Anastomosis technique for pancreatojejunostomy and early removal of drainage tubes may reduce postoperative pancreatic fistula.

BACKGROUND: Postoperative pancreatic fistula (POPF) is one of the most serious complications after pancreaticoduodenectomy (PD). Various factors have been reported as POPF risks, but the most serious of these is soft pancreas. To reduce POPF occurrences, many changes to the PD process have been proposed. This study evaluates short-term results of anastomosis technique for PD. METHODS: In total, 123 patients with soft pancreases who had undergone PD at Yamanashi University between January 2012 and August 2020 were retrospectively analyzed. We divided these patients into two groups depending on the time PD was performed: a conventional group (n = 67) and a modified group (n = 56). RESULTS: The rate of clinically relevant POPF was significantly lower in the modified group than that in the conventional group (5.4% vs 22.4%, p value < 0.001), with there being only one case of POPF in the modified group. There were no cases of POPF-related hemorrhaging in the modified group. On the third day after the operation, the amylase levels in the drainage fluid for the modified group became less than half (1696 vs 650 U/L). Multivariate analysis showed that the modified method was the independent predictors to prevent clinical POPF (p value = 0.002). CONCLUSIONS: Our novel anastomosis technique for pancreatojejunostomy reduced POPF in PD, especially in cases where the patient had a soft pancreas.

Stratification of Prognosis in Patients With Ampullary Carcinoma After Surgery by Preoperative Platelet-to-lymphocyte Ratio and Conventional Tumor Markers.

BACKGROUND/AIM: The platelet-to-lymphocyte ratio (PLR) has recently been suggested as a new predictor of the prognosis in several carcinoma types. However, the clinical impact remains controversial in patients with ampullary carcinoma. Thus, the aim of this study was to investigate other useful biomarkers for identifying poor prognosis in patients with ampullary carcinoma. PATIENTS AND METHODS: Forty-one patients with ampullary carcinoma underwent pancreaticoduodenectomy (PD) with curative resection between April 2000 and April 2017. Various clinicopathological findings of the patients and their tumors were evaluated as potential prognostic factors which might enable better stratification of prognosis. RESULTS: Platelet-to-lymphocyte ratio, as well as other markers, was found to be a prognostic factor in patients with ampullary carcinoma. The 2-year disease-free survival percentage was significantly higher in the group with low PLR than in the high PLR group (70.2% vs. 28.6%; p=0.005). Combinational analysis of the PLR and conventional TMs enabled us to stratify prognosis of the patients more clearly than by each marker alone. CONCLUSION: PLR was a useful prognostic factor for patients with ampullary cancer. The combination of preoperative PLR and conventional TMs markers may be powerful predictive factors for postoperative prognosis in patients with ampullary carcinoma following PD.

Use of a Reinforced Triple-row Stapler Following Distal Pancreatectomy Reduces the Incidence of Postoperative Pancreatic Fistula in Patients With a High BMI.

BACKGROUND/AIM: Although perioperative management and operative techniques for pancreatic surgery have improved, postoperative pancreatic fistula (POPF) remains the major cause of morbidity and mortality following distal pancreatectomy (DP). The purpose of this study was to evaluate the superiority of the reinforced stapler compared to the bare triple row stapler. PATIENTS AND METHODS: A total of 93 patients who underwent DP at the First Department of Surgery at Yamanashi University were examined. The patients were divided into two groups according to the closure method for the pancreatic stump; the bare triple-row stapler (BTRS) group and the reinforced triple-row stapler (RTRS) group. The postoperative outcomes were then compared in terms of several clinicopathological factors between the two groups. RESULTS: Seven patients were diagnosed with Grade B/C POPF in this series. The incidence of POPF in the RTRS group was lower than that in the BTRS group (3.6% vs. 13.5%), although there was no significant difference (p=0.077). Further detailed analysis demonstrated that RTRS significantly reduced POPF compared to BTRS in obese patients with a BMI >25.0 kg/m2 (p=0.038). CONCLUSION: Reinforced triple-row staplers may reduce the incidence of severe POPF, especially in obese patients with a BMI >25 kg/m2.

Feasibility of Combination Therapy with Nab-paclitaxel Plus Gemcitabine in Patients with Recurrent Pancreatic Cancer.

