Cobalt 60 radiotherapy for treatment of squamous cell carcinoma of the nasal cavity and paranasal sinuses in three horses

Three adult horses underwent aggressive treatment of squamous cell carcinoma of the nasal cavity and paranasal sinuses, using course-fractionated cobalt 60 radiotherapy. Squamous cell carcinoma of the nasal cavity and paranasal sinuses is not commonly diagnosed in horses. Historically, horses with this type of neoplasm have not been treated or have undergone some form of surgery. The prognosis for long-term survival or cure has been poor. Long-term results of cobalt 60 radiotherapy were good to excellent and exceeded those usually reported for horses treated surgically. On the basis of these results, use of radiotherapy for these neoplasms is recommended.     

Squamous cell carcinoma in ovarian endometriosis. A case report

A primitive squamous cell carcinoma of the ovary arose in ovarian endometriosis. The patient underwent a radical hysterectomy and radiotherapy. The other few similar reported cases had a poor prognosis. In our case the patient died 11 months after surgery.     

Management for stage II glottic carcinoma: radiation therapy or surgery

AIM: To analyze the results of stage II glottic carcinoma treated with radiotherapy or surgery. PATIENTS AND METHOD: One hundred thirty-four patients with squamous cell carcinoma of the T2N0M0 glottic carcinoma treated at the Osaka Medical Center for Cancer and Cardiovascular Diseases from 1979 through 1991 were reviewed. The 5-year disease-free survival and laryngeal preservation rate and prognostic factors were examined. Treatment was radiation therapy with salvage surgery for failure or surgery alone. RESULTS: The 5-year disease-specific survival rate for the radiotherapy group was 100% and for the surgery group, 93% (p = 0.055). In the surgery group 5-year disease-specific survival rate for the subgroup of cord mobility was 94% and that of impaired cord mobility, 89% (p = 0.5354). Concerning laryngeal preservation the radiotherapy group showed better preservation rate than the surgery group in the subgroup of cord mobility, i.e., 41/51 (80%) versus 6/55 (11%) (p < 0.001) although significant difference was not observed in the lesion with impaired cord mobility, 2/5 versus 4/22 (p = 0.171). CONCLUSION: We recommend radiation therapy for stage II glottic carcinoma with normal cord mobility, although further study is needed to improve the preservation rate of the larynx with keeping the disease-specific survival for the lesion with impaired cord mobility.     

Postoperative radiation for squamous cell carcinoma metastatic to cervical lymph nodes from an unknown primary site: outcomes and patterns of failure

BACKGROUND: This retrospective study assesses the outcomes and patterns of failure in patients with squamous cell carcinoma metastatic to cervical lymph nodes from an unknown primary site treated with combined surgery and postoperative radiotherapy. METHODS: One hundred thirty-six patients with squamous cell carcinoma metastatic to cervical lymph nodes from an unknown primary source were treated postoperatively with radiotherapy at the University of Texas M. D. Anderson Cancer Center between the years 1968 and 1992. Stage distribution was: N1, 31 patients; N2a, 49; N2b, 25; N2c, 3; N3, 18; and Nx, 10. Thirty-nine patients had excisional biopsies only, 64 patients underwent modified neck dissections, and 33 had radical neck dissections. Extracapsular extension was present in 87 cases. Fifty-nine patients had multiple nodes involved. The median duration of follow-up for surviving patients was 8.7 years. RESULTS: Twelve patients, all with extracapsular nodal disease, developed regional relapse. The 5-year actuarial rates of regional relapse in patients with and without extracapsular nodal disease were 16% and 0%, respectively (p = .004). Nine patients (22%) with extracapsular disease and multiple nodes relapsed compared with three patients (7%) with extracapsular disease and a solitary node (p = .02). None of the patients treated with excisional biopsy and radiotherapy relapsed regionally. No statistically significant relationship between dose, treatment duration, time interval between surgery, and the start of radiotherapy and relapse was detected. The 2-, 5-, and 10-year actuarial disease-specific survival rates were 82%, 74%, and 68%, respectively. Fourteen patients developed cancers in head and neck mucosal sites; six of these cancers were located in unirradiated tissues. CONCLUSIONS: Relapse occurred infrequently in patients treated with excisional biopsies and postoperative radiotherapy. Extracapsular extension and multiple nodes were associated with worse regional control and disease-specific survival. These results appear consistent with those expected for patients with advanced neck disease and a known primary site, and the absence of a primary site should not exclude patients from studies aiming to improve outcomes in patients with extensive neck disease from a head and neck squamous cell cancer. We continue to recommend radiation to the necks and pharyngeal axis for patients suspected of having residual microscopic disease following surgery for squamous cell carcinoma metastatic to the neck from an unknown primary site.     

