Near-Apneic Ventilation Decreases Lung Injury and Fibroproliferation in an Acute Respiratory Distress Syndrome Model with Extracorporeal Membrane Oxygenation.

RATIONALE: There is wide variability in mechanical ventilation settings during extracorporeal membrane oxygenation (ECMO) in patients with acute respiratory distress syndrome. Although lung rest is recommended to prevent further injury, there is no evidence to support it. OBJECTIVES: To determine whether near-apneic ventilation decreases lung injury in a pig model of acute respiratory distress syndrome supported with ECMO. METHODS: Pigs (26-36 kg; n = 24) were anesthetized and connected to mechanical ventilation. In 18 animals lung injury was induced by a double-hit consisting of repeated saline lavages followed by 2 hours of injurious ventilation. Then, animals were connected to high-flow venovenous ECMO, and randomized into three groups: 1) nonprotective (positive end-expiratory pressure [PEEP], 5 cm H2O; Vt, 10 ml/kg; respiratory rate, 20 bpm), 2) conventional-protective (PEEP, 10 cm H2O; Vt, 6 ml/kg; respiratory rate, 20 bpm), and 3) near-apneic (PEEP, 10 cm H2O; driving pressure, 10 cm H2O; respiratory rate, 5 bpm). Six other pigs were used as sham. All groups were maintained during the 24-hour study period. MEASUREMENTS AND MAIN RESULTS: Minute ventilation and mechanical power were lower in the near-apneic group, but no differences were observed in oxygenation or compliance. Lung histology revealed less injury in the near-apneic group. Extensive immunohistochemical staining for myofibroblasts and procollagen III was observed in the nonprotective group, with the near-apneic group exhibiting the least alterations. Near-apneic group showed significantly less matrix metalloproteinase-2 and -9 activity. Histologic lung injury and fibroproliferation scores were positively correlated with driving pressure and mechanical power. CONCLUSIONS: In an acute respiratory distress syndrome model supported with ECMO, near-apneic ventilation decreased histologic lung injury and matrix metalloproteinase activity, and prevented the expression of myofibroblast markers.

Changes in the pattern of fibrosis in the rat lung with repetitive orotracheal instillations of gastric contents: evidence of persistent collagen accumulation.

Recurrent aspiration of gastric contents has been associated with several interstitial lung diseases. Despite this association, the pathogenic role of aspiration in these diseases has been poorly studied and little is known about extracellular matrix (ECM) changes in animal models of repetitive events of aspiration. Our aim was to study the repair phase of lung injury induced by each of several instillations of gastric fluid in Sprague-Dawley rats to evaluate changes in ECM and their reversibility. Anesthetized animals received weekly orotracheal instillations of gastric fluid for 1, 2, 3, and 4 wk and were euthanized at day 7 after last instillation. For reversibility studies, another group received 7 weekly instillations and was euthanized at day 7 or 60 after last instillation. Biochemical and histological measurements were used to evaluate ECM changes. Lung hydroxyproline content increased progressively and hematoxylin and eosin, Masson's trichrome, and alpha-SMA stains showed that after a single instillation, intra-alveolar fibrosis predominated, whereas with repetitive instillations this fibrosis pattern became less prominent and interstitial fibrosis progressively became evident. Both type I and III collagen increased in intra-alveolar and interstitial fibrosis. Imbalance between matrix metalloproteinase-2 (MMP-2) activity and tissue inhibitor of metalloproteinase-2 (TIMP-2) expression was observed, favoring either collagen degradation or accumulation depending on the number of instillations. Caspase-3 activation was also dose dependent. ECM changes were partially reversible at long-term evaluation, since Masson bodies, granulomas, and foreign body giant cells disappeared, whereas interstitial collagen accumulated. In conclusion, repetitive lung instillations of gastric fluid induce progressive fibrotic changes in rat lung ECM that persist at long-term evaluation.

Elastin degradation products in acute lung injury induced by gastric contents aspiration.

