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Introduction: Postoperative reflux esophagitis represents a major complication of laparoscopic distal gastrectomy (LDG) with Billroth-I reconstruction (LDGBI). This study aimed to evaluate the nutritional effect and preoperative risk factors of postoperative reflux esophagitis in patients undergoing LDGBI for gastric cancer., Methods: We retrospectively analyzed data of patients with (reflux [+]) and without (reflux [-]) postoperative reflux esophagitis who underwent LDGBI in our institution. Patient backgrounds, surgical outcomes, and perioperative nutritional status were compared. Preoperative risk factors for postoperative reflux esophagitis were also evaluated., Results: Between January 2009 and December 2016, 242 patients underwent LDG for gastric cancer. Of these, 218 underwent Billroth-I reconstruction. Seventy-three patients were excluded because of nutritional or oncological reasons. Finally, 23 patients were enrolled as the reflux (+) group and 122 as the reflux (-) group. Although the preoperative/postoperative bodyweight ratio and albumin and hemoglobin values plateaued beyond 6 months postoperatively in the reflux (-) group, these parameters continued to decrease beyond this time in the reflux (+) group. The mean ± SD bodyweight ratios at 3 years postoperatively were 82.83% ± 9.73% and 89.45% ± 8.04% for the reflux (+) and reflux (-) group, respectively (P = .0006). Multivariate analysis revealed that postoperative reflux esophagitis was associated with postoperative body weight loss. Another multivariate analysis revealed preoperative hiatal hernia as an independent predictive factor for postoperative reflux esophagitis., Conclusion: The risk of reflux esophagitis after LDGBI in patients with hiatal hernia should be considered when deciding therapeutic approaches for such patients., (© 2023 The Authors. Asian Journal of Endoscopic Surgery published by Asia Endosurgery Task Force and Japan Society of Endoscopic Surgery and John Wiley & Sons Australia, Ltd.)

Background/aim: Although peripheral neuropathy (PN) is a common adverse event in patients treated with oxaliplatin as first-line chemotherapy (1st-OX) for advanced gastric cancer, the effect of PN on the efficacy of paclitaxel at second-line chemotherapy (2nd-PTX) remains unclear. We investigated the association between PN induced by 1st-OX and efficacy of 2nd-PTX in patients with advanced gastric cancer (AGC)., Patients and Methods: The study subjects were patients with AGC who received 1st-OX followed by 2nd-PTX at Gifu University Hospital between January 2015 and December 2019. Primary outcome was time to treatment failure (TTF) of 2nd-PTX. Secondary outcomes included overall survival (OS), response rate and adverse events during the period of 2nd-PTX. The association between incidence of grade ≥2 peripheral neuropathy (G2PN) and TTF or OS was also evaluated using Cox proportional hazards analysis., Results: A total of 54 patients with AGC who received 1st-OX followed by 2nd-PTX were eligible. Incidence rates of G2PN at the start of 2nd-PTX was 20.3% (11/54). Median duration of TTF and OS were not significantly longer in patients with G2PN than in those without it (TTF: 4.7 months vs. 3.7 months, p=0.264, OS: 10.6 months vs. 8.5 months, p=0.706). Cox proportional hazards analysis indicated that there was no significant relationship between the incidence of G2PN and TTF, or between the incidence of G2PN and OS. However, development of grade ≥3 PN was significantly higher in patients with G2PN than in those without it (45.5% vs. 2.3%, p<0.001)., Conclusion: G2PN induced by 1st-OX may not affect efficacy of 2nd-PTX in patients with AGC but could be a risk for grade ≥3 PN of 2nd-PTX., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Gastric carcinosarcoma is most frequently diagnosed at an advanced stage when the tumor is generally large with invasion into other organs, lymph node metastasis, and distant metastasis. Standard chemotherapy has not been established, and surgery is the only curative treatment. Here, we present a case of postoperative recurrence of gastric carcinosarcoma under long-term tumor control with pazopanib., Case Presentation: A 77-year-old man was referred to our hospital because of nausea and vomiting. Computed tomography and upper gastrointestinal endoscopy revealed a type 1 tumor arising from the gastric antrum and extending into the duodenal bulb. He underwent distal gastrectomy (D2) with Roux-en-Y reconstruction. Histopathologically, the tumor had mixed adenocarcinoma and sarcoma components. According to the tumor-node-metastasis classification, the diagnosis was primary gastric carcinosarcoma pT1bN1M0 stage IB. Liver metastasis was detected 2 months after surgery; multiple lung metastases were detected 17 month after surgery. A genomic profiling test was performed using liver specimens as the patient became refractory to chemotherapy commonly used for gastric cancer, and the test revealed FGFR2 amplification along with TP53 R209*, AKT3 N127D, NOTCH1 A2036T, and POLD1 M161I. The patient was treated with pazopanib (800 mg/daily), and the tumor growth was controlled for 11 months., Conclusions: We report a case of postoperative recurrence of gastric carcinosarcoma under long-term tumor control with pazopanib. This case suggested that pazopanib may be effective in treating gastric carcinosarcoma., (© 2022. The Author(s).)

