Primary Colonic Lymphoma Research Articles

Concomitant adenocarcinoma and colonic non-Hodgkin's lymphoma in a patient with ulcerative colitis: A case report and molecular analysis

Ulcerative colitis (UC) complicated by colonic lymphoma is rare, although UC is often accompanied by adenocarcinoma of the colon. A concurrent existence of adenocarcinoma and lymphoma in a patient with UC is extremely rare, and has not yet been analyzed at the molecular level. We report a 64-year-old female patient with concomitant adenocarcinoma and diffuse large B-cell lymphoma (DLBCL) in the colon of UC. The genetic changes in these two neoplasms were analyzed. The colon adenocarcinomas had a mutation in MSH6 gene, DNA methylation in CDKN2A gene, and increased microsatellite instability (MSI), although these genetic changes were not recognized in either DLBCL or non-neoplastic UC mucosa. The DLBCL was diagnosed as primary colonic lymphoma, and confirmed Epstein-Barr virus (EBV) infection. The adenocarcinomas and the non-neoplastic UC mucosa were EBV-negative. Our case presented here clearly shows that the development of adenocarcinoma and lymphoma in the colon with UC was caused by individual mechanisms.

Une gammapathie monoclonale associée à un lymphome colique primitif à cellules du manteau

The association of a monoclonal gammopathy (MG) with a B cell non-Hodgkin's lymphoma (NHL) is a well-known phenomenon. It has been recognized in many subtypes of primary gastrointestinal lymphoma but its association with primary colonic mantle cell lymphoma has never been yet described. We report a 65-year-old man who presented with an exudative ascites and constipation. Serum electrophoresis showed a monoclonal peak in the gamma region of 45g/L and immunoelectrophoresis confirmed the presence of monoclonal gammopathy of IgM kappa type. Bone marrow aspirate was normal. Radiologic and endoscopic investigations evidenced a primary colonic mantle cell lymphoma. Although the association of an MG with an NHL and, in particular, to a primitive digestive location appears a rare phenomenon, endoscopic investigations in patients with MG appears legitimate in the presence of any digestive sign.

Rapidly Growing Large B-Cell Lymphoma of the Colon

Purpose: Lymphomas may appear in the colon as primary malignancy or as a part of systemic disease. The incidence of this tumor is increasing, and its presentations are varied. Knowledge of the forms of presentation is therefore important in order to suspect the disease and reach an early diagnosis. Additionally, colonic lymphoma often requires a multidisciplinary treatment approach. We present a case that illustrates these points. Methods: A 59 years old male was admitted with a chief complaint of left sided dull, non-radiating abdominal pain associated with 20 lbs of weight loss over the last 2 months. On physical examination, his abdomen was soft with normal bowel sounds and mild tenderness in the left lower quadrant without any rebound. A firm mass with an irregular margin, about 10 × 12 cm in size was palpable in left lower quadrant of the abdomen. Rectal exam was positive for fecal occult blood. All laboratory tests including CBC were normal. He had had an unremarkable screening colonoscopy about 18 months prior to this visit. CT scan of abdomen showed an 8 × 17 cm lobulated irregular soft tissue mass in left lower quadrant arising from the descending colon. A colonoscopy showed a 15 cm long circumferential, ulcerated, friable, nearly obstructing lesion in the descending colon 60 cm from the anal verge. The biopsy findings, negative for cytokeratin and CD 117 and equivocal for CD45, were suspicious for lymphoma, although not conclusive. The patient underwent surgical resection of the tumor. Results: Histopathological examination of surgical specimen confirmed the diagnosis of large B cell lymphoma. Margins of the resected colon and adjacent lymph nodes were tumor free. The patient was started on adjuvant chemotherapy with R-CHOP regimen. At six months the patient has not shown any evidence of recurrence of his disease. Conclusion: Primary colonic lymphoma is a rare entity. We found our case unique because of the large size of tumor, the rapidity of growth and the lack of traditionally described risk factors for the development of lymphoma. Our case illustrates that treatment involving a multi-disciplinary approach including surgery and chemotherapy is considered ideal.Figure