BACKGROUND: Gastric contents aspiration is a high-risk condition for acute lung injury (ALI). Consequences range from subclinical pneumonitis to respiratory failure, depending on the volume of aspirate. A large increment in inflammatory cells, an important source of elastase, potentially capable of damaging lung tissue, has been described in experimental models of aspiration. We hypothesized that in early stages of aspiration-induced ALI, there is proteolytic degradation of elastin, preceding collagen deposition. Our aim was to evaluate whether after a single orotracheal instillation of gastric fluid, there is evidence of elastin degradation. METHODS: Anesthesized Sprague-Dawley rats received a single orotracheal instillation of gastric fluid and were euthanized 4, 12 and 24 h and at day 4 after instillation (n = 6/group). We used immunodetection of soluble elastin in lung tissue and BALF and correlated BALF levels of elastin degradation products with markers of ALI. We investigated possible factors involved in elastin degradation and evaluated whether a similar pattern of elastin degradation can be found in BALF samples of patients with interstitial lung diseases known to have aspirated. Non-parametric ANOVA (Kruskall-Wallis) and linear regression analysis were used. RESULTS: We found evidence of early proteolytic degradation of lung elastin. Elastin degradation products are detected both in lung tissue and BALF in the first 24 h and are significantly reduced at day 4. They correlate significantly with ALI markers, particularly PMN cell count, are independent of acidity and have a similar molecular weight as those obtained using pancreatic elastase. Evaluation of BALF from patients revealed the presence of elastin degradation products not present in controls that are similar to those found in BALF of rats treated with gastric fluid. CONCLUSIONS: A single instillation of gastric fluid into the lungs induces early proteolytic degradation of elastin, in relation to the magnitude of alveolar-capillary barrier derangement. PMN-derived proteases released during ALI are mostly responsible for this damage. BALF from patients showed elastin degradation products similar to those found in rats treated with gastric fluid. Long-lasting effects on lung elastic properties could be expected under conditions of repeated instillations of gastric fluid in experimental animals or repeated aspiration events in humans.

Acute lung injury by gastric fluid instillation: activation of myofibroblast apoptosis during injury resolution.

BACKGROUND: Gastric contents aspiration in humans has variable consequences depending on the volume of aspirate, ranging from subclinical pneumonitis to respiratory failure with up to 70% mortality. Several experimental approaches have been used to study this condition. In a model of single orotracheal instillation of gastric fluid we have shown that severe acute lung injury evolves from a pattern of diffuse alveolar damage to one of organizing pneumonia (OP), that later resolves leaving normal lung architecture. Little is known about mechanisms of injury resolution after a single aspiration that could be dysregulated with repetitive aspirations. We hypothesized that, in a similar way to cutaneous wound healing, apoptosis may participate in lung injury resolution by reducing the number of myofibroblasts and by affecting the balance between proteases and antiproteases. Our aim was to study activation of apoptosis as well as MMP-2/TIMP-2 balance in the sub-acute phase (4-14 days) of gastric fluid-induced lung injury. METHODS: Anesthesized Sprague-Dawley rats received a single orotracheal instillation of gastric fluid and were euthanized 4, 7 and 14 days later (n = 6/group). In lung tissue we studied caspase-3 activation and its location by double immunofluorescence for cleaved caspase-3 or TUNEL and alpha-SMA. MMP-2/TIMP-2 balance was studied by zymography and Western blot. BALF levels of TGF-ß1 were measured by ELISA. RESULTS: An OP pattern with Masson bodies and granulomas was seen at days 4 and 7 that was no longer present at day 14. Cleaved caspase-3 increased at day 7 and was detected by immunofluorescence in Masson body-alpha-SMA-positive and -negative cells. TUNEL-positive cells at days 4 and 7 were located mainly in Masson bodies. Distribution of cleaved caspase-3 and TUNEL-positive cells at day 14 was similar to that in controls. At the peak of apoptosis (day 7), an imbalance between MMP-2 activity and TIMP-2 expression was produced by reduction in TIMP-2 expression. CONCLUSIONS: Apoptosis is activated in Masson body-alpha-SMA-positive and -negative cells during the sub-acute phase of gastric fluid-induced lung injury. This mechanism likely contributes to OP resolution, by reducing myofibroblast number and new collagen production. In addition, pre-formed collagen degradation is favored by an associated MMP-2/TIMP-2 imbalance.

Resolution of lung injury after a single event of aspiration: a model of bilateral instillation of whole gastric fluid.