Background: In Japan, S-1 adjuvant chemotherapy for 1 year is the standard of care for the treatment of stage II and III patients under 80 years old with gastric cancer after curative operation. However, the feasibility of S-1 chemotherapy in patients over 80 years old has not yet been elucidated., Methods: To clarify the current treatment situation and feasibility of S-1 treatment in patients over 80 years old, a questionnaire survey of the patients treated from January 2011 to December 2012 was conducted at 58 member institutions of the Stomach Cancer Study Group of the JCOG (Japan Clinical Oncology Group)., Results: Gastrectomy was performed in 15,573 patients of all ages, and 1,660 (10.7%) patients were over 80 years of age. Of these elderly patients, 661 (4.2%) were diagnosed as stage II and III. While S-1 adjuvant chemotherapy was recommended to 248 (37.5%) of the stageII/III patients, only 99 (15.0%) of them actually received S-1. Interestingly, the creatinine clearance rate was between 30 and 80 mL/min in 87 (87.9%) of the patients suggesting that S-1 dose modification should be considered. Moreover, S-1 compliance was poor in patients with more than 15% body weight loss., Conclusion: In general practice, surgery alone can be regarded as the standard of care for stage II and III gastric cancer patients over 80 years old. The feasibility and efficacy of S-1 adjuvant chemotherapy should be elucidated in a randomized control trial considering the vulnerabilities of the elderly.

From January 2016 through December 2017, 18 patients received paclitaxel plus ramucirumab combination therapy and 1 patient received ramucirumab monotherapy. Thus, a total of 19 patients were analyzed in terms of both therapeutic effect and adverse events. The response evaluation of the targeted lesion was as follows; CR: 0, PR: 1, SD: 16, PD: 2. The median of overall survival and progression-free survival of the combination therapy was 9.9 months and 4.2 months, respectively. Although more than half of the patients were enforced after tertiary therapy in our department, the therapeutic effect of paclitaxel plus ramucirumab combination therapy was considerably satisfactory. Neutropenia as an adverse event was observed in 13(68.4%)out of 19 patients, and 8 patients(42.1%)had neutropenia greater than Grade 3. Non -hematologic toxicity was observed in 17 cases(89.5%), and anorexia, nausea, diarrhea, dysgeusia, peripheral neuropathy, hair loss, and fatigue were determined to be either Grade 1 or 2. Alternatively, 1 patient developed Grade 3 interstitial pneumonia, and 3 patients(15.8%)had complicated Grade 3 high blood pressure. Only 2 patients who had severe adverse events, one was interstitial pneumonia and the other was high blood pressure, discontinued paclitaxel plus ramucirumab combination therapy.

