Optimization of Erlotinib Plus Sulindac Dosing Regimens for Intestinal Cancer Prevention in an Apc-Mutant Model of Familial Adenomatous Polyposis (FAP).

A clinical trial in patients with familial adenomatous polyposis (FAP) demonstrated that sulindac plus erlotinib (SUL+ERL) had good efficacy in the duodenum and colon, but toxicity issues raised concerns for long-term prevention. We performed a biomarker study in the polyposis in rat colon (Pirc) model, observing phosphorylated Erk inhibition in colon polyps for up to 10 days after discontinuing ERL+SUL administration. In a follow-up study lasting 16 weeks, significant reduction of colon and small intestine (SI) tumor burden was detected, especially in rats given 250 ppm SUL in the diet plus once-a-week intragastric dosing of ERL at 21 or 42 mg/kg body weight (BW). A long-term study further demonstrated antitumor efficacy in the colon and SI at 52 weeks, when 250 ppm SUL was combined with once-a-week intragastric administration of ERL at 10, 21, or 42 mg/kg BW. Tumor-associated matrix metalloproteinase-7 (Mmp7), tumor necrosis factor (Tnf), and early growth response 1 (Egr1) were decreased at 16 weeks by ERL+SUL, and this was sustained in the long-term study for Mmp7 and Tnf. Based on the collective results, the optimal dose combination of ERL 10 mg/kg BW plus 250 ppm SUL lacked toxicity, inhibited molecular biomarkers, and exhibited effective antitumor activity. We conclude that switching from continuous to once-per-week ERL, given at one-quarter of the current therapeutic dose, will exert good efficacy with standard-of-care SUL against adenomatous polyps in the colon and SI, with clinical relevance for patients with FAP before or after colectomy. PREVENTION RELEVANCE: This investigation concludes that switching from continuous to once-per-week erlotinib, given at one-quarter of the current therapeutic dose, will exert good efficacy with standard-of-care sulindac against adenomatous polyps in the colon and small intestine, with clinical relevance for patients with FAP before or after colectomy.

Surgical Treatment in Small-Cell Lung Cancer: Single-Center Experience and Survival.

OBJECTIVE: To evaluate the clinical outcomes of patients with different stages of small-cell lung cancer (SCLC) who underwent surgical treatment. MATERIAL AND METHODS: This retrospective study consisted of 13 patients with SCLC at a tertiary care health center. This study was conducted between 2011 and 2018 at Gaziantep University Faculty of Medicine, Thoracic Surgery Department. Patient follow-up data were collected from medical files. Patients were analyzed according to age, sex, site of resection, clinical stage, pathological stage, recurrence, operation type, chemotherapy, radiotherapy. RESULTS: The study group consisted of 3 females and 10 males (n = 13). The mean age of the patients was 65 ± 9.3 (52-85) years. The most common location of the primary tumor was the right upper lobe (6 patients, 46.2%). The mean tumor size was 4.36 ± 2.38 cm (1-8.5). In our study, 3 patients had already metastases (2 brain and 1 had metastases in more than 2 anatomic sites). Patients with solitary metastases, who underwent lung resection and metastasis excision had similar survival according to patients without metastases. CONCLUSION: Our results show that surgical treatment in SCLC could be contributed to the survival of patients. Therefore, patients must be given a chance for surgery, especially considering that the advances in diagnostic and surgical capabilities have increased the likelihood of early diagnosis and effective surgery.

Acute changes in colonic PGE2 levels as a biomarker of efficacy after treatment of the Pirc (F344/NTac-Apc am1137) rat with celecoxib.