Primary Colonic Lymphoma

Surgical resection of primary colonic lymphoma can be an important therapeutic tool. We performed a nonrandomized retrospective descriptive study at the University hospital tertiary care center. From January 1990 to June 2002, a total of 15 patients with primary colonic lymphoma were identified from the tumor registry at University of Alabama at Birmingham and retrospectively reviewed under Institutional Review Board approved protocol. Demographic data, clinical features, treatment method (surgery and/or chemotherapy), recurrence rate, and survival were analyzed. The results are presented as mean +/- standard deviation or median and range. Differences in survival were evaluated by the log-rank test and the interval of disease-free survival was calculated using the Kaplan-Meier method. A P value of <0.05 was considered statistically significant. Main outcome measures included surgical results, morbidity, mortality, and recurrence rate. Mean age was 51.5 years (standard deviation 16.4), 33 per cent were male and 67 per cent were female. Presenting symptoms were diarrhea (53.5%), lower gastrointestinal bleeding (13.3%), and nausea and vomiting (46.7%) secondary to low-grade obstruction. Concomitant colorectal disease was present in one patient with ulcerative colitis. Preoperative diagnosis of lymphoma was made in 13 patients (87%) with colonoscopy and biopsy. CT scan was performed in all patients; and none had radiographic evidence of systemic extension. Only one patient had a history of lymphoproliferative disease and exposure to radiation. The most common disease location was the cecum (60%), followed by the right colon (27%), and the sigmoid colon (13%). The mean lactic dehydrogenase (LDH) value was 214.9 u/L (range 129-309). Thirty-three per cent of the patients had an LDH value that was above the upper normal limit. LDH returned to normal after treatment in all patients. Operations performed consisted of right hemicolectomy (13), total proctocolectomy with ileal J J-pouch (1), and sigmoid colectomy (1). Eighty-seven per cent had negative margins at the time of operation. Twelve patients received postoperative chemotherapy (80%). According to the clinical classification of primary non-Hodgkin lymphoma (NHL) of the gastrointestinal tract (Lugano, 1993) all patients corresponded to stage IE. Mean hospital stay was 6.4 days (range 3-26). There was no surgical mortality and the morbidity rate was 20 per cent (3 patients). One patient had a systemic recurrence (7%) approximately 4 months after surgical resection. Mean follow-up was 31 months (median 2-73). Surgical resection of localized, primary colonic lymphoma provides excellent local disease control and should be considered a primary treatment option. The role of chemotherapy remains controversial depending on the grade, stage, and extension of residual disease.

Primary colorectal lymphomas: Review of the literature

Primary colorectal lymphoma is an infrequent disease of unknown origin and with a growing incidence. Primary colorectal lymphoma accounts for only about 0.2% of large intestinal malignancies. The aim of this study is to review, identify and underline risk factors, presentation, treatment and prognosis of primary colorectal lymphoma, using the three most important studies made in the last years: the Chung-Wei Fan study from the division of colon and rectal surgery, in Taipei [Fan CW, Changchien CR, Wang JY. Primary colorectal lymphoma. Disease of the Colon and Rectum 2000;43:1277-82]; the Wong and Eu [Primary colorectal lymphomas. Colorectal Diseases 2006;8:586-91] study from the Department of colorectal surgery in Singapore and the study of Doolabh et al. [Primary colon lymphoma. Journal of Surgical Oncology 2000;74:257-62] University of Texas Southwestern Medical School, Dallas, Texas.

Primary Diffuse Large B-Cell Lymphoma of the Colon: Surgery for Local Disease Control Does Not Improve Outcome.