Background: Robotic surgery for gastric cancer has been adopted to overcome technical difficulties in performing laparoscopic gastrectomy. This study aimed to investigate the feasibility and safety of robotic gastrectomy in elderly gastric cancer patients., Methods: Patients who underwent laparoscopic or robotic gastrectomy from 2003 to 2010 in a single high-volume center were included in this study. We retrospectively compared preoperative characteristics, perioperative factors, and oncological parameters among an elderly (≥70 years old) robotic gastrectomy group (n = 49), a younger (<70 years old) robotic gastrectomy group (n = 321), and an elderly laparoscopic gastrectomy group (n = 132)., Results: The elderly robotic group presented with more comorbidities than the younger robotic group. Except for number of retrieved lymph nodes (36.5 vs. 41.5; P = 0.007), short-term operative outcomes including complications and pathological parameters were comparable between the two robotic groups. The elderly robotic group showed comparable disease-specific survival to the younger robotic group although overall survival was worse. Compared to their laparoscopic counterparts, the elderly robotic group showed longer mean operation time (227 vs. 174 min). Nevertheless, the incidence and severity of postoperative complications was not different between the two elderly groups. Overall and disease-specific survival were also comparable between the elderly groups. In multivariate analysis, age and surgical approach were not risk factors for overall and major complications., Conclusions: The outcomes of robotic gastrectomy in the elderly did not differ from those in younger robotic gastrectomy patients and were comparable to those in elderly patients who underwent laparoscopic gastrectomy. Thus, robotic gastrectomy could be a safe and feasible approach in elderly patients.

Background: 5-Fluorouracil (5-FU) has been a mainstay of chemotherapy for gastric cancer. Vandetanib is a tyrosine kinase inhibitor with inhibitory activity against vascular endothelial growth factor receptor and epidermal growth factor receptor (EGFR). We investigated the combination effect of vandetanib with 5-FU on gastric cancer cells., Materials and Methods: Anticancer efficacy was assessed by 3-(4,5-dimethyl-2-tetrazolyl)-2,5-diphenyl-2H tetrazolium bromide assay of five gastric cancer cell lines, MKN1, MKN7, MKN45, MKN74, and TMK1. Signal expression was examined by western blot, and the cell-cycle distribution was assessed by flow cytometry. In vivo anticancer activity of vandetanib with/without 5-FU was tested in MKN74 cells on nude mice., Results: Vandetanib inhibited the growth of all cell lines. In MKN7 and MKN74 cells, the combination of 5-FU and vandetanib had synergistic effects, but effects were only additional against the other cell lines in vitro. Combination chemotherapy in vivo also significantly inhibited tumor growth compared to single use of each drug. Flow cytometry showed vandetanib increased the proportion in the G 1 phase, and in MKN74, combination therapy increased the early S phase and caused bimodal peaks in the G 1 phase. The level of expression of cyclin D1 was clearly strong in MKN7 and MKN74 in the natural state, and the expression of cyclin D1, E2 promoter binding factor 1 and thymidylate synthase (TYMS) was inhibited by vandetanib, but not in MKN1 cells. The synergistic effect disappeared in MKN7 and MKN74 cells in vitro when cyclin D1 was knocked-down by siRNA., Conclusion: The synergistic effect of vandetanib with 5-FU is related to vandetanib-induced reduction of TYMS via down-regulation of cyclin D1. Hyperexpression of cyclin D1 might be a biomarker of the synergistic effect., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Objective: The prognoses of gastric cancer patients vary greatly among countries. Meanwhile, tumor-node-metastasis (TNM) staging system shows limited accuracy in predicting patient-specific survival for gastric cancer. The objective of this study was to create a simple, yet universally applicable survival prediction model for surgically treated gastric cancer patients., Summary Background Data: A prediction model of 5-year overall survival for surgically treated gastric cancer patients regardless of curability was developed using a test data set of 11,851 consecutive patients., Methods: The model's coefficients were selected based on univariate and multivariate analysis of patient, tumor, and surgical factors shown to significantly impact survival using a Cox proportional hazards model. For internal validation, discrimination was calculated with the concordance index (C-statistic) using the bootstrap method and calibration assessed. The model was externally validated using 4 data sets from 3 countries., Results: Our model's C-statistic (0.824) showed better discrimination power than current tumor-node-metastasis staging (0.788) (P < 0.0001). Bootstrap internal validation demonstrated that coefficients remained largely unchanged between iterations, with an average C-statistic of 0.822. The model calibration was accurate in predicting 5-year survival. In the external validation, C-statistics showed good discrimination (range: 0.798-0.868) in patient data sets from 4 participating institutions in 3 different countries., Conclusions: Utilizing clinically practical patient, tumor, and surgical information, we developed a universally applicable prediction model for accurately determining the 5-year overall survival of gastric cancer patients after gastrectomy. Our predictive model was also valid in patients who underwent noncurative resection or inadequate lymphadenectomy.

