year-old man was referred to our hospital with the chief complaint of nausea and vomiting. These symptoms were caused by a right mesocolonic tumor pushing the duodenum. The patient underwent laparoscopic tumorectomy and complete surgical excision. The postoperative course was uneventful, with no complications. Pathological examination confirmed that the tumor was an enlarged lymph node, typical of hyaline vascular-type CD; however, follicular dendritic cell proliferative lesions were noted. We report a rare case of hyaline-vascular-type CD with follicular dendritic cell proliferative lesions associated with malignancy, as limited case reports exist on this particular disease.

Prognostic factors to predict the survival in patients with advanced gastric cancer who receive later-line nivolumab monotherapy-The Asahikawa Gastric Cancer Cohort Study (AGCC).

BACKGROUND: Chemotherapy for advanced gastric cancer is recommended in the guidelines; however, later-line treatment remains controversial. Since immune checkpoint inhibitors have been used for the treatment of various malignancies, trials have been performed for gastric cancer. A phase 3 trial indicated the survival benefit of nivolumab monotherapy for gastric cancer patients treated with prior chemotherapy regimens. PATIENTS AND METHODS: A regional cohort study was undertaken to determine the real-world data of nivolumab treatment for patients with advanced or recurrent gastric cancer. The patients were enrolled for 2 years from October 2017 to October 2019 and were prospectively followed for 1 year to examine the overall survival (OS). The patient characteristics were analyzed in a multivariate analysis and a nomogram to predict the probability of survival was generated. RESULTS: In total, 70 patients who received nivolumab as ≥third-line chemotherapy were included in the Asahikawa Gastric Cancer Cohort. The median OS was 7.5 (95% CI, 4.8-10.2) months and the response rate was 18.6%. Diffuse type classification, bone metastasis, high neutrophil/lymphocyte ratio, and high CRP were associated with poor OS/prognosis in the multivariate analysis. A nomogram was developed based on these clinical parameters and the concordance index was 0.80 (95% CI, 0.68-0.91). The responders were aged and were frequently diagnosed with intestinal type gastric cancer, including patients with a HER2-positive status (27.3%) or microsatellite instability-high (27.3%) status. CONCLUSIONS: The regional cohort study of nivolumab monotherapy for gastric cancer patients revealed prognostic factors and a nomogram was developed that could predict the probability of survival.

[Two cases of neuroendocrine carcinoma of the rectum].

We report two cases of neuroendocrine carcinoma of the rectum. CASE 1: A 50s woman was diagnosed as rectal cancer and underwent anterior resection of the rectum and lymphnode dissection. The histological diagnosis was neuroendocrine carcinoma with peritoneal dissemination. She was treated with chemotherapy as an outpatient. One year later from the operation, multiple liver metastases were revealed and she died eight months later. CASE 2: A 50s man underwent endoscopic mucosal resection (EMR) of the rectum as rectal tumor and histological diagnosis was an early well-moderate deferenciated carcinoma and its cut-tend was unclear. He received a careful follow-up. One year later, a follow-up colonoscopy revealed a submucosal tumor in the lower rectum. He was diagnosised with local reccurence of rectal cancer, and then underwent an abdominoperineal resection of the rectum and lymphnode dissection. The histological diagnosis was poorly differenciated neuroendocrine carcinoma with lymphnode metastasis. Two months later from the operation, a local reccurence was revealed and he was treated with octreotide and irradiation.

[A case of AFP-producing gastric cancer patient with liver relapse occurred three months after endoscopic mucosal resection (EMR) and gastrectomy].

A 60s male was admitted to our hospital for a diagnosis of gastric tumor sized 20 mm in diameter at the fornix of the stomach. Endoscopic mucosal resection (EMR) was performed, and the resected tumor was pap, m, ly0, v0, HMX, VM0, pathologically. One month after the EMR, the local recurrence was confirmed and a partial gastrectomy was performed. Pathological findings were tub1, sm2, ly1, v1, HM0, VM0. Total gastrectomy was added because of the possibility of the lymph node metastasis. Pathological findings revealed no residual cancers. The final pathological diagnosis was T1b(sm2) N0H0P0M0, Stage IA, based on the Japanese classification of gastric cancer. Three months thereafter, CT showed multiple liver metastases. Immunohistochemical study of the operated tumor revealed AFP-producing gastric cancer. Chemotherapy was performed, but he died of the gastric cancer. Endoscopic treatment is a minimally invasive therapeutic strategy, but it requires a considerable care in application.

The impact of neoadjuvant systemic therapy on breast conservation rates in patients with HER2-positive breast cancer: Surgical results from a phase II randomized controlled trial.