Gastric aspiration is a high-risk condition for lung injury. Consequences range from subclinical pneumonitis to respiratory failure, with fibrosis development in some patients. Little is known about how the lung repairs aspiration-induced injury. By using a rat model of single orotracheal instillation of whole gastric contents, we studied the time course of morphological and biochemical changes during injury and resolution, and evaluated whether repair involved long-term fibrosis. Anesthetized rats received one gastric fluid instillation. At 4, 12, and 24 hours and 4 and 7 days, we performed lung histological studies and biochemical measurements in bronchoalveolar lavage fluid and lung tissue. Physiological measurements were performed at 12 to 24 hours. Long-term outcome was studied histologically at day 60. During the first 24 hours, severe peribronchiolar injury involving edema, intra-alveolar proteinaceous debris, hemorrhage, increased neutrophils and cytokines, and physiological dysfunction were observed. At days 4 and 7, an organizing pneumonia (OP) pattern developed, with foreign-body giant cells and granulomas. Lung matrix metalloproteinase 9 and 2 activities increased, with metalloproteinase-9 linked to early inflammation and metalloproteinase-2 to OP. At day 60, lung architecture was normal. In conclusion, a continuum of alterations starting with severe injury, evolving toward OP and later resolving, characterizes the rat single aspiration event. In addition to identifying markers of staging and severity, this model reveals that OP participates in the repair of aspiration-induced injury.

Acute lung injury induced by whole gastric fluid: hepatic acute phase response contributes to increase lung antiprotease protection.

BACKGROUND: Gastric contents aspiration in humans is a risk factor for severe respiratory failure with elevated mortality. Although aspiration-induced local lung inflammation has been studied in animal models, little is known about extrapulmonary effects of aspiration. We investigated whether a single orotracheal instillation of whole gastric fluid elicits a liver acute phase response and if this response contributes to enrich the alveolar spaces with proteins having antiprotease activity. METHODS: In anesthetized Sprague-Dawley rats receiving whole gastric fluid, we studied at different times after instillation (4 h -7 days): changes in blood cytokines and acute phase proteins (fibrinogen and the antiproteases alpha1-antitrypsin and alpha2-macroglobulin) as well as liver mRNA expression of the two antiproteases. The impact of the systemic changes on lung antiprotease defense was evaluated by measuring levels and bioactivity of antiproteases in broncho-alveolar lavage fluid (BALF). Markers of alveolar-capillary barrier derangement were also studied. Non-parametric ANOVA (Kruskall-Wallis) and linear regression analysis were used. RESULTS: Severe peribronchiolar injury involving edema, intra-alveolar proteinaceous debris, hemorrhage and PMNn cell infiltration was seen in the first 24 h and later resolved. Despite a large increase in several lung cytokines, only IL-6 was found elevated in blood, preceding increased liver expression and blood concentration of both antiproteases. These changes, with an acute phase response profile, were significantly larger for alpha2-macroglobulin (40-fold increment in expression with 12-fold elevation in blood protein concentration) than for alpha1-antitrypsin (2-3 fold increment in expression with 0.5-fold elevation in blood protein concentration). Both the increment in capillary-alveolar antiprotease concentration gradient due to increased antiprotease liver synthesis and a timely-associated derangement of the alveolar-capillary barrier induced by aspiration, contributed a 58-fold and a 190-fold increase in BALF alpha1-antitrypsin and alpha2-macroglobulin levels respectively (p < 0.001). CONCLUSIONS: Gastric contents-induced acute lung injury elicits a liver acute phase response characterized by increased mRNA expression of antiproteases and elevation of blood antiprotease concentrations. Hepatic changes act in concert with derangement of the alveolar capillary barrier to enrich alveolar spaces with antiproteases. These findings may have significant implications decreasing protease burden, limiting injury in this and other models of acute lung injury and likely, in recurrent aspiration.

[Electrocautery and bronchoscopy as a first step for the management of central airway obstruction and associated hemoptysis]. / Electrocauterio y broncoscopia flexible como primera medida en la obstrucción central de la vía aérea y hemoptisis asociada.