Conversion therapy for gastric cancer (GC) has been the subject of much recent attention. It is defined as a surgical treatment aiming at an R0 resection after chemotherapy for tumors that were originally unresectable or marginally resectable for technical and/or oncological reasons. However, the indications for resection remain to be clarified. In the present review, we focus on the biology and heterogeneous characteristics of stage IV GC and propose new categories of classification. Stage IV GC patients can be divided based on the absence (categories 1 and 2) or presence (categories 3 and 4) of macroscopically detectable peritoneal dissemination, which has a different biological outcome compared to hematological metastasis. Category 1 is defined oncologically as stage IV but the metastasis is technically resectable. Category 2 includes a marginally resectable metastasis or patients for whom the operation would not necessarily be the best choice. Category 3 includes a potentially unresectable metastasis of peritoneal dissemination that is only macroscopically detectable. Category 4 includes noncurable metastasis with peritoneal and other organ metastasis. The indications for conversion therapy might include the patients from category 2, some patients from category 3 and a very small number of patients from category 4. The longer survival can be expected for patients corresponding to categories 1, 2 and, to a lesser extent, 3, while the treatment of other patients focuses on "care." The provision of conversion therapy for stage IV GC patients might be one of the main roles of surgical oncologists in the near future.

Objective: Anemia after gastrectomy is commonly neglected by clinicians despite being an important and frequent long-term metabolic sequela. We hypothesized that the incidence and timing of the occurrence of iron deficiency after gastrectomy is closely associated with the extent of gastrectomy and the reconstruction method, and we investigated the treatment outcomes of iron supplementation to understand iron metabolism and determine the optimal reconstruction method after gastrectomy., Patients and Methods: Using a prospective gastric cancer database, we identified 381 patients with early gastric cancer with complete hematologic parameters who underwent gastrectomy between January 2004 and May 2008. Kaplan-Meier methods, Cox regression, and logistic regression were used to evaluate the associations of the extent of gastrectomy and reconstruction method with iron metabolism., Results: The prevalence of iron deficiency 3 years after gastrectomy was 69.1%, and iron-deficiency anemia was observed in 31.0% of patients. Iron deficiency developed in 64.8% and 90.5% of patients after distal gastrectomy and total gastrectomy within 3 years after surgery (P < 0.0001), respectively. Iron deficiency was significantly more frequent in women than in men (P < 0.0001) and after gastrojejunostomy than after gastroduodenostomy (P < 0.0001). Serum ferritin levels were different according to the extent of gastrectomy and reconstruction method. The proportion of patients treated for iron-deficiency anemia was also significantly different according to the extent of gastrectomy (P = 0.020)., Conclusions: Iron deficiency occurs in most patients with gastric cancer after gastrectomy, and its incidence was different according to the extent of gastrectomy and reconstruction method. To improve iron metabolism after distal gastrectomy, gastroduodenostomy would be the method of reconstruction whenever possible.

Background/aims: Although the feasibility of laparoscopic resection of gastric gastrointestinal stromal tumors (GISTs) has been established, various aspects are debated. This paper describes the problems of minimally invasive resection of gastric GISTs and compares this experience with an extensive literature review., Methodology: Between October 2003 and June 2012, 24 consecutive patients undergoing laparoscopic resection of gastric GISTs were enrolled in a prospective study. A comparison with authors' experience with laparoscopic wedge-segmental resection of GISTs was also carried out., Results: Twenty-four patients, mean age 64.0 +/- 11.2 years, were submitted to laparoscopic wedge-segmental gastric resections. Mean tumor size was 3.1 +/- 1.2 cm, mean operative time was 118.0 +/- 57.3 min, mean blood loss was 21.6 +/- 47.7 mL, and mean hospital stay was 7.1 +/- 1.9 days. There were no major operative complications or mortalities. All lesions had negative resection margins. Postoperative complications were detected in 2 patients. The rate of complication of grade 2 was 8.3%. At a mean follow-up of 23.9 months, all patients were disease-free. Morbidity, mortality, length of stay, and oncologic outcomes were comparable to experience with an extensive literature review. The stomach was divided into 3 areas (U, M, L area). When operation time and blood loss were examined, a significant difference was not indicated. However, both operation time and blood loss of M area tended to be low compared with U area. According to the mitotic index, 21 (87.5%) tumors were evaluated as low risk, 2 (7.3%) tumors as medium risk, and 1 (4.2%) tumor as high risk., Conclusions: Laparoscopic resection is safe and effective in treating gastric GISTs. Therefore, a minimally invasive approach should be the preferred surgical treatment in patients with small- and medium-sized gastric GISTs.