OBJECTIVE: This study sought to evaluate short-term treatment with COX-2 inhibitors and acute changes in colonic PGE2 levels as predictors of long-term efficacy in a genetic model of colorectal cancer. METHODS: Celecoxib oral suspension (40 mg/kg BID) was dosed to Apc-mutant Pirc (F344/NTac-Apcam1137) rats for 4 days (short-term group), or the equivalent dose of 1500 ppm celecoxib was administered in the diet for 4 months (long-term group). Percent inhibition of colonic PGE2 was calculated, and the reduction in colonic PGE2 was assessed in relation to suppression of adenomatous colon polyps. RESULTS: Colonic mucosa PGE2 was fourfold higher in Pirc than in F344 wild-type rats (21 vs. 5.6 pg/mg epithelial tissue), due at least in part to higher COX-2 expression, and this was confirmed by elevated PGE2-d11 levels in Pirc colonic S9 incubations. In the 4-day study, dose-dependent reductions in PGE2 were observed in colonic epithelium (-33% (P>0.05) and -57% (P=0.0012)), after low- and high-dose celecoxib treatments of 4 mg/kg and 40 mg/kg (bid), respectively. In the 4-month study, 1500 ppm celecoxib suppressed colonic epithelium PGE2 by 43.5%, and tumor multiplicity by 80% (P<0.0015). Suppression of plasma 6-keto PGF1α also was corroborated following long-term treatment with 1500 ppm celecoxib (P<0.05). CONCLUSIONS: Acute changes in colonic mucosa PGE2 provided a rapid means of predicting long-term chemopreventive effects from celecoxib, and might be useful for screening of new COX-2 inhibitor compounds.

Acetylation of CCAR2 Establishes a BET/BRD9 Acetyl Switch in Response to Combined Deacetylase and Bromodomain Inhibition.

There continues to be interest in targeting epigenetic "readers, writers, and erasers" for the treatment of cancer and other pathologies. However, a mechanistic understanding is frequently lacking for the synergy observed when combining deacetylase and bromodomain inhibitors. Here we identify cell cycle and apoptosis regulator 2 (CCAR2) as an early target for acetylation in colon cancer cells treated with sulforaphane. N-terminal acetylation of CCAR2 diminished its interactions with histone deacetylase 3 and ß-catenin, interfering with Wnt coactivator functions of CCAR2, including in cells harboring genetically encoded CCAR2 acetylation. Protein domain arrays and pull-down assays identified acetyl "reader" proteins that recognized CCAR2 acetylation sites, including BRD9 and members of the bromodomain and extraterminal domain (BET) family. Treatment with the BET inhibitor JQ1 synergized with sulforaphane in colon cancer cells and suppressed tumor development effectively in a preclinical model of colorectal cancer. Studies with sulforaphane+JQ1 in combination implicated a BET/BRD9 acetyl switch and a shift in the pool of acetyl "reader" proteins in favor of BRD9-regulated target genes. SIGNIFICANCE: These results highlight the competition that exists among the "readers" of acetylated histone and nonhistone proteins and provide a mechanistic basis for potential new therapeutic avenues involving epigenetic combination treatments.

Endobronchial lesions cases treated with interventional bronchoscopic techniques: Our single-center experiences.

BACKGROUND: In this study, we aimed to present our experience with interventional bronchoscopy in the treatment of endobronchial lesions in our clinic. METHODS: Between January 2010 and December 2018, a total of 18 patients (11 males, 7 females; mean age 55.1 years; range, 17 to 82 years) who were diagnosed with an endobronchial lesion using bronchoscopy in our clinic were retrospectively analyzed. Demographic characteristics, presenting symptoms, bronchoscopic procedure, location of the lesion, pathological diagnosis, treatment approaches, success of the bronchoscopic treatment, and follow-up outcomes of the patients were evaluated. RESULTS: Control bronchoscopy was performed in 14 patients and a second control bronchoscopy was performed in eight patients. The lesions were located in the right bronchial system in nine (50%), in the left bronchial system in six (33%), and in the trachea in three patients (17%). Except for one pregnant patient, all interventional procedures were performed with a rigid bronchoscope under general anesthesia. Distal areas which were unable to be reached with the rigid bronchoscope were evaluated by a flexible bronchoscope. There were no complications in any of the patients. At the end of the study, the final control biopsies of all patients were found to be normal. The success rate of interventional bronchoscopic methods was 100%. CONCLUSION: Interventional bronchoscopic methods are the most effective procedures in the diagnosis and treatment of bronchial lesions with a high success rate. Based on our study findings, we suggest that bronchoscopic methods should be preferred as the first-line treatment of benign and selected some malignant endobronchial lesions.

Cardiac findings of sternal fractures due to thoracic trauma: A five-year retrospective study.