BACKGROUND/AIM: Nab-paclitaxel plus gemcitabine (nab-P+Gem) is one of most reliable and effective regimens for borderline or unresectable pancreatic cancer (PC). However, the feasibility and clinical benefits of this regimen have never been evaluated for patients with recurrent PC after pancreatectomy. The aim of this study was to investigate the feasibility of combination therapy with nab-paclitaxel plus gemcitabine (nab-P+Gem) for patients with recurrent PC. PATIENTS AND METHODS: Twenty-two patients with recurrent PC received an intravenous infusion of nab-P (125 mg/m2) and Gem (1,000 mg/m2) on days 1, 8, and 15 of a 4-week cycle. The primary end-point of this study was completion of the 4 cycles. The secondary end-points were the safety, efficacy, and disease control rate. RESULTS: The treatment completion rate of the 4 cycles was 90.9%. The objective response rate was 13.6% and the disease control rate was 63.6%. The median progression-free survival was 7.2 months. The most common grade 3 or higher hematological toxicity was neutropenia (72.7%). There was no treatment-related death. Furthermore, the chemotherapeutic effects varied with the time of recurrence. CONCLUSION: Combination nab-P+Gem therapy was well-tolerated and effective in patients with recurrent PC.

Successful laparoscopic partial gastrectomy and spleen-preserving distal pancreatectomy for gastric duplication cyst connecting with the pancreatic tail.

INTRODUCTION: Gastrointestinal duplication cyst is a congenital rare disease that may occur in any region from mouth to anus. Among them, gastric duplication cysts are very rare. CASE REPORT: Here we report A 23-year-old Japanese man who visited our hospital to evaluate an abdominal tumor. Abdominal computed tomography showed a well-circumscribed homogenous low-density mass measuring 6.2 × 6.0 cm between the pancreatic tail and the upper posterior wall on the gastric greater curvature, and the mass seemed to originate from the pancreatic tail. We found intraoperatively that the mass adhered to the stomach and pancreatic tail strongly, so we performed laparoscopic partial gastrectomy and spleen-preserving distal pancreatectomy. Pathological findings showed that the lining epithelium of the cystic mass consisted of the gastric foveolar epithelium with fundic glands. Furthermore, the pancreatic tissue of the pancreatic tail and the muscular layer of the cystic mass were intermingled. DISCUSSION: GDCs are usually diagnosed at a younger age and in adults, they are very rare. Therefore, surgical resection is considered to be the best treatment due to the difficulty of diagnosis, and also that it mimics a pancreatic cystic tumor, and malignant transformation. Complete resection of the cyst is the ideal technique and laparoscopic surgery should be selected whenever possible. CONCLUSION: We experienced a case of GDC continuous to both stomach and pancreatic tail. Laparoscopic surgery is safety and useful even if GDC is continuous with both the stomach and the pancreas.

Risk factors of postoperative pancreatic fistula after distal pancreatectomy using a triple-row stapler.

PURPOSE: Postoperative pancreatic fistula (POPF) is one of the major complications in patients who undergo distal pancreatectomy (DP). Recently, dividing the pancreas by stapler is a commonly performed technique, however, POPF still occurs. Therefore, the purpose of this study was to investigate the risk factors for POPF after DP using a triple-row stapler. METHODS: A total of 75 patients underwent DP using a triple-row stapler (Endo GIA™ Reloads with Tri-Staple™ Technology 60 mm; COVIDIEN, North Haven, CT, USA) at Yamanashi University from December 2012 to December 2016. The clinical risk factors for POPF after DP using a triple-row stapler were identified based on univariate and multivariate analyses. RESULTS: Clinical POPF (ISGPF Grade B and C) was seen in 7 of 75 patients (9.3%). The body mass index (BMI) was significantly higher in the patients with POPF (26.8 ± 0.5 kg/m2) compared with the patients without POPF (21.4 ± 0.4 kg/m2; a cut-off value; 25.7 kg/m2). In addition, the patients with POPF were significantly younger than the patients without POPF (56.4 ± 5.6 vs 67.0 ± 1.5; a cut-off value was 57.0 years old). CONCLUSIONS: BMI and age were found to be significant risk factors for POPF after DP using a triple-row stapler.

Pancreaticoduodenectomy for pancreas carcinoma occurring in the annular pancreas: report of a case.

The annular pancreas is a rare congenital anomaly in which a ring of the pancreas parenchyma surrounds the second part of the duodenum. Malignant tumors are extremely rare in patients with an annular pancreas. A 64-year-old man presented with appetite loss and vomiting. Abdominal contrast-enhanced computed tomography (CT) indicated pancreas parenchyma surrounding the second part of the duodenum, and a hypovascular area occupying lesion in the annular pancreas. Subtotal stomach-preserving pancreaticoduodenectomy was performed. Histopathology showed pancreatic carcinoma occurring in the complete annular pancreas.

