Afatinib versus methotrexate as second-line treatment in Asian patients with recurrent or metastatic squamous cell carcinoma of the head and neck progressing on or after platinum-based therapy (LUX-Head & Neck 3): an open-label, randomised phase III trial.

BACKGROUND: Treatment options are limited for patients with recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC) following progression after first-line platinum-based therapy, particularly in Asian countries. PATIENTS AND METHODS: In this randomised, open-label, phase III trial, we enrolled Asian patients aged ≥18 years, with histologically or cytologically confirmed recurrent/metastatic HNSCC following first-line platinum-based therapy who were not amenable for salvage surgery or radiotherapy, and had an Eastern Cooperative Oncology Group (ECOG) performance status of 0/1. Patients were randomised (2 : 1) to receive oral afatinib (40 mg/day) or intravenous methotrexate (40 mg/m2/week), stratified by ECOG performance status and prior EGFR-targeted antibody therapy. The primary end point was progression-free survival (PFS) assessed by an independent central review committee blinded to treatment allocation. RESULTS: A total of 340 patients were randomised (228 afatinib; 112 methotrexate). After a median follow-up of 6.4 months, afatinib significantly decreased the risk of progression/death by 37% versus methotrexate (hazard ratio 0.63; 95% confidence interval 0.48-0.82; P = 0.0005; median 2.9 versus 2.6 months; landmark analysis at 12 and 24 weeks, 58% versus 41%, 21% versus 9%). Improved PFS was complemented by quality of life benefits. Objective response rate was 28% with afatinib and 13% with methotrexate. There was no significant difference in overall survival. The most common grade ≥3 drug-related adverse events were rash/acne (4% with afatinib versus 0% with methotrexate), diarrhoea (4% versus 0%), fatigue (1% versus 5%), anaemia (<1% versus 5%) and leukopenia (0% versus 5%). CONCLUSIONS: Consistent with the phase III LUX-Head & Neck 1 trial, afatinib significantly improved PFS versus methotrexate, with a manageable safety profile. These results demonstrate the efficacy and feasibility of afatinib as a second-line treatment option for certain patients with recurrent or metastatic HNSCC. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01856478.

[Efficacy and safety of vandetanib on advanced medullary thyroid carcinoma: single center result from a phase â ¢ study].

Objective: There is no effective therapy for patients with advanced medullary thyroid carcinoma (MTC). Vandetanib,a novel multitargeted receptor tyrosine kinase inhibitor, has previously shown antitumor activity in phase Ⅱ studies of patients with advanced MTC. This study was to evaluate the efficacy and the safety of vandetanib on advanced MTC. Methods: This study was an open, international multi-center phase Ⅲ clinical trial and the study number was NCT01298323. The single-center study was a sub-group analysis of the international study, which was conducted on 9 pathologically confirmed advanced MTC patients by Cancer Hospital Chinese Academy of Medical Sciences between March 2012 and October 2017. Vandetanib (300 mg) was orally administered daily till death or withdrawal. The efficacy was evaluated according to RECIST criteria and the adverse events were evaluated according to NCI criteria. Results: The objective response rate was 3/9,and the disease control rate was 4/9. The median progression-free survival was 44 months. All patients who had the elevated levels of calcitonin (CTN) and carcino-embryonic antigen (CEA) before treatment began to show the decreases in the level of CTN and CEA after 3 months and later showed again the increases in the levels of both tumor markers with tumor progression. By ROC curve analysis, CTN was of statistically significance(P<0.05, 95%CI 0.558-0.834), but CEA was not(P>0.05). Adverse events were generally mild (grade 1 or 2),including hypertension (9 cases),skin rash (9 cases), and diarrhea (6 cases). Two patients developed grade 3 elevation of serum glutamate pyruvate transaminase and one patient developed grade 3 elevation of drug-related bowel disease. No grade 4 drug-related adverse event occurred. Conclusions: Vandetanib is effective and well tolerated for patients with locally advanced or metastatic MTC who have no chance for surgery. This indicates the increase of CTN is clinically relevant to disease progression, but the number of patients are extremely low, and, therefore further research is needed. Long-term use of vandetanib may cause resistance.