BACKGROUND: This study mainly aimed to determine the frequency of sternal fractures in thoracic trauma patients and to assess the differences in surgical need, cardiac findings, and treatment processes between patients with fracture on different sternal zones and displaced and non-displaced sternal fractures. METHODS: We analyzed the data of patients with sternal fracture due to thoracic trauma admitted to a state hospital between January 2011 and December 2015. Patient data comprised demographics, trauma characteristics, clinical findings, and treatment process. RESULTS: Of the 2764 thoracic trauma patients admitted during the study period, 72 (2.6%) had sternal fracture. The median age was 52 (inter quartile range: 61-38) years; the patients were predominantly male (F/M: 18/54). The most common causes of sternal fractures were motor vehicle accident, fall, and work accident. Of all the patients, 15 had displaced fracture. Abnormal echocardiogram findings were significantly more frequent in patients having fractures on the manubrium than in those having fractures on the corpus of the sternum. Patients who had fracture on the corpus had significantly lesser surgery need than those who had fracture on the manubrium of the sternum. Also, there was statistically significant difference between displaced and non-displaced sternal fracture cases in terms of surgery need (p<0.005). CONCLUSION: Abnormal echocardiography findings were more frequent in patients with sternal fracture on the manubrium and displaced fracture.

Surgical treatment of postintubation tracheal stenosis: A retrospective 22-patient series from a single center.

BACKGROUND/OBJECTIVE: We aimed to present cases of postintubation tracheal stenosis (PITS), all due to long-term intubation and treated surgically in a university hospital, and to discuss them in light of the literature. METHODS: In this retrospective study, 22 patients who were treated with tracheal resection and reconstruction due to PITS were included. Demographics, intubation characteristics, localization of stenosis, surgical technique and material, postoperative complications, and survival of patients were recorded. RESULTS: The mean intubation duration was 16.95 days with a median of 15.00 days. Collar incision was applied in 19 cases (86.4%); in two cases (9.1%) a median sternotomy incision was used; and in the remaining case (4.5%), a right thoracotomy incision was made. The mean tracheal stenosis length was 2.14 cm (mean excision length, 2.5 cm). In 17 cases (77.3%), the anterior walls were supported with vicryl (polyglactin) suture one by one. No postoperative complications were observed in 12 cases (54.5%). No recurrence developed during the long-term follow-up of 15 of the 22 patients (68.2%). Two patients (9.1%) died in the early stages after surgery, and five patients (22.7%) had a stent inserted due to restenosis. CONCLUSION: Tracheal resection and end-to-end anastomosis are the most efficient techniques in cases without medical contraindications, despite emerging stent or endoscopic procedures. Endoscopic interventions can be suggested as an alternative to surgery in patients for whom surgery cannot be performed or who develop recurrence.

Prognostic factors in operated T3 non-small cell lung cancer: A retrospective, single-center study of 129 patients.

BACKGROUND: This study aims to investigate the prognostic factors that affect survival rates and durations in patients with T3 non-small cell lung cancer who underwent surgery. METHODS: A total of 129 patients with T3 n on-small c ell l ung c ancer (125 males, 4 females; mean age 60±9.3 years; range 23 to 80 years) who were performed surgery in our clinic between January 1997 and December 2013 were evaluated retrospectively in terms of age, gender, type of resection, tumor histopathology, tumor, node and metastasis staging, lymph node invasion, chemotherapy and radiotherapy, and recurrence. RESULTS: During the evaluation, while 61 patients (47.3%) were alive, 68 (52.7%) had lost their lives. One-, two- and five-year survival rates of the study population were 79.8%, 56.9% and 23.2%, respectively. Mean duration of survival was 41.5±4.0 months (range 33.7-49.4 months). Patient's age or tumor histopathology did not affect the duration of survival. Overall duration of survival was significantly longer in patients of stage IIB, patients who had low stages of lymph node invasion, who were performed lobectomy, who received chemotherapy or radiotherapy or who were without recurrence (p<0.05 for each). Multivariate regression analysis revealed that lymph node invasion, presence of recurrence or pneumonectomy, or failure to have been administered chemotherapy increased mortality risk significantly (hazard ratios 0.217, 3.369, 2.791 and 2.254, respectively). CONCLUSION: Our findings revealed that lymph node invasion, presence of recurrence or pneumonectomy, or failure to have been administered chemotherapy are poor prognostic factors in T3 non-small cell lung cancer. Prognostic factors should be taken into consideration during treatment and follow-up periods of patients with T3 non-small cell lung cancer.