Preoperative gadoxetic Acid-enhanced MRI and simultaneous treatment of early hepatocellular carcinoma prolonged recurrence-free survival of progressed hepatocellular carcinoma patients after hepatic resection.

Background/Purpose. The purpose of this study was to clarify whether preoperative gadoxetic acid-enhanced magnetic resonance imaging (EOB-MRI) and simultaneous treatment of suspected early hepatocellular carcinoma (eHCC) at the time of resection for progressed HCC affected patient prognosis following hepatic resection. Methods. A total of 147 consecutive patients who underwent their first curative hepatic resection for progressed HCC were enrolled. Of these, 77 patients underwent EOB-MRI (EOB-MRI (+)) before hepatic resection and the remaining 70 patients did not (EOB-MRI (-)). Suspected eHCCs detected by preoperative imaging were resected or ablated at the time of resection for progressed HCC. Results. The number of patients who underwent treatment for eHCCs was significantly higher in the EOB-MRI (+) than in the EOB-MRI (-) (17 versus 6; P = 0.04). Recurrence-free survival (1-, 3-, and 5-year; 81.4, 62.6, 48.7% versus 82.1, 41.5, 25.5%, resp., P < 0.01), but not overall survival (1-, 3-, and 5-year; 98.7, 90.7, 80.8% versus 97.0, 86.3, 72.4%, resp., P = 0.38), was significantly better in the EOB-MRI (+). Univariate and multivariate analyses showed that preoperative EOB-MRI was one of the independent factors significantly correlated with better recurrence-free survival. Conclusions. Preoperative EOB-MRI and simultaneous treatment of eHCC prolonged recurrence-free survival after hepatic resection.

Increased prevalence of tumor-infiltrating regulatory T cells is closely related to their lower sensitivity to H2O2-induced apoptosis in gastric and esophageal cancer.

PURPOSE AND EXPERIMENTAL DESIGN: Although an increase in regulatory T cells (Tregs) is observed in tumor microenvironments, the underlying mechanism is not fully clarified. Since it was suggested that Tregs showed a lower sensitivity toward oxidative stress in comparison with conventional T cells, in the present study, we investigated the H(2)O(2) production and apoptosis of Tregs in gastric and esophageal cancer tissues, employing flow cytometric analysis using fresh samples (n = 93) and immunohistochemical analysis (n = 203). RESULTS: The increased tumor-infiltrating Tregs coexisted with elevated H(2)O(2) production according to disease progression. The grade of apoptosis in Tregs was less pronounced than that in conventional T cells, and there was a positive correlation between H(2)O(2) production and the grade of apoptosis in conventional T cells, while there was no correlation between H(2)O(2) production and the grade of apoptosis in Tregs. Moreover, Tregs were less sensitive to H(2)O(2)-induced apoptosis compared with conventional T cells in vitro. CONCLUSIONS: We have demonstrated that the increased prevalence of tumor-infiltrating Tregs closely related to their lower sensitivity to H(2)O(2)-induced apoptosis.

Lapatinib acts on gastric cancer through both antiproliferative function and augmentation of trastuzumab-mediated antibody-dependent cellular cytotoxicity.

BACKGROUND: Trastuzumab has been recently approved for clinical use to treat HER2-expressing advanced gastric cancer, and anti-HER2-targeting therapy has become a promising option for gastric cancer. Lapatinib is a dual tyrosine kinase inhibitor targeting EGFR and HER2. The aim of the present study was to explore the utility of lapatinib for gastric cancer, with a particular focus on trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC). METHODS: Nine gastric cancer cell lines were evaluated for the effects of lapatinib on the cell-surface accumulation of HER2 and analyzed for their additional effects on trastuzumab-mediated ADCC. Also, HER2 signaling with Western blot, proliferative function with the MTT assay, and apoptosis-inducing activity with 7ADD/Annexin-V were investigated when a panel of gastric cancer cell lines was treated with lapatinib. RESULTS: Lapatinib inhibited HER2 signaling and cell proliferation in the panel of gastric cancer cell lines. Lapatinib also induced the accumulation of HER2 on the cell surface, resulting in the enhancement of trastuzumab-mediated ADCC of gastric cancer. CONCLUSIONS: Lapatinib exhibits inhibitory activity in gastric cancer cells, and the combination of lapatinib with trastuzumab may be a promising treatment strategy for gastric cancer patients.