BACKGROUND: Central airway obstruction caused by malignant or benign lesions, associated in some cases with hemoptysis, is a condition with high morbidity and mortality. The use of electrocautery by flexible bronchoscopy is an initial treatment option with immediate improvement of obstruction symptoms. It is as effective as Nd: YAG laser. AIM: To describe the usefulness of electrocautery in the management of central obstruction of the airway and hemoptysis. MATERIAL AND METHODS: A retrospective, descriptive study of patients referred for management of central airway obstruction or associated hemoptysis. Diagnoses, symptoms (dyspnea, cough, and hemoptysis) and radiology before and after the procedures were analyzed. RESULTS: Eighteen patients aged 59 ± 12 years (66% males) were evaluated, registering 25 endoscopic procedures. Three conditions were found: partial or complete airway obstruction, hemoptysis and post lung transplant bronchial stenosis. Seventy two percent presented with dyspnea, 61% with cough and 33% with hemoptysis. Sixty six percent of patients had airway obstruction caused by malignant metastatic lesions. After electrocautery, 17 patients (94.4%) improved their symptoms and achieved complete airway clearing. Three patients had significant bronchial stenosis after lung transplant achieving subsequent clearing after electrocautery. CONCLUSIONS: Electrocautery during flexible bronchoscopy is an effective and safe procedure for the management of central airway obstruction and associated hemoptysis.

Acute herpes simplex virus 1 pneumonitis in a patient with systemic lupus erythematosus.

A woman with severe and longstanding systemic lupus erythematosus presented with a 1-week history of fever up to 38°C and pain in her right flank. Computed tomography scan of the chest revealed interstitial infiltrates and multiple nodules. Bronchoalveolar lavage did not show any inflammatory cells. Gram stain and cultures for aerobic and anaerobic bacteria, fungi, and Nocardia; acid-fast staining; polymerase chain reaction for tuberculosis, cytomegalovirus, herpesvirus 6, and parvovirus B19; and IF staining for pneumocystic and Legionella antigen were all negative. Transbronchial biopsy was nondiagnostic. Open lung biopsy with polymerase chain reaction and immunohistochemistry analyses revealed herpes simplex virus 1 infection. Acyclovir therapy was initiated and was followed by significant improvement. Herpes simplex virus 1 infection (although unusual) should be considered in patients with systemic lupus erythematosus with an atypical clinical presentation.

[Survival of patients with biopsy-proven idiopathic pulmonary fibrosis: Chilean National Thorax Institute experience]. / Supervivencia de pacientes con fibrosis pulmonar idiopática diagnosticados por biopsia quirúrgica de pulmón: experiencia del Instituto Nacional del Tórax.

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is the most prevalent of all interstitial lung diseases. The usual underlying pathological picture is an interstitial pneumonia (UIP). AIM: To describe the evolution of a Chilean cohort of patients with IPF. MATERIAL AND METHODS: Patients with the disease were identified at the pathology registry of National Institute of Thoracic Diseases, Santiago, Chile. Patients were included if they had surgical biopsy of UIP and compatible clinical and radiological characteristics. The medical records of included patients were reviewed, recording clinical information and lung function test results. Survival was analyzed obtaining death records from the Chilean National Identification Service. RESULTS: Data from 142 patients with a mean age of 58 years (42% men), were analyzed. Mean initial lung function showed a forced vital capacity (FVC) of 73%, carbon monoxide diffusing capacity (DLCO) of 57% and a distance covered in 6-minute walk (6MWT) of 95% of expected normal values. The median survival was 80 months. Predictors of survival were a DLCO of less than 40% and an oxygen saturation at the end of the 6MWT of less than 89%. CONCLUSIONS: Survival in this group of patients was higher than the figures reported elsewhere. DLCO and the fall of oxygen saturation after walking were predictors of mortality, as previously described in other populations.

Validation of DOE Factorial/Taguchi/Surface Response Models of Mechanical Properties of Synthetic and Natural Fiber Reinforced Epoxy Matrix Hybrid Material.

