[Double-tract reconstruction after gastrectomy for gastric cancer in patients with concomitant cardiovascular diseases]. / Rekonstruktsiya double-tract posle gastrektomii po povodu raka zheludka u patsientov s konkuriruyushchimi serdechno-sosudistymi zabolevaniyami.

OBJECTIVE: To demonstrate the capabilities and advantages of double-tract reconstruction after gastrectomy for gastric cancer and simultaneous approach in surgical treatment of patients with cardiovascular diseases and gastric cancer. MATERIAL AND METHODS: We present two cases of double-tract reconstruction after gastrectomy and the gastric stump extirpation as a part of simultaneous surgical approach to patients with gastric cancer and cardiovascular diseases. A 62-year-old patient underwent simultaneous gastrectomy with double-tract reconstruction (for the first time In Russia) and aortofemoral replacement. A 61-year-old patient underwent simultaneous coronary artery bypass surgery, gastric stump extirpation with esophagogastrostomy and double-tract reconstruction. RESULTS: In 1 case, postoperative period was complicated by subcompensated stenosis of the right ureter due to hematoma near the right common iliac artery. This event required endoscopic stenting of the right ureter with positive effect. Both patients were discharged in 16 and 23 days after surgery. CONCLUSION: This method may be alternative to modern reconstructions. Currently, digestive tract reconstruction after gastrectomy is still important and requires further study. Simultaneous procedures in patients with cancer and cardiovascular disease became more widespread. To objectify our statements, further research is needed.

Does gastric stump cancer really differ from primary proximal gastric cancer? A multicentre, propensity score matching-used, retrospective cohort study.

BACKGROUND: Although the location of proximal cancer of the remnant stomach is the same as that of primary proximal cancer of the stomach, its clinical characteristics and prognosis are still controversial. AIM: To evaluate the clinicopathological features and prognosis factors of gastric stump cancer (GSC) and primary proximal gastric cancer (PGC). METHODS: From January, 2005 to December, 2016, 178 patients with GSC and 957 cases with PGC who received surgical treatment were enrolled. Patients in both groups underwent 1:1 propensity score matching analysis, and both clinical and pathological data were systematically collected for statistical purposes. Quality of life was evaluated by the C30 and STO22 scale between GSC-malignant (GSC following gastric cancer) and GSC-benign (GSC following benign lesions of the stomach). RESULTS: One hundred and fifty-two pairs were successfully matched after propensity score matching analysis. Of the 15 demographic and pathological variables collected, the analysis further revealed that the number of lymph nodes and positive lymph nodes were different prognostic and clinicopathological factors between PGC and GSC. Univariate and multivariate analyses showed that gender, differentiation degree and tumor-node-metastasis stage were independent risk factors for patients with GSC. Gender, vascular invasion, differentiation degree, depth of infiltration, positive lymph nodes, and tumor-node-metastasis stage were independent risk factors for patients with PGC. The 5-year overall survival and cancer-specific survival of patients with GSC were significantly lower than those in the PGC group, the scores for overall quality of life in the GSC-malignant group were lower than the GSC-benign, and the differences were statistically significant. CONCLUSION: The differences in clinicopathological characteristics between GSC and PGC were clarified, and PGC had a better prognosis than GSC.

Clinicopathological Predisposing Factors for Gastric Stump Cancer and Its Management: A Single-Center Analytical Study.

Background The incidence of gastric stump carcinoma (GSC) is not declining because of the long latency period. The survival rate of treated gastric cancer patients has increased due to early detection and improvements in surgical techniques and chemotherapy. Increased survival rates and improved surveillance following gastric surgery have increased the incidence of GSC. Aim The study aims to investigate the clinicopathological factors affecting the interval between index gastric surgery and the occurrence of GSC, and our experience in the management of GSC is presented. Methods A retrospective review of patients diagnosed with GSC in our institution was completed. Patient characteristics and clinicopathological outcomes were analyzed. Results A total of 28 patients were included in this cohort with 17 (60.71%) males and 11 (39.28%) females. The mean interval from index surgery to the incidence of GSC was 24.42 years for benign etiology and six years for malignant etiology. Index surgeries were truncal vagotomy with 14 gastrojejunostomies (50%) and 14 subtotal gastrectomies (50%). The interval between index surgery and the incidence of GSC is not statistically significant concerning the type of surgery (p: 0.661), pathological TNM (tumor, nodes, metastases) stage (p: 0.520), pathological differentiation (p: 0.828), lymphovascular invasion (p: 0.252), perineural invasion (p: 0.672), and adjuvant therapy (p: -0.655). Survival was significantly higher in those patients who received curative resection in comparison to a palliative procedure (p: 0.041). Conclusion Strict surveillance for at least 10 years after initial gastric surgery is of utmost importance as half of the patients fated to develop GSC will do so within this time. In those patients with early diagnosis, no evidence of metastasis, and good performance status, curative surgery is feasible with acceptable morbidity.