Three-dimensional character of the deformation twin in magnesium.

Deformation twins are three-dimensional domains, traditionally viewed as ellipsoids because of their two-dimensional lenticular sections. In this work, we performed statistical analysis of twin shapes viewing along three orthogonal directions: the 'dark side' (DS) view along the twin shear direction (η1), the twinning plane normal (TPN) view (k1) and the 'bright side' (BS) view along the direction λ(=k1 × Î·1). Our electron back-scatter diffraction results show that twins in the DS and BS views normally exhibit a lenticular shape, whereas they show an irregular shape in the TPN view. Moreover, the findings in the TPN view revealed that twins grow faster along λ the lateral direction than along η1 the forward propagation direction at the initial stages of twin growth. These twin sections are irregular, indicating that growth is locally controlled and the overall shape is not perfectly ellipsoidal. We explain these findings using atomistic models, and ascribe them to differences in the mobility of the edge and screw components of the twinning dislocations.

[Dye-tattooing under ultrasound guidance in preoperative localization of neck recurrences from thyroid cancer].

Objective: To evaluate the efficacy and safety of the application of dye-tattooing under ultrasound guidance in preoperative localization of neck recurrences from thyroid cancer. Methods: Between October 2014 to September 2016, 25 patients with 34 lesions were enrolled. There were 22 cases of papillary thyroid carcinoma and three cases of medullary thyroid carcinoma, all of which could not be detected by computed tomography. Surgeons located the recurrent lesions using dye-tattooing under ultrasound guidance along with radiologist three days before the operation. Results: All lesions were successfully located (100%), 32 of which were located directly and two of which were located indirectly. Postoperative pathological examination confirmed 25 metastases of papillary thyroid carcinoma, two metastases of medullary thyroid carcinoma, and seven cases of false positives. The accuracy of ultrasound diagnosis was 79.4%. After 15 months of follow-up, neither tumor residual nor recurrences was detected according to imaging tests. Conclusions: Dye-tattooing under ultrasound guidance represents a reliable and safe method for localization of neck recurrences from thyroid cancer. The cooperation between experienced surgeons and radiologists will be crucial to successful location.

[Management of T3 supraglottic carcinoma: a retrospective study].

Objective: To discuss the strategy of therapeutic management of T3 supraglottic carcinoma. Methods: A retrospective analysis of 459 patients with T3 supraglottic carcinoma treated in our hospital was performed. We evaluated the results of different managements, including surgery alone, preoperative radiotherapy, postoperative radiotherapy and radiotherapy alone. The extent of the lesion was also put into analysis. Statistical analysis of the overall survival (OS), cause-specific survival (CSS), local control (LC), regional control(RC), function-conservation (FC) were performed with the statistical package from SPSS. Results: In all patients, the rates of 5-year OS, CSS, LC, RC and FC were 64.2%, 71.2%, 87.8%, 78.8% and 64.5% respectively. The OS, LC and FC of the patients treated by surgery alone, preoperative radiotherapy and postoperative radiotherapy had no significant difference, and were remarkably better than that of patients treated by radiotherapy alone (P<0.001). In 412 patients treated by surgery, 300 patients received function-conservation laryngectomy. 209 patients (50.7%, 209/412) survived and maintained well-function of larynx for 5 years, which was significantly better than those in the radiotherapy alone group (27.7%, 13/47). The patients with the lesion invading the pre-epiglottic space but limited in supraglottic area had better OS (70.2%), LC (93.5%) and FC (85.1%). The rate of 5-year neck lymphatic metastasis was 56.2%(258/459), and the 5-year OS of patients with N0, N1, N2 and N3 stage were 76.0%, 66.2%, 50.5% and 13.0% respectively. Conclusions: Surgical treatment was the best therapeutic approach for T3 supraglottic laryngeal carcinoma. Most patients with T3 lesions are suitable for function-conservation laryngectomy. Surgical procedure was determined by tumor invaded location and extension. The combined therapy of surgery and radiotherapy had no significant advantage.

