Impact of serum vitamin D on the response and prognosis in breast cancer patients treated with neoadjuvant chemotherapy.

BACKGROUND: Several studies have recently reported that the relationships between serum vitamin D and the prognosis or the pathological response to neoadjuvant chemotherapy (NAC) in breast cancer. However, there are no data regarding the clinical impacts of the vitamin D in Japanese breast cancer patients so far. PATIENTS AND METHODS: In the present study, a total of 250 patients with clinical Stage I-III primary breast cancer who were treated with NAC and subsequently underwent definitive surgery were included. Serum 25-hydroxvitamin D (25(OH)D) levels were evaluated using blood samples obtained before NAC. RESULTS: The serum 25(OH)D was positively associated with age, and the serum 25(OH)D was significantly higher in postmenopausal women than that in pre/peri-menopausal women. Serum 25(OH)D level was not associated with the achievement of pathological complete response (pCR) in this cohort. The low 25(OH)D levels were significantly associated with shorter time to distant recurrence (TTDR). According to the univariate analysis, high clinical stage before NAC (cStage III) and low serum 25(OH)D level were significantly associated with the shorter TTDR, and pCR was significantly associated with the longer TTDR. According to a multivariate analysis, low serum 25(OH)D level were independent poor prognostic factors for TTDR. CONCLUSIONS: The low 25(OH)D levels were significantly associated with poorer prognosis in Japanese women with operable breast cancer patients treated with NAC.

The clinical usefulness of the CTS5 in the prediction of late distant recurrence in postmenopausal women with estrogen receptor-positive early breast cancer.

BACKGROUND: Clinical Treatment Score post-5 years (CTS5) is a promising prognostic tool to evaluate late distant recurrence (DR) risk for breast cancer after 5-year adjuvant endocrine therapy. PATIENTS AND METHODS: Among 560 postmenopausal women with pathological stage I-III estrogen receptor-positive (ER+) primary breast cancer, 383 women who had received 5-year adjuvant endocrine therapy without any recurrence at 5 years after surgery were included in this study. The CTS5 was calculated for each patient using a previously published formula, and the patients were stratified by their CTS5 values into the low-, intermediate- and high-CTS5 risk groups. RESULTS: According to the CTS5, 205 (53.5%), 106 (27.7%) and 72 (18.8%) patients were classified into the low-, intermediate-, and high-CTS5 risk groups, respectively. A higher ER expression level was significantly associated with the low CTS5. The increased administration of adjuvant chemotherapy was significantly associated with a high CTS5. The occurrence of DR was higher in the intermediate and high CTS5 groups than in the low CTS5 group. The DRFS in the low CTS5 risk group was significantly better than that in the intermediate- or high-risk groups. In the ER-high or HER2-negative (HER2-) group, the DRFS in the low-risk group was significantly better than that of the intermediate- or high-risk groups. However, in the low-ER or HER2-positive group, there was no significant difference in DRFS among the three risk groups. CONCLUSIONS: In postmenopausal women with ER+ breast cancer, low CTS5 was considered to be associated with a very low risk of late DR. Thus, extended endocrine therapy may be unnecessary for patients with low CTS5 scores. Extended endocrine therapy should be offered for patients with intermediate or high CTS5 scores, especially those with high-ER and HER2- breast cancer.

PlexinA1 deficiency in BALB/cAJ mice leads to excessive self-grooming and reduced prepulse inhibition.

PlexinA1 (PlxnA1) is a transmembrane receptor for semaphorins, a large family of proteins that act as axonal guidance cues during nervous system development. However, there are limited studies on PlxnA1 function in neurobehavior. The present study examined if PlxnA1 deficiency leads to behavioral abnormalities in BALB/cAJ mice. PlxnA1 knockout (KO) mice were generated by homologous recombination and compared to wild type (WT) littermates on a comprehensive battery of behavioral tests, including open field assessment of spontaneous ambulation, state anxiety, and grooming, home cage grooming, the wire hang test of muscle strength, motor coordination on the rotarod task, working memory on the Y maze alternation task, cued and contextual fear conditioning, anxiety on the elevated plus maze, sociability to intruders, and sensory processing as measured by prepulse inhibition (PPI). Measures of motor performance, working memory, fear memory, and sociability did not differ significantly between genotypes, while PlxnA1 KO mice displayed excessive self-grooming, impaired PPI, and slightly lower anxiety. These results suggest a crucial role for PlxnA1 in the development and function of brain regions controlling self-grooming and sensory gating. PlxnA1 KO mice may be a valuable model to investigate the repetitive behaviors and information processing deficits characteristic of many neurodevelopmental and psychiatric disorders.

