Analysis of mismatch repair (MMR) proteins expression in a series of malignant pleural mesothelioma (MPM) patients.

BACKGROUND: Promising results have been reported with immune checkpoint inhibitors (ICI) in a small proportion of MPM patients. MMR deficiency (dMMR) has been well described in several malignancies and was approved as a biomarker for anti-PD-1 inhibitors. Next generation sequencing (NGS) data demonstrated that 2% of MPM harbor microsatellite instability. The aim of this study is to characterize MMR by immunohistochemistry (IHC) in a series of MPM including a subset of patients treated with immunotherapy. METHODS: Tumors of 159 MPM p diagnosed between 2002 and 2017 were reviewed. Formalin-fixed, paraffin-embedded tissue was stained for MLH1, MSH2, MSH6 and PMS2 and tumors were classified as dMMR (MMR protein expression negative) and MMR intact (all MMR proteins positively expressed). We retrospectively collected clinical outcomes under standard chemotherapy and experimental immunotherapy in the entire cohort. RESULTS: MMR protein expression was analyzed in 158 samples with enough tissue and was positive in all of the cases. Twenty two patients received ICI with anti-CTLA4 or anti-PD-1 blockade in clinical trials, 58% had a response or stable disease for more than 6 m, with median progression-free survival (PFS) of 5.7 m (2.1-26.1 m). The median overall survival (mOS) in all population was 15 months (m) (13.5-18.8 m). In a multivariable model factors associated to improved mOS were PS 0, neutrophil-lymphocyte ratio (NLR) < 5 and epithelioid histology (p < 0.001). CONCLUSIONS: In our series we were unable to identify any MPM patient with dMMR by IHC. Further studies are needed to elucidate potential predictive biomarkers of ICI benefit in MPM.

Dual MET and ERBB inhibition overcomes intratumor plasticity in osimertinib-resistant-advanced non-small-cell lung cancer (NSCLC).

BACKGROUND: Third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as osimertinib are the last line of targeted treatment of metastatic non-small-cell lung cancer (NSCLC) EGFR-mutant harboring T790M. Different mechanisms of acquired resistance to third-generation EGFR-TKIs have been proposed. It is therefore crucial to identify new and effective strategies to overcome successive acquired mechanisms of resistance. METHODS: For Amplicon-seq analysis, samples from the index patient (primary and metastasis lesions at different timepoints) as well as the patient-derived orthotopic xenograft tumors corresponding to the different treatment arms were used. All samples were formalin-fixed paraffin-embedded, selected and evaluated by a pathologist. For droplet digital PCR, 20 patients diagnosed with NSCLC at baseline or progression to different lines of TKI therapies were selected. Formalin-fixed paraffin-embedded blocks corresponding to either primary tumor or metastasis specimens were used for analysis. For single-cell analysis, orthotopically grown metastases were dissected from the brain of an athymic nu/nu mouse and cryopreserved at -80°C. RESULTS: In a brain metastasis lesion from a NSCLC patient presenting an EGFR T790M mutation, we detected MET gene amplification after prolonged treatment with osimertinib. Importantly, the combination of capmatinib (c-MET inhibitor) and afatinib (ErbB-1/2/4 inhibitor) completely suppressed tumor growth in mice orthotopically injected with cells derived from this brain metastasis. In those mice treated with capmatinib or afatinib as monotherapy, we observed the emergence of KRAS G12C clones. Single-cell gene expression analyses also revealed intratumor heterogeneity, indicating the presence of a KRAS-driven subclone. We also detected low-frequent KRAS G12C alleles in patients treated with various EGFR-TKIs. CONCLUSION: Acquired resistance to subsequent EGFR-TKI treatment lines in EGFR-mutant lung cancer patients may induce genetic plasticity. We assess the biological insights of tumor heterogeneity in an osimertinib-resistant tumor with acquired MET-amplification and propose new treatment strategies in this situation.

[Colonoscopic findings from a pilot screening study for colorectal cancer in Catalonia]. / Hallazgos colonoscópicos del estudio piloto de cribado de cáncer colorrectal realizado en Cataluña.