[Clinical analysis of secondary cervical lymph node dissection in papillary thyroid carcinoma].

Objective: To investigate the value of secondary cervical lymph node dissection in papillary thyroid carcinoma (PTC). Methods: PTC patients with recurrence re-operated in a previously dissected area at our hospital during 2000-2016 were included in this analysis. Patients were divided according to the operative interval of 6 months. The level and number of lymph node metastasis and the number of lymph node dissection were analyzed to calculate the ratio of lymph node metastasis. Results: A total of 336 PTC patients received 360 side lateral cervical lymph nodes dissection. The ratio of recurrence in unilateral lateral neck is 92.9%(312/336). The ratio of recurrence in multiple levels (more than two regions) were 47.5% (171/360). The recurrence ratio of level Ⅱ, Ⅲ, Ⅳ and Ⅴ were 55.6%(200/360), 44.2%(159/360), 59.7%(215/360) and 10.3%(37/360), respectively. Lymph node metastases were inclined to level Ⅱ (33.6%) and Ⅳ (35.8%). The mean number of lymph node dissection and metastasis in the group of operative interval ≤ 6 months was 26.56 per case and 4.37 per case, respectively. The mean number of lymph node dissection and metastasis in the group of operative interval >6 months was 16.80 per case and 3.20 per case, respectively. The number of lymph node dissection and metastasis between these two groups were significantly different (P=0.001, P<0.001). Conclusions: Lymph node metastasis of PTC patients with secondary cervical lymph node dissection are inclined to level Ⅱ and level Ⅳ. Moreover, multi-level metastasis is not rare. Level Ⅱ and level Ⅳ require more attention in the first operation. Most of the patients undergo reoperation because of residual lymph nodes from the previous treatment. Normalization and completeness of the initial dissection are particularly important to PTC patients.

[Clinical features of postoperative cervical lymph nodes recurrence in papillary thyroid carcinoma].

Objective: To analyse the postoperative metastasis or recurrence of cervical lymph nodes in individual neck levels for papillary thyroid carcinoma and to evaluate the outcomes and complications of re-surgery. Methods: A retrospective cohort study of 259 patients who underwent lymph node dissection for PTC relapse from January 2010 to June 2011. Lymph node metastases in each of neck levels were detected, postoperative complications were evaluated, and the patients were followed up with examining thyroglobulin levels to assess the therapeutic effect.Continuous variables were compared with t test.Categorical variables were compared with Fisher's exact test. Results: Lymph node metastasis was found in 259 cases and lymph node metastasis rates in levels Ⅱ, Ⅲ, Ⅳ, Ⅴ and Ⅵ were 43.2%, 50.2%, 45.6%, 8.1% and 59.1% respectively. In 44 cases received the neck dissection of level Ⅱ, the metastasis rates in the levels Ⅱa and Ⅱb were respectively (52.3% vs 18.2%, P=0.887). Recurrence in unilateral lateral neck was more common than that in bilateral lateral neck (73.1% vs 20.6%, P<0.001). The lymph nodes in lateral neck were more likely to metastasize than those in central region (80.7% vs 59.1%, P<0.001). There were 47 cases (18.1%) had postoperative complications, including 10 cases with permanent hypocalcemia. Conclusions: The scope of re-operation for neck metastasis or recurrence in papillary thyroid carcinoma should include the dissection of levels Ⅱ-Ⅳ and Ⅵ. The incidence of postoperative complications for re-surgery is high, and re-surgery should be performed by experienced surgeon.

[Central compartment reoperation for recurrent/persistent differentiated thyroid cancer].