Laparoscopic gastrectomy for remnant gastric cancer: A single-center retrospective study.

BACKGROUND: Laparoscopic gastrectomy (LG) for remnant gastric cancer (RGC) remains controversial because of its rarity and heterogeneity of clinical characteristics. Based on our experience, we posited that our established methodology in LG could be applied to the laparoscopic procedure for RGC surgery and introduced LG for RGC at our institution in 2004. METHODS: This study enrolled 46 patients who underwent LG for RGC between January 2004 and December 2017. Data were obtained through a review of our prospectively maintained database. Laparoscopic total gastrectomy (LTG) was the standard surgical procedure for RGC. Laparoscopic subtotal gastrectomy (LsTG) was performed as an alternative procedure for patients with RGC located near the anastomotic site after primary gastrectomy. The technical and oncological feasibility and safety of LG for RGC were evaluated. RESULTS: LTG for RGC was performed on 36 patients. LsTG for RGC was performed on 10 patients. All patients completed LG procedure and succeeded R0 resection. Complications of Clavien-Dindo classification grade ≥ IIIa occurred in 4 (8.7%) patients. The retrospective video reviews showed that the time for adhesiotomy around the suprapancreatic area and the lesser curvature of the remnant stomach was significantly shorter in the primary-benign group than in the primary-malignant group. With the median follow-up period of 40 months, the 3-year recurrence-free survival and 3-year overall survival rates were 72.3% and 80.2%, respectively. CONCLUSION: LG for RGC represents a safe and feasible surgical option with favorable short-term and long-term outcomes in patients with RGC.

Appraisal of gastric stump carcinoma and current state of affairs.

Gastric stump carcinoma, also known as remnant gastric carcinoma, is a malignancy arising in the remnant stomach following gastrectomy for a benign or malignant condition. Enterogastric reflux and preexisting risk factors in a patient with gastric cancer are the major contributors to the development of gastric stump carcinoma. The occurrence of gastric stump carcinoma is time-dependent and seen earlier in patients operated on for malignant rather than benign diseases. The tumor location is predominantly at the anastomotic site towards the stomach. However, it can occur anywhere in the remnant stomach. The pattern of lymph node involvement and the type of surgery required is distinctly different compared to primary gastric cancer. Gastric stump carcinoma is traditionally considered a malignancy with a dismal outcome. However, recent advances in diagnostic and therapeutic strategies have improved outcomes. Recent advances in molecular profiling of gastric stump carcinoma have identified distinct molecular subtypes, thereby providing novel therapeutic targets. Also, reports of gastric stump carcinoma following pancreatoduodenectomy and bariatric surgery highlight the need for more research to standardize the diagnosis, staging, and treatment of these tumors. The present review aims to provide an overview of gastric stump carcinoma highlighting the differences in clinicopathological profile and management compared to primary gastric carcinoma.

A rare complication of laparoscopic Roux-en-Y gastric bypass: case report of gastric remnant necrosis.

Gastric remnant necrosis is a very rare, but potential life-threatening complication after laparoscopic Roux-en-Y gastric bypass (LRYGB). We report a case of gastric remnant necrosis that was complicated by peritonitis and resulted in septic shock in a 49-year-old woman who had undergone a LRYGB three months prior to admission. An emergent laparoscopy with subtotal gastrectomy was performed. The patient was treated for septic shock and could leave the hospital in a good condition. Potential etiological factors for gastric remnant necrosis were elaborated.

Postoperative Complications and Their Risk Factors of Completion Total Gastrectomy for Remnant Gastric Cancer Following an Initial Gastrectomy for Cancer.