Expression of MHC Class I on breast cancer cells correlates inversely with HER2 expression.

HER2 is a promising target for immunotherapeutic interventions with T cell-based approaches since it is amplified and overexpressed in 20-30% of breast cancers. However, several previous studies including ours showed that HER2-overexpressing tumors may escape cytotoxic T lymphocyte-mediated lysis by downregulating MHC Class I and components of the antigen-processing machinery. The aims of the present study were to analyze the relationship between HER2 and MHC Class I expression and to elucidate the mechanisms underlying MHC Class I downregulation in breast cancer. We explored expression of HER2, MHC Class I, PTEN, Ki67, estrogen and progesterone expression in 70 breast cancer patients by immunohistochemistry (IHC) and analyzed their correlation. We also explored the components of the signal transduction pathway that are involved in the regulation of MHC Class I expression using small-interfering RNAs targeting HER2 as well as an inhibitor of HER2 signaling. HER2 expression in breast cancers correlated inversely with MHC Class I expression analyzed by IHC. HER2 depletion by small-interfering RNAs resulted in MHC Class I upregulation. Moreover, MHC Class I expression on breast cancer cell lines was upregulated by PD98059, an inhibitor of mitogen-associated protein kinases, in a dose-dependent manner. Thus, agents that target the MAPK signaling pathway may increase MHC Class I expression in breast cancer cells.

Immunogenic tumor cell death induced by chemoradiotherapy in patients with esophageal squamous cell carcinoma.

Although it has been shown that chemoradiotherapy may induce immunogenic cell death, which could trigger T-cell immunity mediated by high-mobility group box 1 protein (HMGB1) and calreticulin, there is still limited information to support this theory directly in a clinical setting. In the present study, we evaluated antigen-specific T-cell responses against six cancer-testis antigens in peripheral blood lymphocytes from patients with esophageal squamous cell carcinoma (ESCC) receiving chemoradiation. Expression of HMGB1 and calreticulin within tumor microenvironment was also analyzed in resected samples with and without chemoradiotherapy in relation to patients survival. Tumor antigen-specific T-cell responses were confirmed in six (38%) of 16 patients with ESCC after chemoradiotherapy coexisting with elevated serum HMGB1. In addition, HMGB1 within tumor microenvironment was significantly upregulated in patients with ESCC with preoperative chemoradiotherapy, but not in those without chemoradiotherapy, and the degree of HMGB1 positively correlated with patient survival (n=88). Both irradiation and chemotherapeutic drugs induced upregulation of HMGB1 and calreticulin in nine ESCC cell lines. Furthermore, HMGB1 was able to induce maturation of dendritic cells. Together, our findings indicate that chemoradiation induces tumor antigen-specific T-cell responses, and HMGB1 production is related to clinical outcome after chemoradiation.

[The effect of immune-based therapy with cytotoxic T lymphocyte and molecular targeting therapy for HER2 in esophageal squamous cell carcinoma].

Although esophageal squamous cell carcinoma (ESCC) patients have recently been treated with the combined modality therapy, the prognosis remains poor. For the development of new strategies in ESCC, we examined possibilities of the immune -based therapy with cytotoxic T lymphocyte (CTL) and the molecular targeting therapy for HER2 against ESCC in this study. At first, we assessed HER2 and MHC class I expression by immunohistochemistry in ESCC patients and analyzed the correlation between them. Subsequently, the effect of molecular targeting therapy for HER2 was evaluated in a panel of ESCC cell lines. According to these results, we suggested that HER2 over-expressing ESCC patients (11.8%) are good candidates for the molecular targeting therapy for HER2 and HER2 negative/low-expressing ESCC patients (88.2%) for the immune-based therapy with CTL. Furthermore, the combination therapy of Herceptin and lapatinib is a new promising strategy for HER2 positive ESCC patients (29.4%).

Lapatinib enhances herceptin-mediated antibody-dependent cellular cytotoxicity by up-regulation of cell surface HER2 expression.