Background: Oxaliplatin is effective against many types of cancer, and the combination of 5-fluorouracil (5FU) and oxaliplatin is synergistically effective against gastric cancer, as well as colon cancer. The FANCJ protein is one of the Fanconi anemia (FA) gene products, and its interaction with the tumor suppressor BRCA1 is required for DNA double-strand break (DSB) repair. FANCJ also functions in interstrand crosslinks (ICLs) repair by linking to mismatch repair protein complex MLH1-PMS2 (MutLα). While oxaliplatin causes ICLs, 5FU is considered to cause DSBs. Therefore, we investigated the importance of FANCJ in the synergistic effects of oxaliplatin and 5FU in MKN45 gastric cancer cells and the derived 5FU-resistant cell line, MKN45/F2R., Methods: MKN1, TMK1, MKN45, and MKN45/F2R (5FU-resistant) gastric cancer cells were treated with 5FU and/or oxaliplatin. The signaling pathway was evaluated by a western blotting analysis and reverse transcription polymerase chain reaction (RT-PCR). Drug resistance was evaluated by the 3-(4,5-dimethyl-2-tetrazolyl)-2,5-diphenyl-2H tetrazolium bromide (MTT) assay., Results: In MKN45 cells, the combination of 5FU and oxaliplatin had synergistic effects. DSBs appeared when the cells were treated with 5FU. FANCJ was down-regulated, and BRCA1 was induced in a dose- and time-dependent manner. MKN45 cells showed increased sensitivity to oxaliplatin when FANCJ was knocked down by short interfering (si) RNA. However, these findings were not observed in MKN45/F2R 5FU-resistant cells., Conclusion: These results strongly suggest that the decrease in FANCJ caused by 5FU treatment leads to an increase in sensitivity to oxaliplatin, thus indicating that the FANCJ protein plays an important role in the synergism of the combination of 5FU and oxaliplatin.

Background: Indications for laparoscopic gastrectomy (LG) for early stomach cancer have spread worldwide and evaluation of short-term outcomes has been favorable. The present study aimed to evaluate both technical feasibility and safety of LG and short-and long-term outcomes after LG., Methods: The study group comprised 231 patients who underwent LG during the period from August 2001 through December 2011 at Gifu University School of Medicine., Results: Concomitant resection of other organs was performed in 16 (6.9 %) of the 231 patients, and conversion to open surgery was performed in 5 (2.2 %) patients. The final clinical stage of the patients, according to the Union for International Cancer Control classification, was stage IA in 183 (79.0 %), stage IB in 26 (11.3 %), stage IIA in 9 (2.6 %), stage IIB in 6 (2.6 %), stage IIIA in 5 (2.2 %), and stage IIIB in 2 (0.9 %) patients. Average values of total blood loss and operation time were 133.7 ± 129.0 ml and 328.1 ± 70.1 min, respectively. Postoperative complications were detected in 29 patients (12.6 %), and one patient died. According to the Clavien-Dindo classification of surgical complications, the rate of severe complications of grade ≥ 3a was 6.1 % and that of grade ≥ 3b was 1.3 %. There were no significant differences in complications in relation to clinicopathological or operative procedures. Cancer recurrence was detected in 2 (0.9 %) patients. In the patient with peritoneal dissemination, tumor size and macroscopic type were critical. Five-year overall survival rates were 99.3 % for stage IA, 95.2 % for stage IB, and 50.0 % for stage IIB patients. One recurrence each was detected for stages IA and IIB cancers., Conclusion: The present study showed LG to have a safe postoperative course and to benefit oncologic outcomes.