Efficacy of Adjuvant Combination Therapy With Trastuzumab and Chemotherapy in HER2-positive Early Breast Cancer: A Single Institutional Cohort Study from Clinical Practice.

BACKGROUND/AIM: To evaluate the improvement in the prognosis by adjuvant trastuzumab in clinical practice and the risk factors for distant recurrence, we retrospectively investigated the prognosis of HER2-positive early breast cancer in our department before and after the introduction of adjuvant trastuzumab. PATIENTS AND METHODS: Cohorts A and B included 161 and 182 cases, respectively, who underwent surgery before (2000-2007) and after (2008-2015) the introduction of adjuvant trastuzumab. RESULTS: The rates of relapse-free and distant metastasis-free survival were significantly better in cohort B than in cohort A. The risk factors of distant recurrence found in cohort A, such as the presence of lymph node metastasis, lymphatic invasion, and a low histological grade, did not increase the risk in cohort B. CONCLUSION: Many risk factors seemed to have been negated by adjuvant trastuzumab administration. Therefore, further escalation of adjuvant treatment should be carefully considered.

The comparison of the anatomic stage and pathological prognostic stage according to the AJCC 8th edition for the prognosis in Japanese breast cancer patients: data from a single institution.

BACKGROUND: The TNM system, which reflects the anatomical extent of disease, was used for stage definition. In the recently published AJCC 8th edition, the new staging system of the clinical and pathological prognostic stage, which incorporates biological factors, is introduced. PATIENTS AND METHODS: A total of 2622 patients with primary breast cancer at stage I-III were included in this study. The anatomic stage (aStage) and the pathological prognostic stage (ppStage) for each case were determined according to the definition of the AJCC 8th edition, and the influence of these stages on the prognosis was compared. RESULTS: The stage distributions of aStage and ppStage were as follows: aStage, stage IA (54.8%), IB (1.1%), IIA (26.1%), IIB (9.2%), IIIA (5.6%), IIIB (0.1%), and IIIC (3.1%); and ppStage, stage IA (66.6%), IB (13.1%), IIA (11.1%), IIB (3.2%), IIIA (3.3%), IIIB (1.4%), and IIIC (1.2%). Compared with the aStage, the ppStage stayed the same in 1710 patients (65.2%), was downstaged in 778 patients (29.7%), and was upstaged in 134 patients. The pathological tumor size (pT2) and lymph node metastasis (pN1) were associated with downstaging, and histological grade 3 was associated with upstaging. ER positivity, PgR positivity, and HER2-positivity were significantly associated with downstaging, and the TN subtype was associated with upstaging. Both the aStage and ppStage were significantly associated with the prognosis; however, the Kaplan-Meier curves for the relapse-free survival (RFS), distant recurrence-free survival (DRFS), and overall survival were better stratified by the ppStage. CONCLUSION: The ppStage reflects the prognosis of patients with early breast cancer more accurately than the aStage.

CD44v9 as a poor prognostic factor of triple-negative breast cancer treated with neoadjuvant chemotherapy.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is the standard therapeutic strategy for triple-negative breast cancer (TNBC). TNBC patients with residual disease after NAC have a significantly worse survival than those with pathological complete response (pCR); however, there is no apparent prognostic factor for non-pCR patients. Cancer stemness or epithelial-mesenchymal transition (EMT) might influence the sensitivity to chemotherapy. PATIENTS AND METHODS: Forty-eight patients with TNBC who were treated with NAC were available were included in this study. The expressions of stemness marker CD44v9, EMT marker vimentin and BRCA1, and basal phenotype were evaluated with immunohistochemistry. The relationships between the expression of these proteins and the pCR rate and the prognosis, especially in the patients with residual tumors, were investigated. RESULTS: Among the 48 patients, pCR was achieved in 14 cases. High nuclear grade and basal phenotype in the pre-NAC samples were significantly correlated with pCR (p = 0.0458 and 0.0343). There were no significant relationships between the pCR rate and the expression of CD44v9, vimentin, or BRCA1. Achieving pCR was significantly correlated with longer distant metastasis-free survival (DMFS) (p = 0.0206). High CD44v9 expression was significantly associated with shorter DMFS (p = 0.0291). Among the patients in whom pCR was not achieved, high grade in the residual tumor cells, poor pathological response and high CD44v9 expression in the pre-treatment CNB samples were significantly correlated with a poor DMFS (p = 0.0433, 0.0406 and p = 0.0333). In addition, high grade in the residual tumor cells was significantly associated with high CD44v9 expression in the pre-treatment CNB (p = 0.0389). CONCLUSIONS: High CD44v9 expression in pre-NAC samples was associated with poor prognosis in TNBC patients treated with NAC, especially for those in whom pCR was not achieved.