BACKGROUND: Although it was previously reported that lapatinib combined with Herceptin improved the progression-free survival rate compared with lapatinib alone for patients with Herceptin-refractory HER2-positive metastatic breast cancer, the mechanism is purported to be an antiproliferative effect relating to the synergism of these two agents. MATERIALS AND METHODS: We evaluated how lapatinib interacts with Herceptin in HER2-positive breast cancer, with a particular focus on Herceptin-mediated antibody-dependent cellular cytotoxicity (ADCC). RESULTS: In an in vitro assay, lapatinib induced HER2 expression at the cell surface of HER2-positive breast cancer cell lines, leading to the enhancement of Herceptin-mediated ADCC. Furthermore, we present a case report in which a second Herceptin treatment following lapatinib resulted in the marked shrinkage of multiple metastatic tumors in HER2-positive breast cancer. CONCLUSION: Lapatinib may have the potential to convert Herceptin-refractory to Herceptin-sensitive tumors in HER2-positive breast cancer by up-regulation of the cell surface expression of HER2.

H2O2 production within tumor microenvironment inversely correlated with infiltration of CD56(dim) NK cells in gastric and esophageal cancer: possible mechanisms of NK cell dysfunction.

Human NK cells can be divided into two subsets, CD56(dim)CD16(+)NK and CD56(bright)CD16(-)NK cells, based on their expression of CD56 and CD16. In the present study, we analyzed the relationship between CD56(dim)/CD56(bright) NK cells and H2O2 in tumor-infiltrating NK cells in patients with gastric (n = 50) and esophageal (n = 35) cancer. The ratio of CD56(dim) NK cells infiltrating tumors gradually decreased according to disease progression. H2O2 was abundantly produced within tumor microenvironments, and there was an inverse correlation between CD56(dim) NK cell infiltration and H2O2 production. CD56(dim) NK cells are more sensitive to apoptosis induced by physiological levels of H2O2 than CD56(bright) NK cells. Furthermore, the exposure of NK cells to H2O2 resulted in the impairment of ADCC activity. In conclusion, H2O2 produced within tumor microenvironments inversely correlated with the infiltration of CD56(dim) NK cells, possibly due to their preferentially induced cell death. These observations may explain one of the mechanisms behind NK cell dysfunction frequently observed in tumor microenvironments.

Immunonutritional diet modulates natural killer cell activation and Th17 cell distribution in patients with gastric and esophageal cancer.

OBJECTIVE: Although randomized clinical trials have shown that immunonutrition results in the improvement of postoperative complications, the detailed mechanisms of its immunomodulation are still unclear. In the present study, we investigated if such immunonutrition could affect T-cell and natural killer (NK) cell functions, with particular focus on type 17 helper T (Th17) cells and NK cell-activating markers, in patients with esophageal and gastric cancer and in healthy volunteers. METHODS: Patients (n = 22) and healthy volunteers (n = 10) were orally administered an immunonutritional diet (Impact, 750 mL/d) in addition to a conventional diet for 5 d. The expression of NK cell-activation markers (NKG2D, CD16, CD107a, NKp30, NKp44, and NKp46), frequency of CD56(dim) NK, Th17, and regulatory T cells, and trastuzumab-mediated antibody-dependent cell-mediated cytotoxicity were analyzed before and after immunonutrition. RESULTS: Immunonutrition significantly enhanced antibody-dependent cell-mediated cytotoxic activity as an NK cell function, paralleling the upregulated expression of NKG2D and CD16 and increased frequency of CD56(dim) NK cells. Furthermore, the immunonutrition significantly increased the frequency of Th17 cells. CONCLUSION: Immunonutrition modulates NK and T-cell-mediated immunity.

Lapatinib inhibits receptor phosphorylation and cell growth and enhances antibody-dependent cellular cytotoxicity of EGFR- and HER2-overexpressing esophageal cancer cell lines.

Lapatinib is a dual tyrosine kinase inhibitor of the EGFR and HER2 tyrosine kinase domains. EGFR is expressed in 33.3% and HER2 in 30.3% of esophageal squamous cell carcinomas (ESCCs). To explore the potential utility of Lapatinib for therapy of ESCC patients, we evaluated the effect of Lapatinib on a panel of ESCC cell lines. EGFR and HER2 expression by the cell lines was established, and the effects of Lapatinib on inhibition of the phosphorylation of HER2, antiproliferative effect, apoptosis-inducing activity and accumulation of HER2 and EGFR on cell surface were evaluated. Additionally, the combined effect of Lapatinib together with Herceptin or Cetuximab on cell-mediated cytotoxicity was evaluated. Lapatinib inhibited HER2 phosphorylation in HER2-overexpressing, HER2 gene amplification positive ESCC cell line. Lapatinib also inhibited cell proliferation, induced apoptosis and caused the surface accumulation of HER2 and EGFR in ESCC cell lines. Addition of Lapatinib increased Herceptin-mediated antibody-dependent cell-mediated cytotoxicity by 15-25% with three ESCC target cell lines. Similarly, Cetuximab-mediated antibody-dependent cell-mediated cytotoxicity also increased by 15-30% in two ESCC cell lines on addition of Lapatinib. Cumulatively, the data indicate that Lapatinib has activity in EGFR- and/or HER2-expressing ESCC cells, and the combination therapy of Lapatinib and Cetuximab/Herceptin is a promising strategy in ESCC.