The role of squamous cell carcinoma antigen in the management of laryngeal and hypopharyngeal cancer

BACKGROUND: The efficacy of squamous cell carcinoma antigen (SCC-Ag) in laryngeal cancer to predict those patients who will relapse after primary treatment (surgery or radiotherapy) and its utility to detect relapses early and thereby increase salvage rates and cure were assessed. METHODS: Sixty healthy donors and 168 patients with laryngeal cancer were included in this prospective trial. Squamous cell carcinoma antigen was measured at diagnosis in all patients, 24 hours and 1 week after surgery in 113 patients and every 10 Gy of administered dose and 2 weeks after treatment in 49 patients primarily referred to radiotherapy. The marker was determined every 3-6 months during follow-up. All patients who relapsed had SCC-Ag studies before and after salvage treatment. RESULTS: The selected cut-off value was 1.5 ngr/ml (mean value in control group, 0.65 + 2 standard deviation [0.38]). Seventy-eight percent of patients with cancer had elevated SCC-Ag values at diagnosis. Squamous cell carcinoma antigen was statistically related to TNM categories (T, P < 0.04; N, P < 0.05; Stage, P < 0.01). Seventy-five percent of those patients with previously elevated pretreatment values normalized after treatment. Incomplete surgical resection (P < 0.0001) or persistence of the disease after radiotherapy (P < 0.01) were related to high posttreatment values. Squamous cell carcinoma antigen was elevated in 88% of the patients who relapsed. In 55% of the recurrences, SCC-Ag was elevated 3 months before pathologic confirmation of relapse. Salvage by surgery or radiotherapy was effective in 70% of the patients. Squamous cell carcinoma antigen posttreatment values were the most important factor in predicting disease free survival (DFS) (P < 0.0001) and overall survival (P < 0.03). CONCLUSIONS: Squamous cell carcinoma antigen is an excellent marker of residual disease after primary treatment that can lead to the addition of other therapeutic procedures (surgery and postoperative radiotherapy). The absence of posttreatment SCC-Ag is the best predictor of DFS, its presence detects recurrence in early stages, permitting salvage of an increased proportion of patients primarily referred for palliative treatment.     

Combined chemotherapy and radiotherapy, followed or not by surgery, in squamous cell carcinoma of the esophagus

BACKGROUND: This study was designed to evaluate the feasibility of a neo-adjuvant combined chemo-radiotherapy in patients with localized squamous cell carcinoma of the esophagus. PATIENTS AND METHODS: Forty-two patients with squamous cell carcinoma of the esophagus, stages II and III (or stage I if considered to be poor candidates for immediate curative surgery), age less than 70 years and WHO performance status 0 to 2, were enrolled in a study of radiotherapy combined with chemotherapy, consisting of 2 (operated patients) or 3 (nonoperated patients) courses of cisplatin, vindesine, mitomycin-C or cisplatin, vinblastine. Surgery was routinely proposed to patients. RESULTS: Thirty-seven patients (88%) received full preoperative therapy. Of 30 patients responding to this preoperative therapy, 12 had a third cycle of treatment and 15 had esophagectomy. Three of the operated patients had no pathological evidence of residual tumour. Median survival of all 42 patients is 11 months and the 2-year survival rate is 29%. There is no difference in survival among responding operated or non-operated patients. Our group represents 95% of all eligible cases of squamous cell carcinoma of the esophagus occurring in Geneva during the study period. CONCLUSION: Our series gives a realistic view of the median survival of a population of patients eligible for neo-adjuvant therapy of esophagus cancer, and suggests that secondary surgery might not improve the patient survival. Furthermore, non-selected patients are at high risk for therapy-related death.     