Objective: To analyze the incidences of complications after central compartment reoperation for recurrent/persistent differentiated thyroid cancer, and to investigate the safety and feasiblity of central compartment reoperation. Methord: A total of 109 patients who underwent central compartment reoperation for recurrent/persistent differentiated thyroid cancer from January 1, 2011 to March 31, 2016 in Cancer Hospital, Chinese Academy of Medical Sciences was analysed retrospectively, and the incidences of reoperation-related complications were evaluated. Results: Among 109 patients, only 10 (9.2%) patients were treated initially in our hospital and remaining patients (90.8%) treated initially in the other hospitals. Surgical approaches for thyroid beds: 61 patients (56.0%) underwent supplemented total thyroidectomy, 3 patients (2.8%) for removal of recurrent thyroid cancer, 2 patients (1.8%) with supplemented total thyroidectomy and removal of recurrent thyroid cancer, and 12 cases (11.0%) had bilateral thyroid lobectomy. Central compartment lymph node dissection: 66 patients (60.6%) underwent bilateral central neck dissection, 40 patients (36.7%) with unilateral central neck dissection. A total of 16 patients (14.7%) had complications. Transient and permanent vocal fold paralysis developed in 9(8.3%) and 2(1.8 %) patients, respectively. Transient and permanent hypoparathyroidism occurred in 2(1.8%) patients and 11 patients (10.1%), respectively. Postoperative bleeding happened in 1 patient (0.9%). with follow-up from 7 to 61 month, median follow-up was 17.2 months. All patients survived, with recurrence in 3 (2.8%) patients. Conclusions: It seems the incidences of complications for thyroid carcinoma reoperation in central compartment is low for the experienced surgeon. The reoperation was safe and feasible.

[Value of jugulo-omohyoid lymph nodes in predicting lateral cervical occult metastasis in patients with papillary thyroid carcinoma].

Objective: To investigate the value of jugulo-omohyoid lymph nodes (JOHLN) in predicting occult lateral cervical lymph node metastasis in patients with papillary thyroid carcinoma (PTC). Methods: The clinicopathological data of 136 out of 2 100 PTC patients, who had a high risk of lateral neck lymph node metastasis and treated by us from January 2010 to December 2015, were retrospectively analyzed. Super selective neck dissection (SSND, level Ⅲ and Ⅳ)was performed and JOHLNs were sent for frozen section in all the 136 cases. The clinicopathological data was analyzed and the significance of JOHLN in predicting lateral cervical LNM was calculated using the SPSS software package. Results: Of the 136 patients, total thyroidectomy was performed in 76 cases (55.9%) and unilateral lobectomy plus isthmus was performed in the other 60 cases (44.1%). SSND was performed in 72 patients (52.9%), level Ⅱ-Ⅳ dissection in 15 (11.0%), and level Ⅱ-Ⅴ dissection in 49 (36.0%). According to the pathological results, 38 patients were pN0(27.9%), 18 (13.2%) were pN1a and 80 (58.8%) were pN1b. The lymph node metastasis(LNM) rates at level Ⅱ-Ⅵ were 19.9%, 43.4%, 42.6%, 2.9%, and 59.6%, respectively. The sensitivity, specificity and accuracy of JOHLN in predicting lateral neck metastasis were 58.8%, 62.9%, and 76.7%, respectively. The rates for predicting level Ⅱ metastasis were 81.5%, 43.2%, and 59.4%, respectively. None of the patients died in the follow-up. Only 1 recurrence was found in level Ⅱ and regional control was achieved after level Ⅱ and Ⅴ dissection. Conclusions: JOHLN has a high accuracy for predicting lateral cervical lymph node metastasis and high sensitivity for level Ⅱ metastasis. For patients with high risk of lateral cervival metastasis, super-selective neck dissection including level Ⅲ and Ⅳ can confirm the stage and reduce the risk of reoperation. Dissection for level Ⅱ, Ⅲ, and Ⅳ is recommended.

[Gastric pull-up reconstruction after pharyngoesphagectomy for advanced hypopharyngeal or cervical esophageal squamous cell carcinoma].