Purpose: Primary colorectal large B-cell lymphoma is rare and accounts for less than 1% of all malignancies in the colon. Standard treatment for limited stage diffuse large B-cell lymphomas (DLBCL) includes systemic therapy combined with involved field radiation therapy. However, radiation therapy may often not be feasible in patients with primary colon lymphoma. For primary DLBCL of the colon particularly the cecum, surgical resection prior to the administration of systemic chemotherapy has been considered to improve local control. The goal of this study was therefore to determine whether surgical resection improves the outcome of patients with primary DLBCL of the colon.Methods: Clinical information and outcomes on all the patients with primary DLBCL of the colon seen at Mayo Clinic, Rochester, between January 1980 and June 2005 were retrospectively reviewed.Results: There were 28 patients identified with primary colon DLBCL. Pre-existing conditions like colon polyps, Crohn's disease and diverticulosis were uncommon. The most common presenting symptom was bleeding per rectum seen in 13 patients (46.5%). Other symptoms included abdominal pain, diarrhea and anemia. All patients had early stage disease (stage1–22 patients, stage2–6 patients) at diagnosis. Of the 28 patients, 16 underwent initial surgery followed by chemotherapy, 7 were treated with chemotherapy alone, and 5 patients had inadequate data to determine time to progression or overall survival. Chemotherapy was anthracycline based, with the most common regimen being CHOP (Cyclophosphamide, Doxorubicin, Vincristine, Prednisone). There was no difference in overall survival or time to progression between the 16 patients who received combined modality therapy compared to the 7 patients who received chemotherapy alone. Of the 16 patients who underwent surgical resection followed by chemotherapy, all 5 patients who relapsed, relapsed at other sites in the colon. Conclusion: Surgery as part of combined modality therapy did not appear to improve the outcome of patients with primary DLBCL of the colon. Systemic chemotherapy with an anthracycline-based regimen in combination with rituximab is therefore likely to be sufficient treatment for these patients. Follow-up for these patients should include a colonoscopy to monitor for recurrences at other sites in the colon.

Spontaneous Multiperforation in Lymphomatous Colitis Masquerading as Crohnʼs Disease: Two Cases

Purpose: Lymphomatous colitis is a rare disorder that can simulate inflammatory bowel disease. We describe 2 cases of lymphomatous colitis mimicking Crohn's disease that were complicated by spontaneous multiperforation. Case 1: An 82 year old female with a history of chronic lymphocytic leukemia presented with progressive diarrhea over 5 months, associated with a 20 pound weight loss. Colonoscopy showed moderately severe pancolitis with ileal inflammation. Biopsies were reported as inflammatory colitis. She failed to respond to high dose corticosteroids. Within 4 weeks she required emergent colectomy for spontaneous multiperforation of her colon. Pathology revealed colonic and ileal MALT lymphoma. The colonic lymphoma was distinct from her chronic lymphocytic leukemia, since the former was negative to CD5 and did not have chromosomal trisomy 12, whereas the latter was CD5 positive and positive for trisomy 12. This indicates that the patient had 2 distinct lymphoproliferative diseases. In retrospect, immunoperoxidase stains on the initial biopsies did reveal malignant monoclonal lymphocytes. (See Table) Case 2: A 49 year old female with a history of ulcerative colitis presented with severe watery diarrhea and a 50 pound weight loss. Colonoscopy revealed severe pancolitis with skip areas of normal colon. Biopsies were reported as inflammatory colitis. She failed to respond to high dose corticosteroids, and refused surgery. Within a number of weeks, she required emergent colectomy for spontaneous multiperforation of her colon. Pathology revealed primary colonic non-hodgkins lymphoma (NHL). In retrospect, immunoperoxidase stains on the initial biopsies did reveal malignant monoclonal lymphocytes. (See Table) Conclusion: Lymphomatous colitis can mimick Crohn's colitis. Lymphomatous colitis should be considered in patients with steroid-refractory inflammatory bowel disease. Earlier diagnosis with immunoperoxidase stains looking for monoclonal proliferation of malignant lymphocytes, may prevent progression of necrotizing lymphoma and spontaneous multiperforation.Table: Lymphomatous Colitis: 2 cases

Linfoma de colon como causa de fiebre de origen desconocido

We present a case of a 49 year old man who presented with a 2 month history of fever, nausea vomiting and weight loss (10 kg). He was admitted to the Hospital with the diagnosis of fever of unknown origin. A CT scan showed a wide thickening of the colonic wall (transverse colon and hepatic flexure) suggesting a colon tumor, and a solid mass in the left liver lobe. A colonoscopy was performed showing a circumferential neoplasm and biopsies were taken. The histopathology was informed as a diffuse large B cell lymphoma. Primary colon lymphoma is a rare gastrointestinal tumor that represents less than 1% of the gastrointestinal lymphomas. Based on this case, we reviewed the most recent articles about gastrointestinal lymphomas.