Impact of Visceral Metastasis on Efficacy of Fulvestrant in Patients with Hormone Receptor-positive Recurrent Breast Cancer.

BACKGROUND: Previous studies have suggested that the presence of visceral metastasis is a parameter useful in predicting the treatment efficacy of fulvestrant in patients with advanced breast cancer. PATIENTS AND METHODS: We retrospectively examined the association between treatment efficacy and presence of visceral metastasis in 75 patients with hormone receptor-positive recurrent breast cancer who were treated with fulvestrant or no more than five lines of other endocrine monotherapy after recurrence. RESULTS: Nineteen patients received fulvestrant, 10 of whom had visceral metastasis. The median time to progression was 4 months for the overall study population; it was significantly longer for patients with non-visceral metastasis (5.4 months; 95% confidence interval=3.7-11.2 months) than for those with visceral metastasis (3.3 months; 95% confidence interval, 0.4-5.3 months; p=0.01). No differences in time to progression were found between the groups of patients with visceral metastasis and non-visceral metastasis who underwent other endocrine therapies. CONCLUSION: Fulvestrant is more effective for patients with non-visceral metastasis of recurrent breast cancer with than for those with visceral metastasis.

One-step surgery for acute ischemia of the jejunal loop after pancreatoduodenectomy: report of a case.

BACKGROUND: Pancreatoduodenectomy (PD) is an extensive surgery, and its complications are grave. Acute ischemia of the jejunal loop due to thrombosis of the superior mesenteric vein (SMV) and its branches is one of the most dangerous complications that, although rare, if left untreated leads to abdominal sepsis and death of a patient. CASE PRESENTATION: A 77-year-old man underwent PD for pancreatic cancer. On postoperative day 2, the patient developed a severe anemia with hypotension. The computed tomography showed acute ischemia of the jejunal loop due to thrombosis. The emergent surgery was performed. The removal of the ischemic intestine and re-anastomoses of the biliary and pancreatic ducts could be performed all at once because necrosis and inflammation were still very mild in early stage. CONCLUSION: If suspicion for thrombosis of the SMV and its branches is raised, re-laparotomy should be considered. Early re-operation can lead to removal of the ischemic intestine and re-anastomoses in one-step surgery.

Risk factors for incisional hernia after hepatic resection for hepatocellular carcinoma in patients with liver cirrhosis.

BACKGROUND: The risk factors for incisional hernia (IH) and the association between liver fibrosis and IH after hepatic resection in patients with hepatocellular carcinoma (HCC) with liver cirrhosis (LC) are still unclear. We aimed to evaluate the rate of IH and to assess the effect of perioperative factors, including serum markers for liver fibrosis, on the risk of IH. METHODS: A total of 192 patients with HCC with LC who received hepatectomy were retrospectively analyzed. The primary end point was the incidence rate of IH and the secondary end points were associations between IH and 22 clinical factors. RESULTS: IH was diagnosed in 60 (31.3%) patients. The estimated incidence rates were 19.8% at 12 months, 32.5% at 36 months, and 38.8% at 60 months. In multivariable analysis, the presence of postoperative intractable ascites (odds ratio 24.83, P = .0003), abdominal wall closure by a single-layer mass closure with a continuous running suture (odds ratio 4.59, P = .0143), preoperative body mass index ≥ 25 kg/m(2) (odds ratio 3.36, P = .0025), and preoperative serum N-terminal pro-peptide of type IV collagen 7S domain (P4NP 7S) levels ≥ 5 ng/mL (odds ratio 3.13, P = .0234) were independent risk factors. CONCLUSION: There are several risk factors for IH after hepatic resection in HCC patients with LC. Preoperative serum P4NP 7S levels ≥ 5 ng/mL are a useful predictive marker, and abdominal wall closure with a continuous running suture by a single-layer mass closure should be avoided.

Nuclear expression of chemokine receptor CXCR4 indicates poorer prognosis in gastric cancer.