PURPOSE: Completion total gastrectomy (CTG) for remnant gastric cancer (RGC) is a technically demanding procedure and associated with increased morbidity. The present study aimed to evaluate postoperative complications and their risk factors following surgery for RGC after initial partial gastrectomy due to gastric cancer excluding peptic ulcer. MATERIALS AND METHODS: We retrospectively reviewed the data of 107 patients who had previously undergone an initial gastric cancer surgery and subsequently underwent CTG for RGC between March 2002 and December 2020. The postoperative complications were graded using the Clavien-Dindo classification. Logistic regression analyses were used to determine the risk factors for complications. RESULTS: Postoperative complications occurred in 34.6% (37/107) of the patients. Intra-abdominal abscess was the most common complication. The significant risk factors for overall complications were multi-visceral resections, longer operation time, and high estimated blood loss in the univariate analysis. The independent risk factors were multi-visceral resection (odds ratio [OR], 2.832; 95% confidence interval [CI], 1.094-7.333; P=0.032) and longer operation time (OR, 1.005; 95% CI, 1.001-1.011; P=0.036) in the multivariate analysis. Previous reconstruction type, minimally invasive approach, and current stage were not associated with the overall complications. CONCLUSIONS: Multi-visceral resection and long operation time were significant risk factors for the occurrence of complications following CTG rather than the RGC stage or surgical approach. When multi-visceral resection is required, a more meticulous surgical procedure is warranted to improve the postoperative complications during CTG for RGC after an initial gastric cancer surgery.

Role of New Anatomy, Biliopancreatic Reflux, and Helicobacter Pylori Status in Postgastrectomy Stump Cancer.

Distal gastrectomy for benign gastroduodenal peptic disease has become rare, but it still represents a widely adopted procedure for advanced and, in some countries, even for early distal gastric cancer. Survival rates following surgery for gastric malignancy are constantly improving, hence the residual mucosa of the gastric stump is exposed for a prolonged period to biliopancreatic reflux and, possibly, to Helicobacter pylori (HP) infection. Biliopancreatic reflux and HP infection are considered responsible for gastritis and metachronous carcinoma in the gastric stump after oncologic surgery. For gastrectomy patients, in addition to eradication treatment for cases that are already HP positive, endoscopic surveillance should also be recommended, for prompt surveillance and detection in the residual mucosa of any metaplastic-atrophic-dysplastic features following surgery.

Accuracy of preoperative staging of gastric stump cancer.

BACKGROUND: In this study, the accuracy of preoperative staging for gastric stump cancer, which has not been thoroughly investigated since the condition is rare, was investigated using computed tomography and gastroscopic imaging. METHODS: Between February 1994 and April 2018, 49 patients with gastric stump cancer, following subtotal or total gastrectomy, were reviewed retrospectively. Preoperative diagnoses of clinical T and clinical N categories were compared with post-operative pathological diagnoses (pT and pN categories). Positive predictive values, accuracy, sensitivity and specificity were also evaluated. RESULTS: The overall accuracy of T staging was 40.8%. The positive predictive value for cT3/T4 was 96.3%, whereas the positive predictive value for cT1/T2 was 72.7%. The overall accuracy for N staging was 61.2%. The positive predictive value of lymph node positive patients was 73.3%. The positive predictive value and sensitivity of over stage II were 96.6% and 84.8%, respectively. CONCLUSIONS: The accuracy of preoperative diagnosis using both computed tomography and gastroscopy imaging may be feasible for T3/T4 advanced gastric stump cancer, whereas diagnosing T1/2 gastric stump cancer must be carefully considered due to high misdiagnosis rates, relating to depth.

Mixed neuroendocrine carcinoma of the gastric stump: A case report.