Establishment of liver metastasis model of human primary colonic lymphoma by orthotopic transplantation

To provide an ideal animal model for exploring pathogenesis and experimental treatment of primary colonic lymphoma. Primary colonic and liver metastatic lymphoma tissues were obtained from the surgical specimens,and transplanted into colonic mucosa of nude mice respectively. The tumorigenesis, invasion, metastasis and morphology of the transplanted tumor were observed. Karyotype was analyzed and DNA content was measured. According to the new WHO classification of malignant lymphoma, two high metastatic models (HCBL-0303 from primary lymphoma and HCBL-0304 from live metastatic lesion) of human primary colonic non-Hodgkin's B cell lymphoma in nude mice were established successfully by orthotopic transplantation. Pathological examination showed poorly differentiated non-Hodgkin's B cell lymphoma of the transplanted tumors, and immunohistochemical staining showed positive expressions of CD19, CD20 and CD22, and negative expressions of CD3 and CD7. The number of chromosome ranged from 55 to 59, and DNA index (DI) was 1.59 - 1.71 (i.e. heteroploid). In HCBL-0303,liver metastasis rate was 63.7% and lymph node metastasis rate was 56.4%. However, in HCBL-0304, both metastasis rates of liver and lymph node were 100%. The transplanted tumors grew autonomously and invasively in nude mice, and further developed hematogenous, lymphatic metastasis and intraperitoneal seeding. HCBL-0303 and HCBL-0304 are the first established high metastatic models of primary colonic lymphoma, and can be applied to the research on pathogenesis, invasion,metastasis and experimental therapy of human primary colonic lymphoma.

Primary Colon Lymphoma in Korea: A KASID (Korean Association for the Study of Intestinal Diseases) Study

Although almost all primary colorectal lymphomas are of B-cell lineage in Western countries, primary colorectal T-cell lymphomas are not uncommon in the East. The aim of this study was to review the clinical characteristics and treatment outcomes of primary colorectal lymphomas, with special emphasis on the differences between T-cell and B-cell lymphomas. Ninety-five cases of primary colorectal lymphomas that satisfied Dawson's criteria were identified from the clinical databases of 13 university hospitals in Korea. The mean age at the time of presentation was 51.1 years and the male:female ratio was 64:31. The clinical information, including endoscopic and histological characteristics, was retrospectively analyzed. Of the primary colorectal lymphomas, 78 cases (82.1%) were of B-lineage and 17 cases (17.9%) were of T-cell lineage. Patients with T-cell lymphomas presented at a younger age than patients with B-cell lymphomas (42.8 vs 52.9 years, respectively; P = 0.016). The most common presenting symptom was abdominal pain (87.1%) for B-cell lymphomas, whereas hematochezia or night fever was more common for T-cell lymphomas (52.9% and 35.3%, respectively). The most common endoscopic type was fungating mass (54.0%) for B-cell lymphomas and ulcerative/ulcero-infiltrative lesions (80.0%) for T-cell lymphomas. Intussusception was more common in B-cell lymphomas than in T-cell lymphomas (30.8% vs 5.9%, respectively; P = 0.035), but perforation was more common in T-cell lymphomas than in B-cell lymphomas (23.5% vs 3.8%, respectively; P = 0.005). The prognosis was significantly worse for T-cell lymphomas than for B-cell lymphomas (P = 0.002). Primary colorectal T-cell lymphomas are characterized by multifocal ulcerative lesions in relatively young patients, a high rate of hematochezia, fever, or perforation, and a poor prognosis even for cases of localized disease.

Laparoscopic colectomy for primary colonic lymphoma

Primary colorectal lymphoma is an infrequent disease of unknown origin and with a growing incidence. Differentiation be-tween primary lymphoma and secondary colorectal involvement is of great therapeutic and prognostic importance. The diagnosis must always be based on histological findings. Different forms of presentation have been described, though all are nonspecific. While full agreement on the best management approach for colorectal lymphoma is lacking, surgical resection is usually the treatment of choice. The role of chemotherapy has not been defined. This study reports on a case of primary lymphoma in the cecum, with clinical manifestations in the form of meteorism and early satiety. The diagnosis was established by colonoscopy and biopsy. The absence of lymph-node involvement, tumor size, existing cardiopulmonary risk factors, and the fact that a full resection of the malignancy proved possible, with tumor-free resection margins, led us to exclude adjuvant chemotherapy. After one year of follow-up the patient remains disease-free.