BACKGROUND: The CXCL12/CXCR4 axis plays a pivotal role in cancer progression and metastases in various epithelial cancer cells. The aim of the present study was to evaluate the localization and correlation between CXCL12/CXCR4 expression and clinicopathological features in gastric cancers. MATERIALS AND METHODS: This study included 111 Japanese patients with primary gastric cancers, which invade submucosa or more, all of whom underwent gastrectomy between 1992 and 1996. Immunohistochemical analysis was performed. RESULTS: A significant correlation was found in the immunoreactivity of nuclear CXCR4 and poor differentiation (p=0.0026), infiltrated pattern (p<0.0001), larger size (p<0.0001), advanced stage (p=0.0342) and reduced 5-year survival rate (30% vs. 61%, p=0.0012). Multivariate analysis revealed that high nuclear CXCR4 immunoreactivity (RR: 3.077, p=0.0329) retained its strength as an independent prognostic factor for overall survival. CONCLUSION: High immunoreactivity of nuclear CXCR4 in gastric cancer suggests that CXCL12 binds to its unique receptor CXCR4 at the membrane, translocates to the nucleus and then becomes more invasive, and thus can be considered a prognostic factor.

Indications for emergency surgery for perforated diverticulitis in elderly Japanese patients ≥80 years of age.

PURPOSE: Perforated diverticulitis (PD) remains a serious acute abdominal condition. The aim of this study was to evaluate indications for emergency surgery in patients ≥80 years of age with PD. METHOD: Twenty patients ≥80 years of age and 28 younger patients who underwent emergency surgery for PD from January 2002 to December 2011 were studied. The demographics and postoperative outcomes were compared. RESULTS: The preoperative characteristics, mortality rate, and postoperative complications were similar between these two groups. All seven patients ≥80 years of age with an American Society of Anesthesiologists (ASA) score of 2 survived after surgery. All five patients with a Mannheim peritonitis index (MPI) score of ≥26 in the elderly group died after surgery. There were significant associations between the mortality, the MPI and ASA score in patients ≥80 years of age. CONCLUSIONS: Best supportive care may be an alternative for patients ≥80 years of age with PD, an ASA score of ≥3 or an MPI score of ≥26.

Immobilization of magnesium ammonium phosphate crystals within microchannels for efficient ammonia removal.

Magnesium ammonium phosphate was formed in flow-through microchannels of silica monoliths using two different methods to fabricate materials that show efficient ammonia adsorption performance from wastewater with low hydraulic resistance. Magnesium ammonium phosphate crystals in these materials release ammonia when heated at 378 K, yielding primarily magnesium hydrogen phosphate. When this material was used for ammonia removal from an aqueous solution containing 100 ppm ammonia in a flow system, the material readily removed ammonia, decreasing the ammonia concentration to 25 ppm. The material can be reactivated by the same procedure and used again for ammonia removal. Hydrodynamic resistance through the lengths of the materials depend on the shape of the immobilized crystals, showing that needle-like crystals are more effective to cause less resistance than plate-like particles. The material containing needle-like crystals causes only approximately one-eighth of the hydraulic resistance that a packed column consisted of spherical particles with a typical bed porosity of 0.5 does. Thus, these results demonstrate the high applicability of the material for ammonia removal from wastewater in a continuous process.

Impact of perioperative peripheral blood values on postoperative complications after esophageal surgery.

PURPOSE: Prediction of the postoperative course of esophagectomy is an important part of the strict perioperative management of patients undergoing surgery for esophageal cancer. METHODS: To evaluate their clinical importance, peripheral blood values, including white blood cell count (WBC), lymphocyte count, and the levels of total protein, transferrin, factor XIII, D-dimer, fibrin, and fibrinogen degradation products (FDP) were measured before and after esophagectomy for esophageal cancer in 24 patients. RESULTS: The preoperative WBC and the pre- and postoperative lymphocyte count were decreased remarkably in patients who received preoperative chemoradiotherapy. The values of perioperative serum transferrin were significantly lower in patients with postoperative pneumonia than in those without. The activity of plasma factor XIII was suppressed on postoperative day (POD) 7 in patients with pneumonia and on POD 14 in patients with leakage. CONCLUSIONS: These results suggest that patients who receive preoperative chemoradiotherapy are potentially immunosuppressed, the preoperative serum transferrin level is a possible predictive marker of postoperative pneumonia, and suppression of factor XIII activity is related to anastomotic insufficiency.

[Two radically resected colorectal carcinoma cases with unresectable liver metastasis after adjuvant chemotherapy with bevacizumab].