Objective: To analyze the clinical results of gastric pull-up reconstruction following total pharyngoesophagectomy. Methods: A total of 90 patients with hypopharyngeal or cervical esophageal cancinoma who underwent gatric pull-up reconstruction after pharyngoesophagectomy between June 2006 and June 2015 were reviewed retrospectively. Clinical data were analyzed. Rates of survival, recurrence and complicates were calculated with SPSS software. Results: Of 90 patients, 8 patients had hypopharyngeal cancinoma invading cervical esophagus, 51 patients had cervical esophageal carcinoma, and 31 patients had hypophageal and esophageal multiple parimary carcinomas. Forty patients were treated with surgery alone, 29 patients with planned surgery, and 21 patients with salvage surgery. After follow up of 6-104 months with a median of 22 months, 54 patients died and the total 3-year survival rate was 36.3%. Seventeen patients developed local recurrences and 10 patients cervical or mediastinal lymph node metastasis (LNM). The 3-year survival rates of patients with and without recurrence or LNM were respectively 5.9%, and 45.7% (χ2=11.564, P=0.001). Twenty-three patients developed distant metastasis. The 3-year survival rate of patients with and without distant metastasis were respectively 22.9% and 41.8% (χ2=4.534, P=0.033). Multivariate analysis showed local recurrence and distant metastasis as predictors for poor survival. The rates of perioperative mortality and anastomotic fistula were 3.3% (3/90) and 13.3%(12/90), respectively. Conclusions: Gastric pull-up reconstruction is a relatively safe and effective method for esophageal reconstruction after removal of hypopharyngeal or cervical esophageal carcinoma. Some patients could achieve good survival with low mortality and acceptable morbidity after multidisciplinary treatments.

Inactivated Pseudomonas aeruginosa inhibits hypoxia-induced pulmonary hypertension by preventing TGF-ß1/Smad signaling.

Pseudomonas aeruginosa is one of the common colonizing bacteria of the human body and is an opportunistic pathogen frequently associated with respiratory infections. Inactivated P. aeruginosa (IPA) have a variety of biological effects against inflammation and allergy. Transforming growth factor-ß (TGF-ß) signaling plays a critical role in the regulation of cell growth, differentiation, and development in a wide range of biological systems. The present study was designed to investigate the effects of IPA on TGF-ß/Smad signaling in vivo, using a hypoxia-induced pulmonary hypertension (PH) rat model. Sprague Dawley rats (n=40) were exposed to 10% oxygen for 21 days to induce PH. At the same time, IPA was administered intravenously from day 1 to day 14. Mean pulmonary artery pressure (mPAP) and the right ventricle (RV) to left ventricle plus the interventricular septum (LV+S) mass ratio were used to evaluate the development of PH. Vessel thickness and density were measured using immunohistochemistry. Primary arterial smooth muscle cells (PASMCs) were isolated and the proliferation of PASMCs was assayed by flow cytometry. The production of TGF-ß1 in cultured supernatant of PASMCs was assayed by ELISA. The expression levels of α-smooth muscle actin (α-SMA), TGF-ß1 and phospho-Smad 2/3 in PASMCs were assayed by western blot. Our data indicated that IPA attenuated PH, RV hypertrophy and pulmonary vascular remodeling in rats, which was probably mediated by restraining the hypoxia-induced overactive TGF-ß1/Smad signaling. In conclusion, IPA is a promising protective treatment in PH due to the inhibiting effects on TGF-ß1/Smad 2/3 signaling.

[Genotype-phenotype correlations in multiple endocrine neoplasia type 2].

OBJECTIVE: To evaluate the relationship between different RET mutations and the aggressiveness of hereditary medullary thyroid cancer (HMTC) or the presentation of other endocrine disorders in patients with multiple endocrine neoplasia type 2 (MEN2). METHODS: A total of 73 thyroid medullary carcinoma patients from 22 Chinese kindreds who were treated in our center from 2010 to 2015 were enrolled. RET genes in the patients and their relatives were screened. RESULTS: According to the clinical data and 2015 American Thyroid Association (ATA) guidelines, patients were classified into 3 RET mutation risk groups: Modest, 24 cases; High, 48 cases; and Highest, 1 case. Multivariate analysis showed an increased likelihood of MTC stage III or IV at diagnosis with increasing of age and risk. The likelihood increased 11.6% per year of age at surgery (95% confidence interval, 1.040-1.198; P=0.002). The likelihood in patients with high risk was 7.9 times higher than patients with modest risk (95% confidence interval, 1.607-38.717; P=0.003). Aside from one patient with MEN2B, other 72 patients were MEN2A, of them, 28 cases from 7 kindreds with classical MEN2A (codon 634 & 618), 14 cases from 3 kindreds with cutaneous lichen amyloidosis (codon 634), 4 cases from 1 kindred with Hirschsprung's disease (codon 620), and 26 cases from 10 kindreds with familial MTC. CONCLUSION: The aggressiveness of HMTC and the presentation of other endocrine diseases are related to specific RET mutations. For RET mutation carriers, MTC and other endocrine diseases should be diagnosed and treated early based on the RET genotypes.