Primary gastrointestinal lymphomas: A radiological–pathological review. Part 1: Stomach, oesophagus and colon

Primary gastrointestinal lymphomas are most common in the stomach, followed by small intestine and then colon. The most frequently used pathology classification of lymphomas is the Revised European and American Lymphoma /World Health Organization classification. The correlation of radiological morphology with histology is relatively poor, although characteristic subtypes will be discussed. In the stomach, the majority of primary lymphomas are of B-cell origin of mucosa-associated lymphoid tissue (MALT) type. Low-grade MALT lymphomas are associated with Helicobacter pylori infection and often respond to eradication of this organism. Radiological features include thickened folds, nodularity, depressed lesions, ulcers, prominent areae gastricae. High-grade (large B-cell) tumour patterns include infiltrative, polypoid, nodular, ulcerated or a combination. Endoscopy, endoscopic ultrasound and CT are important in diagnosis and staging, although appearances on barium studies should be recognized. Primary colonic lymphomas are rare. Most are of B-cell origin. Focal and diffuse forms are seen, the former producing polypoid or nodular or cavitating masses and the latter producing ulcerative or nodular (polyposis) patterns on imaging. Even when circumferential, lymphoma rarely causes obstruction. Small bowel lymphomas will be discussed in the forthcoming part 2 of this review.

Primary colonic Hodgkin’s lymphoma masquerading as Crohn’s disease

Primary gastrointestinal (GI) Hodgkin's disease (HD) is rare, representing less than 0.5% of cases of HD. This is a case of primary colonic HD that was treated as Crohn's disease (CD) for 3 years until the diagnosis of lymphoma was made. A 32 year-old man presented in 1999 with diarrhea and melena. He was diagnosed with CD based on colonoscopy with biopsies. He was managed medically, and did well for a year when he had increased diarrhea. Colonoscopy showed worsened colitis. The patient did not tolerate immunosuppressants, and on Pentasa, his diarrhea improved. In early 2002, he complained of fatigue, abdominal distention and anorexia. CT scan demonstrated small bowel and colonic wall thickening. He was treated for iron and B12 deficient anemia. In June 2002, his symptoms worsened and he was referred to our institution. Exam revealed a cachectic, afebrile male with marked abdominal distention and a large tender palpable mass in the mid abdomen. There was no lymphadenopathy. Laboratory data included WBC 20, HCT 16.6, Platelets 680, albumin <1, and normal liver enzymes. Bone marrow biopsy was negative for lymphoma, and HIV test was negative. CT showed a large mass defining the wall of the ascending colon and terminal ileum with bulky mesenteric lymphadenopathy. Colonoscopy revealed a normal left colon and a 20cm long area in the right colon that was markedly dilated with irregular, erythematous mucosa with ulceration and areas of necrosis. Biopsies demonstrated numerous large, atypical cells, and scattered Reed-Sternberg cells, staining positive for CD 15 and 30. The diagnosis of Hodgkin's lymphoma was made. The patient underwent hemicolectomy and was found to have a mass involving the terminal ileum and right colon. The mesentery was replaced completely by tumor. Pleural fluid contained Reed-Sternberg cells and he was treated for stage IV HD with chemotherapy. He never achieved complete remission, and 8 months after diagnosis was found to have progression of disease. Retrospective review of biopsies from the patient's initial colonoscopies shows nonspecific colitis with mild chronic changes. Deeper sections show rare Reed-Sternberg cells, making HD the patient's primary diagnosis. There are few reports in the literature of primary HD mimicking inflammatory bowel disease (IBD). In our case, we were able to demonstrate that HD was present all along. Primary colonic lymphoma is rare, but should be considered in the differential of IBD, especially with atypical or refractory behavior.

Chromosomal Gains at 9q Characterize Enteropathy-Type T-Cell Lymphoma

Genetic alterations in enteropathy-type T-cell lymphoma (ETL) are unknown so far. In this series, 38 cases of ETL were analyzed by comparative genomic hybridization (CGH). CGH revealed chromosomal imbalances in 87% of cases analyzed, with recurrent gains of genetic material involving chromosomes 9q (in 58% of cases), 7q (24%), 5q (18%), and 1q (16%). Recurrent losses of genetic material occurred on chromosomes 8p and 13q (24% each), and 9p (18%). In this first systematic genetic study on ETL, chromosomal gains on 9q (minimal overlapping region 9q33-q34) were found to be highly characteristic of ETL. Fluorescence in situ hybridization analysis on four cases of ETL, using a probe for 9q34, indicated frequent and multiple gains of chromosomal material at 9q34 (up to nine signals per case). Among 16 patients with ETL who survived initial disease presentation, patients with more than three chromosomal gains or losses (n = 11) followed a worse clinical course than those with three or less imbalances (n = 5). The observation of similar genetic alterations in ETL and in primary gastric (n = 4) and colonic (n = 1) T-cell lymphoma, not otherwise specified, is suggestive of a genetic relationship of gastrointestinal T-cell lymphomas at either localization.