A validation of the factorial, Taguchi and response surface methodology (RSM) statistical models is developed for the analysis of mechanical tests of hybrid materials, with an epoxy matrix reinforced with natural Chambira fiber and synthetic fibers of glass, carbon and Kevlar. These materials present variability in their properties, so for the validation of the models a research methodology with a quantitative approach based on the statistical process of the design of experiments (DOE) was adopted; for which the sampling is in relation to the design matrix using 90 treatments with three replicates for each of the study variables. The analysis of the models reveals that the greatest pressure is obtained by considering only the source elements that are significant; this is reflected in the increase in the coefficient of determination and in the predictive capacity. The modified factorial model is best suited for the research, since it has an R2 higher than 90% in almost all the evaluated mechanical properties of the material; with respect to the combined optimization of the variables, the model showed an overall contribution of 99.73% and global desirability of 0.7537. These results highlight the effectiveness of the modified factorial model in the analysis of hybrid materials.

Regional differences in gallbladder cancer pathogenesis: insights from a comparison of cell cycle-regulatory, PI3K, and pro-angiogenic protein expression.

BACKGROUND: The variable incidence of gallbladder cancer (GBCA) suggests regional pathogenetic differences. This study compares cell cycle-regulatory, angiogenesis-related, and PI3K pathway protein expression in GBCAs from three continents. METHODS: Immunohistochemical expression of several proteins was assessed, correlated with clinicopathologic variables, and compared among centers from Chile (Fundación Arturo López Pérez [FALP]), Japan (Yokohama City University [YCU]), and the United States (Memorial Sloan-Kettering Cancer Center [MSKCC]). Hierarchical clustering was used to partition the data based on protein-expression and treatment center. RESULTS: Tissue from 117 patients (MSKCC = 76; FALP = 22; YCU = 19) was analyzed. Mdm2 overexpression was seen only at MSKCC (p < 0.0001). Absence of p21 (p = 0.03) and VEGFR2 (p = 0.018) were more common and p27 expression was less frequent (p = 0.047) in tumors from YCU. Ki-67 labeling index in YCU tumors (median = 10) was two-thirds lower than at other centers. On hierarchical clustering analysis, all YCU patients (p = 0.017) and those with early tumors (p = 0.017) clustered separately from MSKCC. Median disease-specific survival after curative intent (R0) resection was 27 months and was similar among centers (p = 0.9). Median disease-specific survival of patients with early tumors was 28.4 months and was higher at YCU (not reached, p = 0.06). CONCLUSIONS: Cell cycle-regulatory protein expression patterns of YCU tumors differed from those treated at FALP and MSKCC. The differential clustering of protein expression and survival in patients with early tumors suggest regional differences in pathogenesis and disease biology.

Merkel cell polyomavirus in non-small cell lung carcinomas from Chile.

Lung cancer is a leading pathology strongly associated with the smoking habit. However, a viral etiology for a subset of patients developing lung cancer has been suggested. Polyomaviruses (PyVs) are small double stranded DNA viruses associated with the development of some human diseases. However, a causal role of these viruses in human cancer has been difficult to demonstrate. In this study, eighty-six non-small cell lung carcinomas (NSCLCs), including adenocarcinomas (AdCs) and squamous cell lung carcinomas (SQCs) from Chile were analyzed for the presence of PyVs using polymerase chain reaction (PCR). All of the specimens were positive for a fragment of the betaglobin gene. We found that 4/86 (4.7%) of lung carcinomas were positive for PyVs. After sequencing and BlastN alignment, all four cases were identified as Merkel cell polyomaviruses (MCV) that corresponded to two AdCs and two SQCs. A non-significant statistical association was found between the presence of MCV and clinic-pathological features of the patients and tumors. In addition, 1/4 (25%) of the carcinomas were actively expressing large T antigen (LT) transcripts, as demonstrated by reverse-transcriptase PCR (RT-PCR). Thus a possible role of MCV in a very small subset of patients with lung cancer cannot be ruled out and warrants more investigation.

Clinical characterization and treatment of head and neck mucosal melanoma: a Chilean experience.