[Clinical analysis of lymphocytic thyroiditis coexistent with papillary thyroid carcinoma].

OBJECTIVE: To analyse the clinical features and treatment strategies of papillary thyroid carcinoma(PTC) coexistent with lymphocytic thyroiditis (LT). METHODS: A total of 292 patients including 25 males and 267 females with LT and thyroid nodules treated in the department of head and neck surgery between Sep 2011 and Sep 2014 was analysed retrospectively and divided into two groups according to pathological results, of them 262 patients, with a median age of 47 years old, were LT with PTC and 30 patients, with a median age of 54 years old, were LT with benign nodules. Among 262 patients having LT with PTC, 259 were diagnosed as having malignant or suspicious malignant nodules and 3 having benign nodules with ultrasound before surgery, 98 cases were considered multifocal malignant nodules by preoperative ultrasound, and 112 cases were positive in cervical lymph nodes, including bilateral positive in 37 cases. Of 30 patients having LT with benign nodules, 14 were diagnosed malignant or suspicious malignant nodules and 16 benign nodules. RESULTS: The mean age in 262 patients with PTC was less significantly than that in 30 patients with benign nodules (P<0.05). Ultrasound showed a high proportion of calcification and microcalcification in patients with PTC (34%) compared to patients with benign nodules(13%)(P<0.05). There were not significant differences in the mean levels of serum thyroid stimulating hormone(TSH) (2.80 vs 2.99 mU/L, P=0.233), thyroglobulin(TG) (27.14 vs 18.60 µg/L, P=0.747), and anti-thyroglobulin antibodies(ATG)(417.3 vs 378.7 U/ml, P=0.834) between patients with PTC and those with benign nodules. In patients with PTC, multifocal tumor accounted for 42%. The central and lateral lymph node metastasis rates were respectively 50% and 24%, and the occult metastasis rate of lateral neck lymph node was 16%. Univariate analysis showed that age less than 45 years old, multifocal tumor, tumor diameter more than or equal to 2cm and extrathyroidal extension were associated with central lymph node metastasis (P<0.05), but not with lateral neck metastasis. Multivariate analysis showed a closed correlation only between the lymph node metastases in central and lateral neck levels (P<0.05). CONCLUSIONS: Calcification and microcalcification have the same importance in the ultrasonic diagnosis for PTC in patients with LT. Total thyroidectomy and prophylactic central lymph node should be a choice for LT with PTC. Lymph node metastasis in level Ⅵ indicates the possibility of lateral cervical lymph node metastasis in the patients having LT with PTC.

Primary salivary gland-type carcinomas of the nasopharynx: prognostic factors and outcome.

Primary salivary gland-type carcinomas of the nasopharynx (SNPC) are a rare malignancy with diverse clinical behaviour and different prognoses. Previous studies have reported on limited patient populations, and few long-term studies have outlined outcomes and prognostic factors. Controversy exists regarding the treatment policy for SNPC. The aim of this study was to define management approaches, therapeutic outcomes, and prognostic factors for SNPC. The medical records of 54 patients with SNPC at one institution between 1963 and 2006 were reviewed. Patient records were analysed for management approaches, outcomes, and prognostic factors. After a median follow-up of 61.3 (1.8-245.2) months, the 2-, and 5-year overall survival rates (OS), loco-regional failure free survival rates (LRFFS) and distant failure free survival rates (DFFS) were 84.6% and 61.3%, 74.4% and 55.4%, and 92.0% and 70.0%, respectively. Multivariate analyses indicated that lymph node metastases, date of treatment, and surgical treatment were independent factors for DFFS, whereas histological subtypes and distant metastases were independent factors affecting OS. The optimal treatment policy for patients with SNPC might be surgery plus radiotherapy.