Thymic carcinoma. Ten years' experience in twenty patients

Thymic carcinoma is a rare neoplasm with extremely poor prognosis. To evaluate the outcome of treatment in thymic carcinoma, we reviewed a 10-year (1982 to 1992) experience with 20 consecutive patients in Taichung Veterans General Hospital. There were 9 men and 11 women: ages ranged from 34 to 70 years old (mean 51.4 years). None of these patients had concomitant myasthenia gravis. All of the patients received surgical intervention, and the diagnosis was made by pathologic study. Postoperative staging was made according to the modified Masaoka staging system. None of our patients were in stage I. One patient (5%) had stage II disease, 12 (60%) stage III, and 7 (35%) stage IV. The pathologic subtypes of thymic carcinoma included eight squamous cell carcinomas, seven undifferentiated carcinomas, one lymphoepithelioma-like carcinoma, one clear-cell carcinoma, 1 mucoepidermoid carcinoma, and two carcinoid tumors. Curative resection could be done in seven patients (35%). The overall cumulative survival was 45.9% at 3 years and 34.4% at 5 years. The median survival times for patients with complete and incomplete resection were 39.0 months and 14.3 months, respectively (p = 0.1752). The median survival times of patients with postoperative radiotherapy and without postoperative radiotherapy were 39.3 months and 15.0 months, respectively (p = 0.0738). The median survival times of patients with squamous cell carcinoma and undifferentiated carcinoma were 25.4 months and 11.3 months, respectively (p = 0.1464). Our data show that complete resection, postoperative radiotherapy, and squamous cell carcinoma do not indicate a significantly favorable result, even though they result in longer median survival times. Yet a positive trend of favorable outcome in patients who received postoperative radiotherapy is ambiguously shown.     

Cancer of the oesophagus

Oesophageal cancer is the fourth most common tumour in developing countries, comprising mainly squamous cell tumours, although the incidence of adenocarcinoma has increased enormously over the last decades. Surgical resection has long been acknowledged as the mainstay of treatment, and developments in surgical technique are reviewed. The roles of radiotherapy and chemotherapy in the management of oesophageal cancer remain unclear, especially as the majority of studies to date have been uncontrolled trials. We present an analysis of 601 patients who underwent resection for carcinoma of the oesophagus between 1970 and 1994 in the Department of Clinical Surgery, St James's Hospital, Dublin. The analysis shows clearly that, while peri-operative mortality continues to improve, conventional surgery offers little prospect of cure in the majority of cases. We have therefore embarked upon a prospective controlled trial of neoadjuvant chemoradiotherapy followed by surgery versus surgery alone in patients with adenocarcinoma or squamous cell tumours of the oesophagus. Preliminary results indicate that multi-modality treatment may have a valuable role to play in the treatment of carcinoma of the oesophagus.     

Pelvic recurrence of cervical cancer: the prognostic relationship to the retreatment modalities

OBJECTIVE: To investigate the prognostic factors in relation to retreatment modalities in patients with recurrent cervical carcinoma. METHODS: According to initial therapy, 194 patients with recurrence were grouped as: (1) surgery, 22 cases; (2) surgery and radiotherapy, 24 cases, and (3) radiotherapy alone, 148 cases. Factors such as clinical stage, sites of recurrence, time of diagnosis of recurrence after initial therapy and modalities of retreatment were analyzed. RESULTS: There were 19 cases alloted to stage I, 51 cases to stage II (IIa 23 and IIb 28) and 124 cases to stage III (IIIa 21 and IIIb 103); histopathologically confirmed squamous cell carcinoma in 181 cases and adenocarcinoma 13 cases. Central recurrences were found in 91 cases and lateral or pelvic recurrences in 103 cases. Time of diagnosis of recurrence within 2 years from initial treatments was shown in 118 patients and above 2 years in 76 patients. In 147 of the 194 patients retreated, those of the group 1 obtained a median survival rate of 24 months, which was significantly longer than that of group 2, and group 3. The sites of recurrence did not significantly affect the survival. CONCLUSION: Radiotherapy remains the treatment of choice for patients with pelvic recurrence after surgery. Previously irradiated patients retreated for recurrence by radiotherapy and (or) chemotherapy had lower response rates. The optimal therapy for these patients should be comprehensive managements including surgery, radiotherapy and chemotherapy.     