Nowadays, the advancements of systemic chemotherapy for colorectal carcinoma improve a clinical response rate, and expand the possibility of resection which couldn't operable at the initial visit. In addition, the prognoses of the patients, who had a radical operation for metastasis, are clearly longer than the non-operable patients. Bevacizumab, anti-human VEGF monoclonal antibody, is significantly effective when used in combination with one of the systemic multi-agent chemotherapy such as FOLFOX regimen or FOLFIRI regimen. We report here two cases with colon carcinoma, which had initially unresectable liver metastases, were respond to the treatment of systemic multi-agent chemotherapy with bevacizumab. Then, both cases were able to undergo radical resections of primary tumor and liver metastases safely.

Chemosensitivity and survival in gastric cancer patients with microsatellite instability.

INTRODUCTION: Conflicting data exist regarding the relevance of high-frequency microsatellite instability (MSI-H) for predicting the prognosis and benefits of 5-fluorouracil (5-FU)-based chemotherapy. This study investigated the usefulness of MSI as either a prognostic indicator or predictor of distinct clinical attributes regarding the use of adjuvant chemotherapy with 5-FU and its analogues in gastric cancer. MATERIALS AND METHODS: Data and tumor specimens were collected from 240 gastric cancer patients from 1993 to 2002. Five microsatellite loci were analyzed using a high-intensity microsatellite analysis reported previously. A Cox proportional hazard model was used to compare the clinical data and survival as well as any associations between MSI and 5-FU treatment status of patients with MSI or microsatellite stability (MSS) gastric cancers. A 3-(4,5-dimethyl-2-thiazolyl) -2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was conducted in 168 cases to investigate chemosensitivity to 5-FU. RESULTS: This analysis identified 22 MSI-H (9.4%), 25 MSI-L (10.7%), and 193 MSS (79.9%) tumors. Gastric cancer with MSI-H tended to have increased likelihood to show higher age, antral location of the tumor, and lymph vessel involvement (P < 0.05). Univariate analyses failed to show any difference between the MSI-H and MSS/MSI-L groups with respect to overall survival. Furthermore, survival after the administration of 5-FU did not correlate with MSI status, and MSI was not associated with 5-FU sensitivity by MTT assay. CONCLUSION: The results of this study indicate that MSI status has no clear influence on overall survival or response to 5-FU in gastric cancer.

Preoperative chemoradiotherapy for esophageal cancer: factors associated with clinical response and postoperative complications.

BACKGROUND: The factors associated with the clinical results of preoperative chemoradiotherapy (CRT) for esophageal cancer and its effect on postoperative complications are still unclear. PATIENTS AND METHODS: The 686 patients with esophageal cancer were classified into 376 who received preoperative CRT (group I) and 310 who received surgery alone (group II). RESULTS: A multivariate analysis for group I patients revealed pathologically complete response to be a favorable prognostic factor. Preoperative use of cisplatin was significantly associated with pathological effect and patients' prognosis. Both pulmonary complications and anastomotic leakage more frequently developed in group I (16.0 and 27.9%) than in group II (10.0%, p<0.05 and 16.5%, p<0.01, respectively). A multivariate analysis revealed preoperative CRT to be an independent factor of postoperative complications. CONCLUSION: Although preoperative CRT for esophageal cancer may be associated with postoperative complications, a pathologically complete response, which is associated with a cisplatin-based regimen, is critical for improving patient prognosis.

Checkpoint with forkhead-associated and ring finger promoter hypermethylation correlates with microsatellite instability in gastric cancer.

AIM: To examine the methylation status of the promoter region of the checkpoint with forkhead-associated and ring finger (CHFR) and microsatellite mutator status in 59 primary gastric cancers. METHODS: We investigated the promoter methylation of CHFR in 59 cases of gastric cancer using methylation-specific PCR. Five microsatellite loci were analyzed using high-intensity microsatellite analysis reported previously, and p53 gene mutations were investigated by direct sequencing. RESULTS: Twenty cases (33.9%) showed promoter methylation and no relation was observed with the clinicopathological factors. We found that the promoter methylation of CHFR was frequently accompanied with microsatellite instability (MIN). Seven of 20 (35.0%) cases showed MIN in hypermethylation of the CHFR tumor, while three of 39 (7.7%) cases showed MIN in the non-methylated CHFR tumor (P < 0.01). However, we failed to find any relationship between CHFR methylation and p53 mutation status. CONCLUSION: The coordinated loss of both the mitotic check point function and mismatch repair system suggests the potential to overcome the cell cycle check point, which may lead to an accumulation of mutations. However, the p53 mutation was not related to hypermethylation of the CHFR promoter and MIN, which indicates that an abnormality in p53 occurs as an independent process from the mismatch repair deficiency in carcinogenesis.