OBJECTIVES: Head and neck mucosal melanoma (HNMM) is a rare disease with a poor prognosis. The aim of this research was to analyze clinical characteristics and prognostic factors in a Latin American cohort. STUDY DESIGN: A retrospective chart review of patients with HNMM treated between 2008 and 2019 was conducted. Demographic characteristics, tumor characteristics, surgical treatment, adjuvant therapy, and oncologic outcomes were recorded. RESULTS: Twenty HNMMs were identified; 60% were in men. The most frequent primary location was the nasal cavity (10; 50%). Regional disease was uncommon and limited to the oral cavity. The median overall survival was 29 months; the 3- and 5-year overall survival rates were 37.2% and 26.6%, respectively. Univariate analysis revealed that predictors of a worse overall survival were paranasal location (hazard ratio [HR], 4.61; 95% confidence interval [CI], 1.61-18.40; P = .030), positive lymph nodes (HR, 6.00; 95% CI, 1.30-27.7; P = .022), positive margins (HR, 4.32; 95% CI, 1.08-17.2; P = .039), bone invasion (HR, 3.27;95% CI, 1.05-10.1; P = .041), and lymphovascular invasion (HR, 3.82; CI, 1.03-14.2; P = .045). Three-year recurrence-free survival was 17.3%, and most of the recurrences were with distant disease. CONCLUSIONS: HNMM is an infrequent disease with an aggressive behavior. Survival outcomes are related to location of the primary disease, regional spread, lymphovascular invasion, and bone invasion.

Diagnostic Accuracy of 18F-PSMA-1007 PET/CT Imaging for Lymph Node Staging of Prostate Carcinoma in Primary and Biochemical Recurrence.

Prostate-specific membrane antigen (PSMA)-ligand PET/CT is performed on patients with prostate cancer to stage the disease initially or to identify sites of recurrence after definitive therapy. On the basis of clinical results, 18F-PSMA-1007 is a promising PSMA PET tracer, but detailed histologic confirmation has been lacking. Methods: Ninety-six patients with prostate cancer underwent 18F-PSMA-1007 PET/CT followed by either radical prostatectomy with lymphadenectomy or salvage lymphadenectomy. The histologic findings of PSMA PET-positive nodes were analyzed retrospectively. A lesion-based and patient-based analysis was performed comparing all positive lesions and only lesions larger than 3 mm on histopathology. Results: Of the patients, 90.6% received 18F-PSMA-1007 PET/CT for staging before the primary treatment, whereas 9.4% underwent imaging for biochemical recurrence. In 34.4% of the cohort, positive lymph nodes were present on imaging. In total, 1,746 lymph nodes were dissected in 96 patients. 18F-PSMA-1007 PET had a lesion-based sensitivity of 81.7%, a specificity of 99.6%, a positive predictive value of 92.4%, and a negative predictive value of 98.9% for detecting positive lymph nodes larger than 3 mm. In the analysis of all malignant nodes regardless of size, the overall sensitivity, specificity, positive predictive value, and negative predictive value on lesion-based analysis were 71.2%, 99.5%, 91.3%, and 97.9%, respectively. The patient-based analysis showed a sensitivity of 85.9% and a specificity of 99.5% for lymph nodes larger than 3 mm. Conclusion:18F-PSMA-1007 PET/CT reliably detects malignant lymph nodes and has an exceptional specificity of more than 99% for nodal metastases.

Incidental gallbladder cancer: analysis of surgical findings and survival.

BACKGROUND AND OBJECTIVES: Incidental gallbladder cancer (IGBCA) has risen worldwide and its prognosis depends on complete radical cholecystectomy (CRC). This study evaluated surgical findings during re-operation and survival of patients with IGBCA. METHODS: Demographics, surgical treatment, staging, and survival data for all IGBCA patients who underwent surgery at Instituto Oncológico Fundación Arturo López Pérez (FALP) between 2000 and 2008 were analyzed. Differences between groups were analyzed by Student's t-test, Mann-Whitney, chi-square, or Fisher log-rank tests. RESULTS: Forty-nine patients were studied (38 women/11 men, median age = 58 years). Pathology reports from cholecystectomy showed that 32 patients had a T2 tumor and 12 had positive resection margin. Thirty-six patients underwent surgical re-exploration and 20 underwent CRC; 10 with (+) residual disease and 10 with (-). For patients with at least T1b tumor, median survival was 28 months and 5-year disease-specific survival (DSS) was 29%. The 3-year DSS was 64% for CRC (-), 30% for CRC (+), and 8% for non-resected cases (P < 0.007). The 3-year DSS was better for patients with stage Ib than those with stages II and IV (P < 0.007). CONCLUSIONS: Patients with IGBCA have a high chance of intra-abdominal metastases or local residual disease. In CRC patients, intra-abdominal metastases were associated with a worse prognosis.