Concurrent radiotherapy and chemotherapy with protracted continuous infusion of 5-fluorouracil in inoperable esophageal squamous cell carcinoma

PURPOSE: The feasibility of a concurrent chemoradiotherapeutic protocol for patients with inoperable esophageal squamous cell carcinoma was tested. METHODS AND MATERIALS: Concurrent chemoradiotherapy using protracted low-dose continuous infusions of five-fluorouracil (5-FU; 250-300 mg/m2/24 h) and standard external beam irradiation was given to 28 patients with inoperable esophageal squamous cell carcinoma between November 1991 and June 1993. RESULTS: For 25 patients receiving a total dose of > or = 60 Gy and concurrent 5-FU infusion for more than 5 weeks, the complete response rate was 52%. Local progression-free rate in this chemoradiotherapy group was significantly higher than the historical controls treated by radiotherapy alone (p < 0.05). A multivariate analysis revealed the treatment scheme (concomitant chemoradiotherapy vs. radiotherapy alone) to be a significant factor in local control (p < 0.01). Swallowing pain (39%), anorexia (39%), and nausea (32%) were the most frequent early reactions. Serious late radiation complications have not been observed. CONCLUSION: The concurrent chemoradiotherapy using protracted low-dose continuous infusion of 5-FU and standard radiotherapy is an effective and safe method to obtain a local control in inoperable esophageal squamous cell carcinoma.     

Squamous cell carcinoma of the thoracic esophagus following radiation therapy for breast cancer

Between 1981 and 1995, 4 patients (3 females, 1 male; aged 48-80) were diagnosed with squamous cell carcinoma of the esophagus, following mediastinal irradiation for breast cancer. The interval between irradiation and the presentation of esophageal cancer was 10.75 years on average (7-19). The treatment consisted of: radiotherapy only; a partial esophagectomy with proximal gastrectomy without post-operative radiotherapy; laser photocoagulation for a superficial tumor; and, palliative treatment including gastrostomy, tracheal photocoagulation and chemotherapy for 1 patient suffering from advanced stage cancer with tracheal invasion, respectively. Radiotherapy of the esophageal cancer (exclusive or adjuvant) should take into account previous esophageal radiation therapy. The indications of curative excision surgery are the same as for other types of esophageal cancer, but the anastomoses should be performed in a non-irradiated area. Excision by esophageal stripping without thoracotomy is contraindicated because of the presence of peri-esophageal sclerosis. Preventive measures in radiation therapy for breast cancer are suggested.     

Changes in pain sensitivity during neurosis in rats]

OBJECTIVE: Few cases of verrucous carcinoma of the penis with foci of invasive squamous cell carcinoma have been reported and denominated "hybrid tumors". The accuracy of this term is discussed in this paper. METHODS/RESULTS: A huge penile mass in a patient that had undergone three previous operations for lesions diagnosed as verrucous carcinoma is reported. Partial penectomy was performed. Histological examination showed a very well-differentiated squamous cell carcinoma. PCR (polymerase chain reaction) did not detect any type of human papillomavirus (HPV) in the tumor. CONCLUSIONS: Verrucous carcinoma is a strictly-defined lesion with a different biological behaviour from that of squamous carcinoma. Preoperative deep biopsy may miss the squamous cell carcinoma. Definitive diagnosis can only be achieved by histological examination of the surgical specimen. In future, DNA studies could possibly support preoperative diagnosis of this lesion.     

Factors regulating SCC antigen expression in squamous cell carcinoma of the uterine cervix

Expression of squamous cell carcinoma (SCC) antigen emerged concurrently with squamous formation of the uterine cervix and increased during the neoplastic transformation of the cervical squamous epithelium. SCC antigen expression differed considerably among the histomorphologic cell types of cervical carcinoma. Large cell nonkeratinizing carcinoma contained high levels of the antigen. In contrast, no appreciable expression of SCC antigen was observed in small cell nonkeratinizing carcinoma. The pattern of SCC antigen expression closely coincided with EGF receptor (EGF-R) expression in cervical squamous neoplasia. This suggests that the expression of SCC and EGF-R in cervical carcinoma is related to the differentiation or dedifferentiation processes of the tumor cells. SCC production by CaSki cervical epidermoid carcinoma cells was stimulated by EGF. It seems likely that an autocrine system, in which EGF serves as the signal, may exist in cervical squamous carcinoma. 17beta-estradiol and L-triiodothyronine were found to upregulate EGF-R expression, proliferative potential and SCC production in the CaSki cervical carcinoma cells.     