Primary colonic lymphoma: report of 14 cases

Primary colonic lymphoma: report of 14 cases

上行結腸原発悪性リンパ腫と直腸癌の同時重複の１例および文献からみた臨床的特徴

上行結腸原発悪性リンパ腫と直腸癌の同時重複の１例および文献からみた臨床的特徴

Toxic megacolon:

Primary colonic lymphoma is rare and accounts for less than 1% of colon malignancies. Moreover, diffuse neoplastic invasion of the colon is exceptional. This case describes a patient with primary non-Hodgkin's lymphoma of the colon presenting as toxic megacolon. This unique presentation is the first case reported in the literature of a diffuse colonic lymphoma diagnosed in the setting of a toxic megacolon. Histological confirmation was performed on the piece of colectomy.

Primary colonic lymphoma.

The colon is a rare location for gastrointestinal non-Hodgkin's lymphoma (NHL). This study was undertaken to identify risk factors, presentation, treatment, and prognosis for primary colonic lymphoma (PCL) through review of a large tertiary care hospital system experience. A retrospective review of all patients with colonic malignancy and NHL was performed using pathology and cancer registry databases from January 1989 to December 1998. Criteria for inclusion were no evidence of extraperitoneal disease, no leukemic or lymphomatous abnormalities in the blood, and disease confined to the colon. Seven patients met the inclusion criteria (4 male, 3 female; 33-72 years). They represented 1.4% of all NHL, 14% of gastrointestinal NHL and 0.9% of all colonic malignancies diagnosed during this period. Three of the patients had positive serology for human immunodeficiency virus; one was taking steroids chronically for Addison disease. The most common presentation was nonspecific abdominal pain. The lack of specific symptoms delayed diagnosis from 1-12 months. All patients underwent laparotomy with resection. The most common tumor location was the cecum (5/7, 71%). Regional lymph nodes were affected in all but 1 patient. All tumors were B-cell lymphomas (5 small noncleaved cell, 2 large cell). Six of 7 patients received adjuvant chemotherapy. Of the 6 patients available for follow-up four remain alive (12, 19, 23, and 25 months after diagnosis). In both patients who died the disease recurred diffusely. The colon is a rare location for NHL. Immunosuppression is the most common risk factor. Patients' frequently present with non-specific abdominal pain, this leads to lengthy delays in diagnosis. Most of these tumors are located in the cecal area. Surgery is the most widely utilized form of therapy. Although adjuvant therapy is frequently utilized, its' impact on survival is unclear.

Multifocal primary colonic lymphoma in a patient with posttransplantation lymphoproliferative disease: CT findings.

Multifocal primary colonic lymphoma in a patient with posttransplantation lymphoproliferative disease: CT findings.

Primary Colonic Lymphoma

Primary colonic lymphomas are rare, but we identified 15 cases at our institution between 1973 and 1992. They comprised 5.8% of all cases of gastrointestinal lymphoma (15 of 259) and 0.16% of all cases of colon cancer (15 of 9,193) during the last 20 years. The most common presenting symptoms were abdominal pain and weight loss (40% each). In seven patients (47%), a palpable abdominal mass was noted on the initial physical examination. The most frequent site of involvement was the cecum (73%). Histologically, six (40%) were classified as high-grade and nine (60%) as intermediate-grade non-Hodgkin's lymphoma. The tumors usually presented at an advanced stage: in 13 of 15 patients (87%), the lymphoma had spread to the adjacent mesentery, the regional lymph nodes, or both when first diagnosed. The 5-year survival rate was 27% for all patients and 33% (4 of 12) for patients treated with combination chemotherapy. Two patients relapsed after 8 years of complete remission. Primary colonic lymphomas have an aggressive behavior and only a marginal response to surgery and combination chemotherapy.