Aim: We here describe the clinical course of a 70-year-old male patient with Waldenström macroglobulinemia (WM) putatively transformed from refractory mucosa-associated lymphoid tissue lymphoma (MALTL)., Methods: Immunological staining was performed on formalin-fixed, paraffin-embedded tissue sections, and M-protein and cryoglobulin were identified by immunofixation electrophoresis and the cold precipitation method. Chromosome translocation was analyzed by the G-banded karyotype, and API2/MALT1 fusion gene underwent fluorescent in situ hybridization. Multiplex polymerase chain reaction was performed to analyze the VH-JH or DH-JH rearrangements of the IGH gene., Results: At diagnosis, the WM patient had monoclonal IgM with cryoglobulinemia and hyperviscosity syndrome. Eight years before developing WM, the patient experienced the onset of typical gastric MALT-L with H. pylori infection, but in spite of negative for chromosome translocation, t (11;18) and the successful eradication of H. pylori, the MALT-L relapsed repeatedly, and finally led to systemic metastasis. The lymphoma cells also infiltrated the large intestine and spleen. Immunoglobulin gene analyses of cellular clonality revealed that the same clone had been present in the stomach, bone marrow (BM) at the onset of MALT L, and in the BM at the diagnosis of WM., Conclusions: In this case, lymphoma developed as H. pylori-associated gastric MALT-L with negative for t (11;18), and might be transformed into MW during the systemic metastasis.

In the new era of technical development in surgery, operative devices, molecular targeting and chemotherapeutic agents, surgical oncologists have two main roles in the treatment of gastric cancer. One is to provide patients with minimally invasive surgery, including laparoscopy- or robot-assisted surgery in early gastric cancer patients, and the new concept of surgical intervention toward advanced and metastatic disease. Since recently, laparoscopy-assisted distal gastrectomy has become prevalent in Japan as a surgery which is minimally invasive for the patients and provides them with a good quality of life afterwards. However, the provision of advanced surgical techniques, including lymph node dissection and reconstruction, is more important for patient survival. The second role of surgical oncologists is to evaluate the significant values of the aggressive treatment which we term 'adjuvant surgery' for stage IV gastric cancer patients who have successfully responded to initial chemotherapy for curative intent. Stage IV gastric cancer patients are now being informed about the possibility of longer survival with the new chemotherapeutic and surgical strategic approach., (Copyright © 2011 S. Karger AG, Basel.)

Trefoil factor 2 (TFF2) is mucin associated peptide that has a mucosal barrier function in addition to participating in repair and healing. We examined the localization of TFF2 and gastric mucins in gastric mucous cells, the surface mucous gel layer (SMGL) adherent to normal gastric mucosa, and in the mucoid cap covering gastric erosions. Carnoy's solution, or formalin/picric acid-fixed paraffin embedded materials from resected stomachs and formalin-fixed paraffin embedded gastric biopsy materials were used. Sections were immunostained for the TFF2 and histochemically stained for gastric mucins. In addition, thick sectioned gastric mucosa fixed in Carnoy's solution were stained with FITC-labeled GSA-II lectin specific for gland mucous cell mucin and examined for three-dimensional images of the SMGL using a confocal laser scanning microscope. The TFF2 and gland mucous cell mucin were found intermixed together in the gastric gland mucous cells, in the SMGL in laminated layers, and in the mucoid cap. A laminated arrangement of continuous sheets of gland mucous cell mucin in the SMGL was demonstrated in the three-dimensional images. Co-localization of the TFF2 with gland mucous cell mucin suggests a physical interaction between the TFF2 and gland mucous cell mucin. The TFF2 trapped in the adherent mucins may be responsible for mucosal defense, healing, and repair.

We studied the expression pattern of Na, K-ATPase beta 1 subunit in human normal stomachs and in gastric adenocarcinomas by using anti-Na, K-ATPase beta 1 subunit-specific monoclonal antibody. Tissue samples were processed in formalin solution or in a cold acetic acid-ethanol solution, routinely processed, embedded in paraffin, and an immunoperoxidase method for Na, K-ATPase beta 1 subunit was performed. After antigen retrieval using a steamer in citrate buffer (pH 6.0), tissue sections initially fixed in cold acetic acid-ethanol showed intense immunoreactivity with the antibody at the lateral or basolateral cytoplasmic membrane of normal gastric epithelial cells, at the cytoplasmic membrane of gastric carcinoma cells according to the level of differentiation, and at the cytoplasmic membrane and in the cytoplasm of Schwann cells and neurons in the mesenteric plexus of the gastric wall. Acetic acid-ethanol and paraffin embedding is a useful method for the investigation of the immunohistochemical localization of Na, K-ATPase in normal and diseased tissues.