[Complications and mortality of extended gastrectomy for gastric cancer]. / Gastrectomía extendida en cáncer gástrico. Evaluación de la morbilidad y mortalidad postoperatoria.

BACKGROUND: Extended gastrectomy allows a complete tumor excision in patients with advanced gastric cancer. AIM: To compare the surgical results of extended (ER) and non-extended gastrectomy (NER) among patients with gastric cancer, and determine factors associated with complications and mortality. MATERIAL AND METHODS: Review of medical records of patients with gastric cancer who underwent complete resection between 2002 and 2008 in an oncological hospital. Demographics, patient-related and therapeutic features were compared between groups, and independent factors were established with multivariate analysis. RESULTS: Seventy four patients, (44 men, median age 62 years) underwent an ER and 103 patients, (56 men, median age 61 years) a NER. Specifically, ER included splenectomy alone in 27 patients, splenectomy associated with other procedure in 24, partial esophagectomy in 18, distal pancreatectomy in 13, hemicolectomy in 8, total esophagectomy in 7, partial hepatectomy in 4, and adrenalectomy in 1. Postoperative complications were observed in 19 patients treated with an ER (26%) and in 11 patients treated with a NER (11%), p < 0.05. Serious complications were higher in patients who underwent an ER compared with NER (6 patients (8%) vs. 4 (4%), respectively) p < 0.05. In the same way, mortality was higher in patients treated with ER when it was compared with NER (4 patients (5%) vs two (2%), respectively), p < 0.05. ER and serum albumin levels were independent factors associated to a higher risk of mortality and rate of complications. CONCLUSIONS: ER was associated with a higher rate of general and severe complications, and mortality.

The role of PET-CT in patients with incidental gallbladder cancer.

INTRODUCTION: After a cholecystectomy, incidental gallbladder cancer (IGC) requires accurate imaging studies to determine the actual extent of the disease to properly tailor subsequent treatment. The aim of this study was to evaluate the utility of (18)F-fluorodeoxyglucose positron emission tomography-computed tomography ((18)FDG PET-CT) to provide optimal pre-treatment staging in patients with IGC. MATERIAL AND METHODS: Between January 2006 and August 2008, all patients with IGC and at least muscular layer invasion were studied with (18)FDG PET-CT. The examination was considered positive when the standardized uptake values (SUV) were >/=2.5. In all instances patients were offered to undergo definitive exploration and possible radical resection. RESULTS: The series included 32 patients, 26 women and 6 men, with a median age of 57 years (range 30-81 years). The examination was performed at a median time of 6 weeks after cholecystectomy (range 2-52 weeks). (18)FDG PET-CT was negative in 13 patients and positive in 19 patients: 9 with localized potentially resectable disease (PRD) and in 10 with disseminated disease. Of the 13 patients with negative PET-CT, 9 refused surgery and 4 underwent formal exploration: 3 patients were resected with no disease identified in the final pathology report (FPR) and 1 was not resected as a result of peritoneal carcinomatosis. Of the 9 with PRD, 4 patients refused reoperation and 5 underwent exploration: 3 were resected with residual disease noted in the FPR and 2 did not undergo resection because of dissemination. Two patients with disseminated disease were reoperated and in both instances disseminated disease was confirmed. The median survival for the entire group was 20.3 months (range 1.6-32.9 months). The median survival for those patients with negative PET-CT was 13.5 months (range 5.6-32.9 months), 6.2 months (range 1.6-18.7 months) for localized potentially resectable disease and 4.9 months (range 2-14.1 months) for disseminated disease (P < 0.003). CONCLUSIONS: For patients presenting with stage T1b or greater IGC, the use of (18)FDG PET-CT will help reduce the number of patients undergoing non-therapeutic re-exploration and may help to determine the likely prognosis. (18)FDG PET-CT might be a useful tool for the selection of patients for potentially curative treatment.

Multicenter Validation of Histopathologic Tumor Regression Grade After Neoadjuvant Chemotherapy in Muscle-invasive Bladder Carcinoma.