OBJECTIVE: to evaluate lesions detected in two screening rounds performed in a pilot screening programme for colorectal cancer in Catalonia, Spain. MATERIAL AND METHODS: a colorectal cancer screening programme was initiated in 2000. The target population included men and women aged 50-69 years. Screening consisted of biennial guaiac-based fecal occult blood testing (FOBT), and colonoscopy for participants with a positive FOBT. Any polyps found were removed, and biopsies were performed for any masses. RESULTS: colonoscopies were performed in 442 of 495 people with positive FOBT. In 213 (48.2%), 36 invasive cancers, 121 high-risk adenomas, 29 low-risk adenomas, and 27 hyperplastic polyps were diagnosed. Lesion size was smaller than 10 mm in 25.8% of cases. Most detected lesions (37.2%) were located in the distal colon, followed by the proximal colon (5.7%) and both locations (5.2%). Advanced neoplasm was significantly associated with male gender and distal location. The prevalence of advanced proximal neoplasms among patients with no distal polyps was 5.1%. CONCLUSIONS: the most common lesions detected by colonoscopy were high-risk adenomas located in the distal colon. FOBT is a suitable method for detecting small precancer lesions during population screening, and is thus a key factor in reducing the incidence of colorectal cancer.

[Interventionist endoscopic ultrasonography. A retrospective analysis of 60 procedures]. / Ultrasonografía endoscópica intervencionista. Análisis retrospectivo de 60 procedimientos.

INTRODUCTION AND OBJECTIVE: interventionist endoscopic ultrasonography is increasingly used because of its growing indications. We present here our retrospective and initial experience (60 procedures) with endoscopic ultrasonography (EUS) both for diagnosis (EUS-FNA) and therapy (EUS-guided tumorectomy and mucosectomy). PATIENTS AND METHOD: in a group with 27 cases including 10 submucosal tumors (SMTs), 2 adenopathies, and 15 potential pancreatic tumors (8 pancreatic cancers), a sectorial EUS-FNA at 7.5 MHz was performed for diagnosis prior to therapy (mainly surgical). A pancreatic pseudocyst was drained. In 21 cases with 27 SMTs (10 patients with 13 carcinoids) a tumorectomy was carried out using the standard loop or assisted polypectomy technique with submucosal injection, and in a few cases (two) using elastic band ligation following a radial EUS at 7.5, 12, or 20 MHz. In 6 cases of superficial gastroesophageal cancer or gastric dysplasia an endoscopic mucosal resection (classic EMR) was performed after EUS or MPs at 7.5 and 20 MHz. Fifty-five patients with 60 lesions, 29 femaes and 26 males with a mean age of 60 years (30-88 years) were retrospectively analyzed. RESULTS: diagnostic precision (P), sensitivity (S), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV) for EUS-FNA was 85, 83, 100, 100, and 43%, respectively, when comparing results with specimen histology. P was higher for adenopathies (100%) and pancreatic tumors (87%) than for SMTs (80%). No complications arose, except for one episode of upper gastrointestinal bleeding (UGIB) (3.7%) that was endoscopically and satisfactorily treated in a gastric SMT. In the group with 21 patients (10 carcinoids with 13 tumors) 27 SMTs were endoscopically treated by tumorectomy with no perforation and only 2 UGIBs (7.4%), one of them self-limited, recorded. Endoscopic resection was complete in 92% of cases. No complications occurred with classic EMR, and all patients are still alive with no evidence of relapse, either local or metastatic. In this group the rate of complete resections was 100%. CONCLUSIONS: EUS-FNA is a safe technique with high diagnostic accuracy. EUS-guided tumorectomy and mucosectomy are also safe and effective techniques in the endoscopic management of these tumors.

EUS-guided mucosectomy for gastrointestinal cancer.

INTRODUCTION: the only way of improving prognosis and survival in gastrointestinal cancer is early diagnosis, with intramucosal localization as confirmed by endoscopic ultrasonography (EUS) or 20-MHz miniprobes (MPs) (T1) being most appropriate. Endoscopic mucosal resection (EMR) has proven effective in the treatment of this sort of lesions. PATIENTS AND METHOD: in a group (18 cases) with 15 cases of superficial gastrointestinal cancer and 3 cases of severe gastric dysplasia, 9 cases (3 esophageal, 4 gastric, 2 rectal) underwent a classic EMR following EUS or a 7.5- and 20-MHz miniprobe exploration. RESULTS: ultrasonographic studies showed a T1 in all but one esophageal case (Tis), and in both gastric dysplasias, with no changed layer structure being demonstrated in the latter (T0). No complications arose with classic EMR, and all 9 patients are alive and free from local or metastatic recurrence, except for one esophageal case, which recurred distally to the esophageal lesion (metachronous). CONCLUSIONS: echoendoscopically-assisted EMR is a safe, effective technique in the endoscopic management of superficial gastrointestinal (esophageal, gastric, colorectal) cancer. Recurrence most likely depends upon cancer multiplicity.