Distribution of Th17 cells and FoxP3(+) regulatory T cells in tumor-infiltrating lymphocytes, tumor-draining lymph nodes and peripheral blood lymphocytes in patients with gastric cancer.

Although Th17 cells reportedly play critical roles in the development of autoimmunity and allergic reactions, information on Th17 cells in cancer-bearing hosts is still limited. In the present study, we investigated the distribution of Th17 cells in relation to regulatory T cells (Treg) in the tumor-infiltrating lymphocytes (TILs), regional lymph node lymphocytes, and peripheral blood lymphocytes of gastric cancer patients. Interleukin (IL)-17-producing CD4(+) cells as Th17 cells and CD4(+)CD25(+)FoxP3(+) cells as Treg were evaluated by flow cytometry and expressed as a percentage of the total CD4(+) cells, in addition to performing a Th1/Th2 balance assay. Moreover, immunohistochemical staining for IL-17 and FoxP3 were performed. In TILs from patients with early disease (n = 27), the frequency of Th17 cells was significantly higher than that in the normal gastric mucosa (23.7 ± 8.9 vs 4.5 ± 3.1%). In TILs from patients with advanced disease (n = 28), the frequency of Th17 cells was also significantly higher, but lower compared to early disease, than that in the normal gastric mucosa (15.1 ± 6.2 vs 4.0 ± 2.0%). This observation for Th17 cell-distribution was also confirmed by immunohistochemistry. When the ratio of Th17/Treg in TILs was evaluated in individual cases, it was more markedly increased in early than in advanced disease. In conclusion, the accumulation of Th17 cells as well as Treg in the tumor microenvironment of gastric cancer occurred in early disease and then the infiltration of Th17 cells gradually decreased according to the disease progression, in contrast to increased Treg.

Calcium metabolism and cardiovascular function after spaceflight.

To determine the influence of dietary calcium on spaceflight-induced alterations in calcium metabolism and blood pressure (BP), 9-wk-old spontaneously hypertensive rats, fed either high- (2%) or low-calcium (0.02%) diets, were flown on an 18-day shuttle flight. On landing, flight animals had increased ionized calcium (P < 0.001), elevated parathyroid hormone levels (P < 0.001), reduced calcitonin levels (P < 0.05), unchanged 1,25(OH)(2)D(3) levels, and elevated skull (P < 0.01) and reduced femur bone mineral density. Basal and thrombin-stimulated platelet free calcium (intracellular calcium concentration) were also reduced (P < 0.05). There was a tendency for indirect systolic BP to be reduced in conscious flight animals (P = 0.057). However, mean arterial pressure was elevated (P < 0.001) after anesthesia. Dietary calcium altered all aspects of calcium metabolism (P < 0.001), as well as BP (P < 0.001), but the only interaction with flight was a relatively greater increase in ionized calcium in flight animals fed low- compared with high-calcium diets (P < 0.05). The results indicate that 1) flight-induced disruptions of calcium metabolism are relatively impervious to dietary calcium in the short term, 2) increased ionized calcium did not normalize low-calcium-induced elevations of BP, and 3) parathyroid hormone was paradoxically increased in the high-calcium-fed flight animals after landing.

Dependence of the Reactivities of Titanium Enolates on How They Are Generated: Diastereoselective Coupling of Phenylacetic Acid Esters Using Titanium Tetrachloride.

Oxidative coupling of phenylacetic acid esters was easily achieved by treating the esters with TiCl(4) and then adding Et(3)N to the resulting solution. The products consisted of dl- and meso-2,3-diphenylsuccinic acid esters with the Claisen condensation product, and the ratio of these products depended on the reaction conditions. Reaction conditions suitable for high dl selectivity were determined, and a dimer of titanium enolate was postulated as an intermediate responsible for the high dl selectivity. The selectivities were compared with those in known oxidative couplings in which titanium enolate intermediates are prepared through lithium enolates and silyl enol ethers. The results suggest that the reactivities of titanium enolates intermediates depend on how they are generated.