BACKGROUND: Gastric stump cancer, also known as gastric remnant cancer (GRC), is one of the main complications of postgastrectomy syndrome, which usually occurs following Billroth II reconstruction. The predominant histological subtype of GRC is adenocarcinoma, whereas neuroendocrine carcinoma is relatively rare. In particular, there are few recently reported cases of mixed neuroendocrine carcinoma (MNEC) in the English literature. Here, we present an extremely rare case of MNEC of the gastric stump. CASE SUMMARY: A 59-year-old patient presented to our department owing to chronic constipation. He had undergone subtotal gastric resection 35 years prior to admission because of benign peptic ulcer. After admission, the patient underwent several tests, and gastroendoscopy showed evidence of Billroth II gastrectomy and local thickening of the gastric stump mucosa at the gastrojejunostomy site, with bile reflux; pathological biopsy revealed adenocarcinoma. He was then diagnosed with GRC and underwent total gastrectomy, D2 Lymphadenectomy, and esophagojejunal Roux-en-Y reconstruction. Histopathological examination of the specimen identified MNEC comprising MNEC (60%), adenocarcinoma (30%), and squamous cell carcinoma (10%). Postoperative adjuvant chemotherapy was initiated on September 17, 2020. Taxol plus cisplatin was administered for only one cycle because of severe liver function damage, and the regimen was changed to etoposide plus cisplatin on October 10, 2020 for five cycles. The patient recovered, with no recurrence after 6 mo of follow-up. CONCLUSION: Gastric MNECs (GMNECs) is a rare type of GRC. This study presented the unusual occurrence of GMNEC in the gastric stump. This case will contribute to improvements in our understanding of the carcinogenesis, biology, pathology, and behavior of GMNEC and GRC.

Extensive cutaneous metastasis of recurrent gastric cancer: A case report.

BACKGROUND: Cutaneous metastasis is a rare event associated with poor prognosis for gastric cancer and has been rarely reported in the literature. CASE SUMMARY: A 69-year-old male patient who had undergone salvage gastrectomy and a few courses of adjuvant chemotherapy 3 mo earlier for recurrent gastric cancer developed widespread cutaneous metastases. Due to the patient's intolerance to further adjuvant chemotherapy, he was placed in hospice care and expired 1 mo later. In the literature, gastric cancers are rarely reported as the primary malignancies for cutaneous metastasis. We, thus, provide an update on a case review published in 2014 by reviewing 10 more case reports dated from 2014 to 2020. The average age for the new group of patients was 59.4 ± 18.88-years-old. Thirty percent of the patients presented with cutaneous lesions and advanced gastric cancer synchronously while 70% developed cutaneous metastases 1.3 years to 14 years after the initial treatment for primary gastric cancer. Eighty percent of the patients received either local excision or chemo ± radiation therapy to treat their cutaneous metastases. CONCLUSION: This report highlights cutaneous metastasis as a late and untreatable metastasis of gastric cancer.

Remnant gastric cancer: An ordinary primary adenocarcinoma or a tumor with its own pattern?

BACKGROUND: Remnant gastric cancer (RGC) is defined as a tumor that develops in the stomach after a previous gastrectomy and is generally associated with a worse prognosis. However, there little information available regarding RGCs and their prognostic factors and survival. AIM: To evaluate the clinicopathological characteristics and prognosis of RGC after previous gastrectomy for benign disease. METHODS: Patients who underwent curative resection for primary gastric cancer (GC) at our institute between 2009 and 2019 were retrospectively evaluated. All RGC resections with histological diagnosis of gastric adenocarcinoma were enrolled in this study. Primary proximal GC (PGC) who underwent total gastrectomy was selected as the comparison group. Clinical and pathological data were collected from a prospective medical database. RESULTS: A total of 41 patients with RGC and 120 PGC were included. Older age (P = 0.001), lower body mass index (P = 0.006), hemoglobin level (P < 0.001), and number of resected lymph nodes resected (LN) (P < 0.001) were associated with the RGC group. Lauren type, pathological tumor-node-metastasis, and perioperative morbimortality were similar between RGC and PGC. There was no difference in disease-free survival (P = 0.592) and overall survival (P = 0.930) between groups. LN status was the only independent factor related to survival. CONCLUSION: RGC had similar clinicopathological characteristics to PGC. Despite the lower number of resected LN, RGC had a similar prognosis.

Prevalence and characteristics of gastric remnant cancer: A systematic review and meta-analysis.