Primary malignant fibrous histiocytoma of the thyroid.

AIMS AND METHODS: To study the clinical features, diagnosis, and treatment of primary malignant fibrous histiocytoma of the thyroid (MFH-T). Treatment and outcome were analyzed retrospectively in a consecutive series of 12 patients with primary MFH-T treated at the Cancer Hospital of the Chinese Academy of Medical Sciences from 1987 to 2007. RESULTS: All 12 patients underwent surgery; surgery alone was used in four patients. Five patients were given post-operative radiotherapy, and one patient was given pre-operative radiotherapy. Two patients were given post-operative chemotherapy. Five patients had locoregional recurrence, and five had distant metastases in follow-up. Median survival was 9 months. One patient is alive, and has no evidence of disease. Six patients died six months after treatment, and the other four patients died in 10, 14, 18, and 24 months after treatment, respectively. Nine patients died of the disease, and one patient died of cerebral hemorrhage after treatment. CONCLUSION: Primary MFH-T is very rare and has a poor prognosis. Although surgical resection of MFH-T is the treatment of choice in MFH-T, the results are unsatisfactory.

Cloning and characterization of a hormonally regulated rat long chain acyl-CoA synthetase.

A previously unidentified gonadotropin-regulated long chain acyl-CoA synthetase (GR-LACS) was cloned and characterized as a 79-kDa cytoplasmic protein expressed in Leydig cells of the rat testis. GR-LACS shares sequence identity with two conserved regions of the LACS and luciferase families, including the ATP/AMP binding domain and the 25-aa fatty acyl-CoA synthetase signature motif, but displays low overall amino acid similarities (23-28%). GR-LACS mRNA is expressed abundantly in Leydig cells of the adult testis and to a lesser degree in the seminiferous tubules in spermatogonia and Sertoli cells. It is also observed in ovary and brain. Immunoreactive protein expression was observed mainly in Leydig cells and minimally in the tubules but was not detected in other tissues. In vivo, treatment with a desensitizing dose of human chorionic gonadotropin caused transcriptional down-regulation of GR-LACS expression in Leydig cells. The expressed protein present in the cytoplasm of transfected cells displayed acyl-CoA synthetase activity for long chain fatty acid substrates. GR-LACS may contribute to the provision of energy requirements and to the biosynthesis of steroid precursors and could participate through acyl-CoA's multiple functions in the regulation of the male gonad.

A novel gonadotropin-regulated testicular RNA helicase. A new member of the dead-box family.

A gonadotropin-regulated testicular RNA helicase (GRTH) was identified and characterized. GRTH cloned from rat Leydig cell, mouse testis, and human testis cDNA libraries is a novel member of the DEAD-box protein family. GRTH is transcriptionally up-regulated by chorionic gonadotropin via cyclic AMP-induced androgen formation in the Leydig cell. It has ATPase and RNA helicase activities and increases translation in vitro. This helicase is highly expressed in rat, mouse, and human testes and weakly expressed in the pituitary and hypothalamus. GRTH is produced in both somatic (Leydig cells) and germinal (meiotic spermatocytes and round haploid spermatids) cells and is developmentally regulated. GRTH predominantly localized in the cytoplasm may function as a translational activator. This novel helicase could be relevant to the control of steroidogenesis and the paracrine regulation of androgen-dependent spermatogenesis in the testis.

The rat 17beta-hydroxysteroid dehydrogenase type III: molecular cloning and gonadotropin regulation.