Cell cycle arrest and release in starfish oocytes and eggs

A neural net-based, semiautomated, interactive computerized cell analysis system (The PAPNET system, Neuromedical Systems, Suffern, NY) was used to examine cells from 138 esophageal smears obtained by lavage, brushings, or balloon from as many patients. From each smear, trained human observers examined 128 cell images selected by the machine. Abnormal cells were identified in all 35 patients with cancer, whether esophageal, gastric, oral, or metastatic. Further, in 11 smears, the displayed images allowed the recognition of effects of radiotherapy and, in 14 smears, the diagnosis of a specific tumor type, such as squamous cell carcinoma (8 patients) or adenocarcinoma (6 patients). In 3 additional cases, the diagnosis of "carcinoma, not further specified," was established. One case of esophageal carcinoma in situ, not previously recognized on a smear or in the biopsy specimen, and one case of gastric adenocarcinoma, not recognized in the smear, were identified in PAPNET-generated images. The possible application of the apparatus to the triage of smears and population screening for esophageal and gastric carcinoma precursors is discussed.     

Preoperative irradiation therapy and radical hysterectomy: prognostic value of tumor regression after initial irradiation of squamous cell carcinoma of the cervix

OBJECTIVE: To investigate the role of tumor persistence in patients submitted to irradiation therapy and radical hysterectomy. DESIGN: A retrospective analysis of prognostic factors. LOCATION: Hospital A.C. Camargo, S?o Paulo, Brazil, a private non-profitmaking foundation and tertiary referral centre. PATIENTS: A total of 629 cases of invasive squamous cell carcinoma of the cervix were studied. Criteria for inclusion in the study were: confirmed histological diagnosis of squamous cell carcinoma and no previous treatment (except for preoperative radiotherapy carried out at the Hospital A.C. Camargo itself). At the end of the follow-up period, 410 patients (65%) had no evidence of disease and 219 (34.8%) had died because of the tumor. INTERVENTION: The patients were submitted to radical surgery and radiation therapy, separately or in combination between 1953 and 1982. MAIN OUTCOMES MEASURES: Multivariate analysis of the different variables was performed according to the Cox regression method. RESULTS: The variables of prognostic value were, in decreasing order of importance: the decade of patient admission (p = 0.0001), the modality of therapy employed (p = 0.0005), the presence of residual tumor in the surgical specimens (p = 0.0055) and the clinical stage of the disease (p = 0.0575). CONCLUSION: Radiation therapy controlled a considerable number of local tumors and pelvic lymph nodes but not all of them in every patient. There is a specific group of patients for whom radical surgery is necessary to achieve control of the disease.     

Survival of patients with carcinoma of the esophagus treated with combined-modality therapy

Since 1985, 229 cases of carcinoma of the esophagus have been considered for entry into a protocol with the use of preoperative chemotherapy and radiation therapy followed by surgical intervention as the primary element of treatment. One hundred sixty-five patients (93 with adenocarcinoma and 72 with squamous cell carcinoma) had esophagogastrectomy. The 5-year survival of the protocol patients who underwent resection was 25% for both groups--squamous cell carcinoma and adenocarcinoma. Of the protocol patients with squamous cell carcinoma who underwent resection, 40% had a sterilized specimen, whereas of those with adenocarcinoma, 20% had a sterilized specimen. If the patient had a sterilized specimen, the 5-year survival was approximately 60% for adenocarcinoma and 40% for squamous cell carcinoma. Those patients with adenocarcinoma and Barrett's esophagus had a 5-year survival of 55%. Of the patients who underwent only esophagectomy and esophagogastrectomy and had not been entered into the protocol, none lived beyond 3 years. The operative mortality rate for those who had esophagogastrectomy was 5%. Sixty-four patients completed the radiation therapy and chemotherapy but did not undergo surgical procedures because of progressive disease or refusal. Of those patients who completed chemotherapy and radiation therapy without surgical intervention, 5-year survival was 18% in patients with squamous cell carcinoma, whereas no patients with adenocarcinoma survived beyond 3 years. The finding of a sterilized specimen after esophagectomy is a favorable prognostic factor in patients with adenocarcinoma or squamous cell carcinoma. The finding that patients with Barrett's esophagus and adenocarcinoma have an improved chance for survival is perhaps related to an earlier diagnosis. It is clear that some patients with squamous cell carcinoma who did not undergo surgical procedures did have a sterilized specimen, because the survival in this group approached 20% at 5 years.     