The incidence and outcomes of GRC remain variable. Minority published researches have paid attention to the characteristics of GRC. This study aimed to make a systematic review and meta-analysis of the prevalence of GRC, with a focus on characteristics and survival rates of GRC. PubMed, EMBASE, and CENTRAL were searched for related clinical studies. Data were pooled using Stata 11.0, and subgroup and sensitivity analyses were performed if necessary and feasible. Moreover, SPSS (version 19.0) was used for comparing the clinical characteristics of GRC. Twenty studies were selected in this meta-analysis. The results indicated that the pooled prevalence of GRC was 2.6% (95% confidence interval (CI), 2.2-3.0%, p = 0.000). European population and American populations have a higher rate of prevalence of GRC than Chinese populations and Japan. There is no significant difference in histology and the TNM stage between the benign group and the malignant group. The five-year survival rate for GRC cases with benign primary gastric diseases is poorer than the primary gastric diseases malignant. Gastric remnant cancer is not a very rare clinical problem, especially for European and American patients. Active treatment and regular follow-up are conductive to increase 5-years survival rate.

Laparoscopic Completion Total Gastrectomy for Remnant Gastric Cancer.

Background: Remnant gastric cancer (RGC) is increasing due to past use of subtotal gastrectomy to treat benign diseases, improvements in the detection of gastric cancer, and increased survival rates after gastrectomy for gastric cancer. Laparoscopic access provides the advantages and benefits of minimally invasive surgery. However, laparoscopic completion total gastrectomy (LCTG) for RGC is technically demanding, even for experienced surgeons. Because of its rarity and heterogeneity, no standard surgical strategy has been established and few surgeons will develop technical expertise to carry out this procedure. Aim: To describe our standard technique, giving surgeons a head start in LCTG and report the early experience with this stepwise approach. Materials and Methods: We detail all the steps involved in the procedure, including trocar placement and surgical description. Results: Between 2009 and 2019, a total of 8 patients with past history of RGC were operated with this technique. All patients had been previously operated by open method, 7 due to peptic ulcer disease and 1 due to gastric cancer. Their mean age at the time of the first surgery was 38.9 years (range 25-56 years) and the mean interval between the first and the second gastrectomy was 32.1 years (range 13.6-49). Billroth II was the previous reconstruction in all cases. A 5-trocar technique was used followed by total gastrectomy with side-to-side stapled intracorporeal esophagojejunostomy anastomosis and Roux-en-Y reconstruction. The mean operation time was 272 minutes (range 180-330) and median blood loss was 247 mL (range 50-500). There was no conversion and no major intraoperative complication. Major postoperative complications occurred in 3 patients. Conclusion: Completion total gastrectomy for RGC is a morbid procedure and laparoscopic access is technically feasible, hopefully carrying the benefits of faster recovery, reduced postoperative pain, and wound complications. By standardizing the approach, the learning curve may be shortened and better results achieved.

Development and characterization of a mouse model of duodenogastric reflux.

AIMS: Rat models of duodenogastric reflux have been used to study gastric stump cancer (GSC), but the underlying molecular mechanisms are poorly understood. Unlike rats, mice can be genetically modified, providing a superior model for studying the molecular mechanisms underlying GSC development, which is associated with duodenogastric reflux. This study aimed at developing a mouse model of duodenogastric reflux. MAIN METHOD: C57BL/6 mice were randomly assigned to the control (n = 6), sham operation (n = 9), or gastrojejunostomy group (n = 12). Mice were sacrificed at 1, 3, and 6 months after surgery. Stomach tissue was stained with hematoxylin and eosin. Lesions were classified as chronic inflammation, intestinal metaplasia, or atypical hyperplasia. KEY FINDINGS: Nine mice underwent gastrojejunostomy without mortality. The animals in the gastrojejunostomy group exhibited chronic inflammation at 1, 3, and 6 months after surgery, showing intestinal metaplasia (n = 2) and atypical hyperplasia (n = 1) at 3 months and intestinal metaplasia (n = 2) and atypical hyperplasia (n = 2) at 6 months. The mice in the control group did not exhibit chronic inflammation or intestinal metaplasia, whereas those in the sham operation group exhibited chronic inflammation at 1, 3, and 6 months after surgery, without intestinal metaplasia or atypical hyperplasia. Intestinal metaplasia or atypical hyperplasia were more common in the gastrojejunostomy group than in the sham operation group (p = 0.012). SIGNIFICANCE: A duodenogastric reflux mouse model can be created using gastrojejunostomy without gastrectomy.

Prognosis and clinicopathologic features in patients with gastric stump cancer after curative surgery.