17Beta-hydroxysteroid dehydrogenase (17betaHSD), the enzyme that catalyzes the final step of testosterone biosynthesis in the testis, was cloned from a rat Leydig cell complementary DNA library to gain insights into the functional requirements, activation mechanisms, and molecular regulation. The 17betaHSD complementary DNA encoded 306 amino acids (molecular mass of 33.7 kDa) and displayed 75% and 85% amino acid sequence homology to the human and mouse 17betaHSD type III enzymes, respectively. Northern analysis revealed a single 1.4-kb messenger RNA (mRNA) species in rat Leydig cells, whereas ovarian mRNA was detected only by RT-PCR amplification. The cloned 17betaHSD expressed in mammalian cell lines specifically catalyzed the reductive reaction in androgen formation with androstenedione as the preferred substrate. This reaction was significantly reduced in the absence of glucose. Expression of the endogenous 17betaHSD gene in rat Leydig cells was inhibited by a single dose of hCG in vivo, with maximum reduction of steady state mRNA levels at 24 h and recovery at 9 days. Such agonist-induced down-regulation of 17betaHSD expression, which preceded the marked reduction of LH receptors, resulted from changes at the transcriptional level and was accompanied by loss of enzymatic activity. These studies have demonstrated a glucose requirement for optimal activity of the enzyme in vitro and for a role of gonadotropin in regulating the expression of 17betaHSD gene in vivo. Cloning of the 17betaHSD type III enzyme from rat Leydig cells will facilitate further investigation of the molecular regulation of its activity in the testis.

Regulation of 3beta-hydroxysteroid dehydrogenase in gonadotropin-induced steroidogenic desensitization of Leydig cells.

3Beta-hydroxysteroid dehydrogenase/delta5-delta4 isomerases (3beta-HSD) are enzymes that catalyze the conversion of delta5 to delta4 steroids in the gonads and adrenal for the biosynthesis of sex steroid and corticoids. In gonadotropin-desensitized Leydig cells, from rats treated with high doses of human CG (hCG), testosterone production is markedly reduced, a finding that was attributed in part to reduction of CYP17 expression. In this study, we present evidence for an additional steroidogenic lesion induced by gonadotropin. Using differential display analysis of messenger RNA (mRNA) from Leydig cells of rats treated with a single desensitizing dose of hCG (2.5 microg), we found that transcripts for type I and type II 3beta-HSD were substantially (5- to 8-fold) down-regulated. This major reduction, confirmed by RNase protection assay, was observed at the high hCG dose (2.5 microg), whereas minor or no change was found at lower doses (0.01 and 0.1 microg). In contrast, 3beta-HSD mRNA transcripts were not changed in luteinized ovaries of pseudopregnant rats treated with 2.5 microg hCG. The down-regulation of 3beta-HSD mRNA in the Leydig cell resulted from changes at the transcriptional level. Western blot analysis showed 3beta-HSD protein was significantly reduced by hCG treatment, with changes that were coincidental with the reduction of enzyme activity and temporally consistent with the reduction of 3beta-HSD mRNA but independent of LH receptor down-regulation. The reduction of 3beta-HSD mRNA resulting from transcriptional inhibition of gene expression, and the consequent reduction of 3beta-HSD activity could contribute to the inhibition of androgen production in gonadotropin-induced steroidogenic desensitization of Leydig cells. The gender-specific regulation of 3beta-HSD by hCG reflects differential transcriptional regulation of the enzymes to accommodate physiological hormonal requirements and reproductive function.

Horizontovertical laryngectomy for supraglottic carcinoma.

Recent decades have seen the expansion of indications for partial laryngectomy. This study focused on the application of horizontovertical laryngectomy for T2 and selected T3 and T4 supraglottic carcinomas. An osteomuscular flap was designed to reconstruct the laryngeal defect to preserve all the essential laryngeal functions. Seventy-six patients treated between November 1979 and October 1990 were reviewed retrospectively. All but two were followed up for at least 5 years. There were 11 cases of T2, 57 cases of T3, and 8 cases of T4 tumors. The survival rates of 7 cases of stage II, 56 cases of stage III, and 13 cases of stage IV carcinoma were 100%, 84.3%, and 74.3%, respectively. The functional recovery was satisfactory; 78.4% of 74 patients underwent decannulation, and all but one patient resumed a normal diet. This study showed that conservation surgery is reliable for selected supraglottic cancers, even for those lesions that extend beyond the confines of the supraglottis.