A rare case of peripherally located non-bronchial pulmonary mucous gland adenoma.

Pulmonary mucous gland adenomas are rare benign tumors, which need to be differentiated from malign lung masses. The differential diagnosis is of particular importance for those arising from lung parenchyma in atypical locations. In this article, we report a 70-year-old male patient, who had complaints of cough and expectoration for almost two years. Chest computed tomography showed a 1 cm nodule at the left lower lobe of lung. The tumor was totally resected with mini-thoracotomy and wedge resection and sent to the pathology department for a frozen examination. The frozen result was reported as benign. The pathological diagnosis was mucous gland adenoma. The patient had no postoperative complication and made a complete recovery. Pulmonary mucous adenomas may rarely originate from lung parenchyma and be seen in patients with peripherally located lung lesions.

Outcomes after lobectomy and pneumonectomy in lungcancer patients aged 70 years or older.

BACKGROUND/AIM: For the early stage of nonsmall-cell lung cancer, surgical resection provides the best survival, but the surgical risk generally increases with age because of the increased prevalence of comorbidities, especially cardiovascular disorders. The aim of this study was to compare survival and mortality rates of two groups with different ages, younger and older than 70 years, who went curative resection for nonsmall-cell lung cancer. MATERIALS AND METHODS: We analyzed the patients who underwent curative lung cancer surgery in the Department of Thoracic Surgery of Gaziantep University Research Hospital between January 1997 and November 2014. Patients were divided into 2 groups according to their ages. RESULTS: A total of 497 patients were included in data analysis (381 were under 70 years old and 116 of them were ≥70 years old). The older group showed a 1.4-fold increased risk of mortality hazard ratio when the probability of survival was analyzed by histological type, lymph node involvement, disease stage, and age. CONCLUSION: There was no distinct increase in 30-day mortality rates of patients with nonsmall-cell lung cancer who were ≥70 years old, but the hazard rate for long-term survival was higher in the older group. Curative pulmonary resections due to lung cancer should be carefully performed in septuagenarians.

[A rare complication of blunt trauma; diaphragm-pericardium rupture and cardiac herniation in a child case]. / Künt travmanin nadir komplikasyonu; Çocuk olguda diyafram-perikart rüptürü ve kardiyak herniasyon.

Diaphragma and pericardium rupture is rarely seen after blunt trauma. It's treatment is surgery. A 4-year-old male patient who was operated for diaphragm and pericardium rupture which developed after blunt trauma; rarity of this union, differences in the clinical and radiological features in children was examined.

[Treatment for esophageal perforations: analysis of 11 cases]. / Özofagus perforasyonlarinda tedavi: On bir olgunun analizi.

BACKGROUND: We present 11 cases with esophageal perforations who were treated in our department, with the intent of underlining the importance of surgical intervention. METHODS: We retrospectively analyzed 11 cases of esophageal perforation who were treated from 2005 to 2010. The cases diagnosed within the first 24 hours were regarded as early diagnoses; those diagnosed later than this period were regarded as late diagnoses. RESULTS: The mean age of the patients was 45.8 years. Following the perforation, 3 of the patients had early diagnoses and the others had late diagnoses. Of the 3 cases with early diagnosis, all had primary repair; of the late diagnosis cases, 4 had primary repair, 2 had colonic interposition, 1 had stent implantation, and 1 received medical treatment. All the cases with late diagnoses underwent drainage. The 3 cases who received early treatment recovered without complications. Of the other 8 cases, 1 had leakage from the anastomosis and 1 developed a fistula. Two (18.1%) of our patients died. CONCLUSION: Treatments performed before the development of mediastinitis are lifesaving in esophageal perforation patients. We think that surgical treatment performed within the first 72 hours that includes primary repair would yield favorable results.