Background: Gastric stump ("remnant") cancer is the development of a malignancy related to previous gastric surgery. Prognosis in gastric stump cancer, compared with that in primary gastric cancer, is still controversial. Methods: From January 1988 to December 2012 at a single medical centre in Taiwan, 105 patients with gastric stump cancer, including 85 with previous peptic ulcer disease and 20 with previous gastric cancer, were analyzed for clinicopathologic characteristics and overall survival (os). Results: The 5-year os rates for patients with gastric stump cancer and with primary gastric cancer were 51.2% and 54.5% respectively (p = 0.035). Analysis of clinicopathologic characteristics indicated that, compared with patients having primary gastric cancer, those with gastric stump cancer had more lymph node metastasis (p < 0.001) and had been diagnosed at a more advanced stage (p = 0.047). Multivariate analysis with os as an endpoint showed that age [p = 0.015; hazard ratio (hr): 2.300; 95% confidence interval (ci): 1.173 to 4.509], tumour size (p = 0.037; hr: 1.700; 95% ci: 1.031 to 2.801), stromal reaction (p = 0.021; hr: 1.802; 95% ci: 1.094 to 2.969), and pathologic N category (p = 0.001; hr: 1.449; 95% ci: 1.161 to 1.807) were independent predictors in gastric stump cancer. The os rates for patients with gastric stump cancer who previously had gastric cancer or peptic ulcer disease were 72.9% and 50.0% respectively (p = 0.019). The Borrmann classification was more superficial (p = 0.005), lymph node metastases were fewer (p = 0.004), and staging was less advanced (p = 0.025) in patients with gastric stump cancer who previously had gastric cancer than in their counterparts who previously had peptic ulcer disease. Conclusions: Survival is poorer in patients with gastric stump cancer who previously had peptic ulcer disease than in those who previously had primary gastric cancer. Patients with gastric stump cancer who previously had gastric cancer and could receive curative gastrectomy tended to have a better prognosis because of a more superficial Borrmann classification. Regular follow-up in patients who have undergone gastric surgery is recommended for the early detection of gastric stump cancer.

[Two unusual causes of peptic anastomotic ulcer]. / Dve neobychnye prichiny pepticheskoi yazvy anastomoza.

Two unusual cases of anastomotic ulcer complicated by bleeding after gastric resection are reported. There were retained antrum in one patient and long 'dry' intestinal loop after laparoscopic Roux resection in another one. Emergency gastric stump resection with Haberer procedure were successfully performed in both cases.

Is subtotal gastrectomy feasible for the treatment of gastric stump cancer located at the anastomotic site after distal gastrectomy for benign lesions?

BACKGROUND: Total gastrectomy (TG) is a widely accepted procedure for treating gastric stump cancer (GSC). However, subtotal gastrectomy (SG) would benefit elective patients with GSC. The aim of this study was to clarify the safety and long-term prognosis of SG in treating GSC after distal gastrectomy for benign lesions. METHODS: A total of 53 patients with GSC located at the anastomotic site or gastric body between May 1999 and December 2018 at our hospital were included. In total, 21 patients underwent SG, and the remaining 24 patients underwent TG. Clinicopathological data, operative data, and overall survival (OS) were compared. RESULTS: The operative duration, estimated blood loss volume, and length of hospital stay were similar between the SG and TG groups. The postoperative complications were similar between the two groups, but no cases of anastomotic leakage were noted in the SG group. TG was associated with significantly more retrieved lymph nodes than SG (18.5 ± 11.5 vs. 10.7 ± 9.2; p = 0.017), while the number of metastatic lymph nodes did not differ between the groups (2.9 ± 3.5 vs. 1.9 ± 3.6; p = 0.329). The median survival time in the SG group was 81.0 months (95% confidence interval (CI), 68.906 to 93.094 months), which was similar to the 45.0 months (95% CI, 15.920 to 74.080 months) observed in the TG group (p = 0.236). Both univariate and multivariate analyses showed that tumor location and histological type were prognostic factors, while surgery type was not a prognostic factor. Further stratified analyses according to tumor location revealed that OS was not significantly different between the two groups among patients with tumors located at the anastomotic site, while OS in the TG group was significantly better than that in the SG group among patients with tumors located in the gastric body (p = 0.046). CONCLUSIONS: The results of the current study indicate that SG is a suitable alternative surgical procedure for GSC located at the anastomotic site after distal gastrectomy for benign lesions. The short-term outcomes and long-term prognoses of SG are comparable with those of TG.