Endoscopic staging of low-grade gastric MALT lymphoma.

INTRODUCTION: Endoscopic ultrasonography (EUS) has already proven useful in the assessment of submucosal lesions, and the staging of gastrointestinal cancer, particularly gastric MALT-type lymphoma. The goal of this paper was EUS staging. PATIENTS AND METHOD: 24 patients (10 females, 14 males) with a median age of 56 years and possibly gastric MALT lymphoma (25 cases) were studied using videoendoscopy, biopsies, and echoendoscopy with 7.5- and 20-MHz radial EUS, and also with 12- and 20-MHz miniprobes (MPs). Nineteen patients were definitely evaluated (7 females, 12 males) as having 20 MALT-type lymphomas, as five patients were post-hoc disregarded when an invasive, high-grade gastric lymphoma (3c) or plasmocytoma (2c) was subsequently demonstrated. Of these 19 patients, all had T1 lesions except for two with T2 lesions; one patient had a gastroduodenal T1 lymphoma. Echographic findings with MPs were compared to EUS (gold standard) and histology both before and after eradication. Then, patients were followed up every 1-3-6 months using videoendoscopy and MPs. RESULTS: Echoendoscopy correctly identified T stages in 90% of cases. MPs identified T stages in 88% of cases, and N stages in 33% of cases, with results being slightly inferior to those obtained with conventional EUS (91 vs. 45%); they were consequently used for follow-up. After eradication, all but two patients are in complete remission and have been followed every 1-3-6 months using MPs without echographic abnormalities, except for a patient who relapsed.

[Diagnosis and treatment of esophageal ulcers in patients seropositive for the human immunodeficiency virus (HIV-positive)]. / Diagnóstico y tratamiento de las úlceras esofágicas en los pacientes seropositivos para el virus de la inmunodeficiencia humana (VIH-positivo).

Esophageal ulcers are often found in patients with human immunodeficiency virus infection. We have retrospectively reviewed the upper endoscopies performed in these patients during the last four years. 149 examinations were realized in 73 patients. Fourteen patients with esophageal ulcers were diagnosed. A severe immunological impairment was present in all patients (CD4 24.4 +/- 31.1 cells/ul). Symptoms were non-specific, with prevailing dysphagia and odynophagia. The etiological diagnosis was reached by histological studies and cultures in 5 cases (36%), three due to Herpes virus type I, one due to Cytomegalovirus and another one to Mycobacterium tuberculosis. Patients with multiple ulcers or small ones were successfully treated with antiviral drugs, even when the etiological studies were negative. Corticosteroids were useful in single and large ulcers in which diagnostic tests were negative.

Comparative study of spermatogonial survival after x-ray exposure, high LET (HZE) irradiation or spaceflight.

Spermatogonial cell loss has been observed in rats flown on Space Lab 3, Cosmos 1887, Cosmos 2044 and in mice following irradiation with X-ray or with high energy (HZE) particle beams. Spermatogonial loss is determined by cell counting in maturation stage 6 seminiferous [correction of seminferous] tubules. With the exception of Iron, laboratory irradiation experiments (with mice) revealed a similar pattern of spermatogonial loss proportional to the radiation dose at levels less than 0.1 Gy. Helium and Argon irradiation resulted in a 5% loss of spermatogonia after only 0.01 Gy exposure. However, significant spermatogonial loss (45%) occured at this radiation level with Iron particle beams. The loss of spermatogonia during each space flight was less than 10% when compared to control (non-flight) animals. This loss, although small, was significant. Although radiation may be a contributing factor in the loss of spermatogonia during space flight, exposure levels, as determined by dosimetry, were not significant to account for the total cell loss observed.

Superficial esophageal carcinoma: a report of 12 cases.

Twelve cases of superficial carcinoma of the esophagus, representing 4.9% of patients with carcinoma of the esophagus, were evaluated. All the patients were male smokers who drank alcohol excessively. The main clinical features were dysphagia, asthenia, anorexia, and weight loss. Most of the lesions were elevated and all endoscopic biopsies were positive for cancer. Half of the cases showed invasion of the submucosa; the remainder involved mucosa only. Ten patients are alive and free of metastatic disease.