BACKGROUND: Neoadjuvant systemic therapy (NST) induces tumor shrinkage and boosts the chance of breast-conserving thearpy (BCT) in patients with breast cancer. However, only a few trials have evaluated the effect of NST in conversion from BCT ineligibility to BCT eligibility in HER2-positive breast cancer. METHODS: We conducted the surgical sub-study of a phase II randomized trial, which compared standard neoadjuvant treatment or an experimental treatment modified according to the interim Ki-67 evaluation in women with stage II or III HER2-positive breast cancer. The treating surgeons assessed eligibility for BCT before and after NST. We evaluated the change in BCT eligibility following NST. We also analyzed the type of surgery performed and the success rate of BCT. RESULTS: Two hundred six patients were included in this study. Of these, 44.0% were considered BCT candidates at baseline, while 69.8% were deemed eligible for BCT after NST (P < 0.001). Among non-BCT candidates at baseline, 46% successfully converted to BCT candidates. Of 139 patients deemed eligible for BCT following NST, 84.2% attempted BCT, and successful BCT, defined as tumor-free at all surgical margins, was achieved in 96.8% of patients. Different treatment arms did not affect the rate of post-NST BCT eligibility (70.0% vs 69.7%). CONCLUSIONS: This study demonstrated that NST resulted in an absolute increase of 25.8% in the rate of BCT eligibility in HER2-positive breast cancer. About a half of non-BCT candidates converted to BCT candidates. BCT was successful in most patients who attempted BCT. There were still patients who chose mastectomy even though they were deemed eligible for BCT. Patients considered BCT-ineligible due to large tumor size most likely converted to BCT-eligible with NST. On the other hand, NST had less impact on the surgical indication of patients with multicentric disease or probable poor cosmetic outcome.

A Correlation Analysis Between Metabolism-related Genes and Treatment Response to S-1 as First-line Chemotherapy for Metastatic Breast Cancer: The SELECT BC-EURECA Study.

INTRODUCTION: The previous randomized phase 3 trial (SELECT BC) showed that S-1 as a first-line chemotherapy for metastatic breast cancer (MBC) is non-inferior to taxane with respect to overall survival. This study aimed to identify the usefulness of metabolism-related genes as predictive biomarkers for the response to S-1 compared with taxane using tumor tissue samples from the previous trial.   PATIENTS AND METHODS: In this SELECT BC-EURECA study, 147 patients with human epidermal growth factor 2 (HER2)-negative MBC who received either S-1 or taxane were evaluated. Formalin-fixed paraffin-embedded specimens were collected, and 14 genes involved in the pyrimidine metabolic pathway, estrogen receptor, progesterone receptor, HER2, Ki67, and beta-tubulin were measured using reverse transcription polymerase chain reaction in microdissected tumor specimens. The expression of each gene was categorized as low, intermediate, and high by tertile values.   RESULTS: Interaction tests to identify biomarkers for the response to S-1 compared with taxane, revealed the following as the top 3 biomarkers: RRM1 (P value = 0.24), GGH (P value = 0.25), and MTHFR (P value = 0.28). In the S-1 group, lower GGH and higher MTHFR expression were significantly correlated with better time to treatment failure. In the taxane group, there was no gene that was identified as a significant indicator of treatment failure. CONCLUSION: This biomarker analysis from SELECT BC did not identify any predictive biomarkers for the response to S-1 compared with taxane. Future studies with larger sample size and information on not only mRNA, but also protein and DNA for broad functional analyses are needed.

[Two cases of gastric endocrine cell carcinoma].

Gastric endocrine cell carcinoma is rare and associated with a poor prognosis. The first case was a man in his sixties with gastric endocrine cell carcinoma, of which a clinical finding was T2N1M0H1 (Stage IV). S-1 + CDDP therapy was selected and failed. CDDP+CPT-11 therapy was started and CT showed a partial response in ten months. But the tumor was re-grown and the patient died twenty months after diagnosis. The second case was a man in his seventies with gastric endocrine cell carcinoma, of which a clinical finding was T3N1M0H0P0, Stage IIIa, underwent total gastrectomy. Abdominal contrast-enhanced CT scan performed a month after the operation disclosed hepatic metastasis. After two months of S-1 regimen, CDDP + CPT-11 therapy was started.

[A case of metastasis to the stomach from primary adenocarcinoma of the lung cancer].

We report a case of gastric metastasis of lung cancer performed gastrectomy for the primary foci. A 70s woman was diagnosed as having right lung cancer and underwent right lower lobectomy and lymph node dissection. The histological diagnosis was adenocarcinoma (pT4, N2, M0). Four years later, positron emission tomography (PET)-CT revealed a tumor in the stomach and para-aortic lymph nodes swelling. The submucosal tumor was showed in the cardia by endoscopic examination. Biopsy showed a papillary adenocarcinoma. With the diagnosis of gastric metastasis from lung cancer, she was operated on. A proximal gastrectomy was carried out. The histopathological examination demonstrated papillary adenocarcinoma similar to that of the lung cancer with lymph node metastasis. No postoperative complications occurred and she was discharged from the hospital. Since then, she was treated with adjuvant chemotherapy as an outpatient.

[A case of long-term survival of unresectable-advanced gastric cancer due to chemotherapy].

The case was a 50s male with chief complaints of body weight loss and nausea. A clinical finding was Stage IV gastric cancer of poorly differentiated adenocarcinoma. We diagnosed it unresectable and started 5-FU+CDDP as the first-line chemotherapy. Partial response (PR) was observed and progression free time was 7 months. After 9 courses of 5-FU+ CDDP, the tumor grew and an oral intake was getting impossible. Gastro-jejunostomy was performed and then started a weekly PTX as the second-line chemotherapy after operation. The response was progressive disease (PD) after 4 courses of weekly PTX. Then we started S-1+CPT-11 as the third-line chemotherapy. We could continue S-1+CPT-11 for 9 courses without a severe adverse effect. Overall survival was 26.2 months.