Response classification after neoadjuvant chemotherapy in muscle-invasive bladder carcinoma is based on the TNM stage at radical cystectomy. We recently showed that histopathologic tumor regression grades (TRGs) add prognostic information to TNM. Our aim was to validate the prognostic significance of TRG in muscle-invasive bladder cancer in a multicenter setting. We enrolled 389 patients who underwent cisplatin-based chemotherapy before radical cystectomy in 8 centers between 2010 and 2016. Median follow-up was 2.2 years. TRG was determined in radical cystectomy specimens by local pathologists. Central pathology review was conducted in 20% of cases, which were randomly selected. The major response was defined as ≤pT1N0. The remaining patients were grouped into partial responders (≥ypT2N0-3 and TRG 2) and nonresponders (≥ypT2N0-3 and TRG 3). TRG was successfully determined in all cases, and interobserver agreement in central pathology review was high (κ=0.83). After combining TRG and TNM, 47%, 15%, and 38% of patients were major, partial, and nonresponders, respectively. Combination of TRG and TNM showed significant prognostic discrimination of overall survival (major responder: reference; partial responder: hazard ratio 3.5 [95% confidence interval: 1.8-6.8]; nonresponder: hazard ratio 6.1 [95% confidence interval: 3.6-10.3]). This discrimination was superior compared with TNM staging alone, supported by 2 goodness-of-fit criteria (P=0.041). TRG is a simple, reproducible histopathologic measurement of response to neoadjuvant chemotherapy in muscle-invasive bladder cancer. Integrating TRG with TNM staging resulted in significantly better prognostic stratification than TNM staging alone.

Association of Chronic Pancreatitis and Malignant Main Duct IPMN: A Rare but Difficult Clinical Problem.

We report the case of a 70-year-old woman who consulted for recurrent short episodes of mild-to-moderate abdominal pain. Dilated main pancreatic duct was seen on CAT scan and magnetic resonance, with multiple calcifications and intraductal stones, typical in CP. However, for a more pronounced cystic dilatation in the pancreatic head, we could not exclude the coexistence of a main duct IPMN. ERCP was performed, with pancreatic sphincterotomy and extraction of pancreatic stones, but, at the same time, mucin extrusion was seen from the dilated duct through the papilla. Pancreatoduodenectomy was performed. Surgery and histology confirmed malignant IPMN with the typical image of chronic pancreatitis and intraductal stones in the vicinity. The patient is doing well 4 years after the surgery, without recurrence of the malignant disease, with changes of chronic pancreatitis in the pancreatic remnant. This paper discusses the possible relationships between the two entities and emphasizes the need of differential diagnosis.

A 10-Gene Classifier for Indeterminate Thyroid Nodules: Development and Multicenter Accuracy Study.

BACKGROUND: In most of the world, diagnostic surgery remains the most frequent approach for indeterminate thyroid cytology. Although several molecular tests are available for testing in centralized commercial laboratories in the United States, there are no available kits for local laboratory testing. The aim of this study was to develop a prototype in vitro diagnostic (IVD) gene classifier for the further characterization of nodules with an indeterminate thyroid cytology. METHODS: In a first stage, the expression of 18 genes was determined by quantitative polymerase chain reaction (qPCR) in a broad histopathological spectrum of 114 fresh-tissue biopsies. Expression data were used to train several classifiers by supervised machine learning approaches. Classifiers were tested in an independent set of 139 samples. In a second stage, the best classifier was chosen as a model to develop a multiplexed-qPCR IVD prototype assay, which was tested in a prospective multicenter cohort of fine-needle aspiration biopsies. RESULTS: In tissue biopsies, the best classifier, using only 10 genes, reached an optimal and consistent performance in the ninefold cross-validated testing set (sensitivity 93% and specificity 81%). In the multicenter cohort of fine-needle aspiration biopsy samples, the 10-gene signature, built into a multiplexed-qPCR IVD prototype, showed an area under the curve of 0.97, a positive predictive value of 78%, and a negative predictive value of 98%. By Bayes' theorem, the IVD prototype is expected to achieve a positive predictive value of 64-82% and a negative predictive value of 97-99% in patients with a cancer prevalence range of 20-40%. CONCLUSIONS: A new multiplexed-qPCR IVD prototype is reported that accurately classifies thyroid nodules and may provide a future solution suitable for local reference laboratory testing.