Development of a huge varix following endovascular embolization for cerebellar arteriovenous malformation. A case report

A case is presented of a patient with bilateral retinoblastoma, treated at infancy with surgery, chemotherapy and radiotherapy, who subsequently developed at least four additional histologically distinct malignancies: a Ewing sarcoma of the left fibula, two extraskeletal osteosarcomas of the left lower extremity, a mucoepidermoid carcinoma of the right parotid gland and a squamous cell carcinoma of the left paranasal cavity. In addition to retinoblastoma, patients with a germline RB-1 mutation are at high risk of second primary malignancies. An additive carcinogenic effect of cytotoxic therapy in these patients has been assumed. Patients with hereditary retinoblastoma should be under life-long follow-up programmes including a regular head and neck examination for detection of new primaries, especially in the radiation field of the presenting retinoblastoma.     

Salvage therapy of advanced squamous cell carcinoma of the mouth cavity and oropharynx. Results of interstitial high-dose-rate brachytherapy combined with ablative tumor surgery

PURPOSE: The clinical effect of high-dose-rate (HDR) interstitial brachytherapy combined with tumor resection was investigated in this retrospective study on patients with recurrent oral and oropharyngeal squamous cell carcinoma. PATIENTS AND METHODS: Oral and oropharyngeal squamous cell carcinoma in 38 patients were treated over a period of 7 years (1988-1994) by HDR interstitial brachytherapy using Gammamed 12i equipment. Pretreatment of patients in terms of irradiation and surgery differed (33 irradiated with a total dose between 60.0 and 75.6 Gy, including 8 patients with additional surgery; 1 patient with surgery alone, and 4 patients without any pretreatment). Indications for interstitial brachytherapy differed according to individual responses to treatment and medical histories. RESULTS: Interstitial brachytherapy was successful in the majority of patients, i.e. complete remission: 12, partial remission: 19, no change: 2, progression: 5. Local control and overall survival including patients with surgical treatment was 59% and 81% at 6 months and 47% and 49% after 12 months, respectively. CONCLUSION: Interstitial HDR brachytherapy with Iridium 192 is recommended in patients with local recurrences or second primary carcinomas after previous external radiotherapy in the head and neck region. Combination of interstitial brachytherapy and surgery is preferable for these patients.     

Fatal thyroid carcinoma. Anaplastic transformation of adenocarcinoma

Prognosis of well-differentiated carcinoma of the thyroid gland is generally favorable, while that of anaplastic carcinoma, extremely poor. Well-differentiated carcinoma may sometimes be fatal; the most common underlying cause is considered to be due to anaplastic transformation of the original well-differentiated carcinoma to a less differentiated form. We studied 27 consecutive autopsy cases of fatal thyroid cancer treated at the Ito Hospital, Tokyo, during a five-year period, 1969-1973. We found uniform histological features of anaplastic carcinoma in 10 cases and of well differentiated carcinoma in four cases. In addition, co-existence of well-differentiated and anaplastic carcinomas was observed in nine cases and well differentiated and squamous cell carcinomas in four. Circumstantial evidence strongly suggests that malignant transformation is a part of the natural history of thyroid carcinoma, from well-differentiated carcinoma to less differentiated forms, either squamous cell or anaplastic carcinoma.     

Hybrid verrucous squamous cell carcinoma of sinonasal tract: a case report

Verrucous carcinoma is a variant of squamous cell carcinoma and should be distinguished from benign papilloma and well-differentiated nonverrucous squamous cell carcinoma. It is rare tumor of the sinonasal tract. Occasionally, conventional squamous cell carcinomatous components may be seen in verrucous carcinoma. This entity is called a hybrid verrucous squamous cell carcinoma. We report a case of hybrid verrucous squamous cell carcinoma occurring in the nasal cavity and paranasal sinus of a 67-year-old male. The removed mass shows the typical feature of verrucous carcinoma, but focally conventional squamous cell carcinomatous area is also noted. The treatment of this case follows verrucous carcinoma, but close follow up is mandatory because it may potentially spread to regional lymph nodes in contrast to pure form of verrucous carcinoma.