A randomised phase II study of osimertinib and bevacizumab versus osimertinib alone as second-line targeted treatment in advanced NSCLC with confirmed EGFR and acquired T790M mutations: the European Thoracic Oncology Platform (ETOP 10-16) BOOSTER trial.

BACKGROUND: While osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) is the standard treatment in patients with advanced non-small-cell lung cancer (NSCLC) with sensitising EGFR and acquired T790M mutations, progression inevitably occurs. The angiogenic pathway is implicated in EGFR TKI resistance. PATIENTS AND METHODS: BOOSTER is an open-label randomised phase II trial investigating the efficacy and safety of combined osimertinib 80 mg daily and bevacizumab 15 mg/kg every 3 weeks, versus osimertinib alone, in patients with EGFR-mutant advanced NSCLC and acquired T790M mutations after failure on previous EGFR TKI therapy. Primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints were overall survival (OS), objective response rate (ORR) and adverse events (AEs). RESULTS: Between May 2017 and February 2019, 155 patients were randomised (combination: 78; osimertinib: 77). At data cut-off of 22 February 2021, median follow-up was 33.8 months [interquartile range (IQR): 26.5-37.6 months] and 129 (83.2%) PFS events were reported in the intention-to-treat population. There was no difference in median PFS between the combination [15.4 months; 95% confidence interval (CI) 9.2-18.0 months] and osimertinib arm (12.3 months; 95% CI 6.2-17.2 months; stratified log-rank P = 0.83), [hazard ratio (HR) = 0.96; 95% CI 0.68-1.37]. Median OS was 24.0 months (95% CI 17.8-32.1 months) in the combination arm and 24.3 months (95% CI 16.9-37.0 months) in the osimertinib arm (stratified log-rank P = 0.91), (HR = 1.03; 95% CI 0.67-1.56). Exploratory analysis revealed a significant interaction of smoking history with treatment for PFS (adjusted P = 0.0052) with a HR of 0.52 (95% CI 0.30-0.90) for smokers, and 1.47 (95% CI 0.92-2.33) for never smokers. ORR was 55% in both arms and the median time to treatment failure was significantly shorter in the combination than in the osimertinib arm, 8.2 months versus 10.8 months, respectively (P = 0.0074). Safety of osimertinib and bevacizumab was consistent with previous reports with grade ≥3 treatment-related AEs (TRAEs) reported in 47% and 18% of patients on combination and osimertinib alone, respectively. CONCLUSIONS: No difference in PFS was observed between osimertinib plus bevacizumab and osimertinib alone. Grade ≥3 TRAEs were more common in patients on combination.

Indications for diagnostic open biopsy of mammographic screen-detected lesions preoperatively diagnosed as fibroadenomas by needle biopsy and their outcomes.

AIM: To identify the clinical, radiological, and histopathological factors that resulted in a diagnostic open biopsy of mammographic screen-detected lesions diagnosed preoperatively as fibroadenomas by needle biopsy. MATERIALS AND METHODS: BreastScreen WA data over 10 year period from 1 January 1999 to 31 December 2008 was reviewed. RESULTS: Among the 760,027 women screened in Western Australia between 1999 and 2008, 31 had a fine-needle aspiration (FNA) or a core biopsy (CB) diagnosing a fibroadenoma and subsequently underwent a diagnostic open biopsy (DOB). Three were preoperatively diagnosed as fibroadenoma by initial FNA but subsequent CB showed that these were not fibroadenomas and, therefore, were excluded from the present series. Of the 28 cases, DOB identified 21 fibroadenomas, two cellular fibroadenomas, two benign phyllodes tumours, one malignant phyllodes tumour, one fibroadenoma containing ductal carcinoma in situ (DCIS), and one case of a 40mm adenosis tumour with a small 5mm fibroadenoma. The lesions ranged from 5-100mm in size with an average size of 28mm. DOB and CB results were concordant in 25 (89%) of the cases. The primary clinical indications for undergoing DOB included indeterminate histopathological findings of cellular fibroadenomas versus phyllodes tumour (n = 10), enlarging size (n = 4), large size (n = 5), fibroadenomas with atypia (n = 1), discordant radiological and pathological findings (n = 3), patient preference (n = 1), association with a second screen-detected lesion requiring excision (n = 2), and an unknown indication (n = 1). CONCLUSION: CB diagnosis of fibroadenomas is a safe diagnosis unless it has atypical clinical, radiological, or pathological features.

Two biomarker-directed randomized trials in European and Chinese patients with nonsmall-cell lung cancer: the BRCA1-RAP80 Expression Customization (BREC) studies.

BACKGROUND: In a Spanish Lung Cancer Group (SLCG) phase II trial, the combination of BRCA1 and receptor-associated protein 80 (RAP80) expression was significantly associated with outcome in Caucasian patients with nonsmall-cell lung cancer (NSCLC). The SLCG therefore undertook an industry-independent collaborative randomized phase III trial comparing nonselected cisplatin-based chemotherapy with therapy customized according to BRCA1/RAP80 expression. An analogous randomized phase II trial was carried out in China under the auspices of the SLCG to evaluate the effect of BRCA1/RAP80 expression in Asian patients. PATIENTS AND METHODS: Eligibility criteria included stage IIIB-IV NSCLC and sufficient tumor specimen for molecular analysis. Randomization to the control or experimental arm was 1 : 1 in the SLCG trial and 1 : 3 in the Chinese trial. In both trials, patients in the control arm received docetaxel/cisplatin; in the experimental arm, patients with low RAP80 expression received gemcitabine/cisplatin, those with intermediate/high RAP80 expression and low/intermediate BRCA1 expression received docetaxel/cisplatin, and those with intermediate/high RAP80 expression and high BRCA1 expression received docetaxel alone. The primary end point was progression-free survival (PFS). RESULTS: Two hundred and seventy-nine patients in the SLCG trial and 124 in the Chinese trial were assessable for PFS. PFS in the control and experimental arms in the SLCG trial was 5.49 and 4.38 months, respectively [log rank P = 0.07; hazard ratio (HR) 1.28; P = 0.03]. In the Chinese trial, PFS was 4.74 and 3.78 months, respectively (log rank P = 0.82; HR 0.95; P = 0.82). CONCLUSION: Accrual was prematurely closed on the SLCG trial due to the absence of clinical benefit in the experimental over the control arm. However, the BREC studies provide proof of concept that an international, nonindustry, biomarker-directed trial is feasible. Thanks to the groundwork laid by these studies, we expect that ongoing further research on alternative biomarkers to elucidate DNA repair mechanisms will help define novel therapeutic approaches. TRIAL REGISTRATION: NCT00617656/GECP-BREC and ChiCTR-TRC-12001860/BREC-CHINA.

Impact of smoking status on the relative efficacy of the EGFR TKI/angiogenesis inhibitor combination therapy in advanced NSCLC-a systematic review and meta-analysis.

BACKGROUND: The ETOP 10-16 BOOSTER trial failed to demonstrate a progression-free survival (PFS) benefit for adding bevacizumab to osimertinib in second line. An exploratory subgroup analysis, however, suggested a PFS benefit of the combination in patients with a smoking history and prompted us to do this study. METHODS: A systematic review and meta-analysis to evaluate the differential effect of smoking status on the benefit of adding an angiogenesis inhibitor to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor therapy was carried out. All relevant randomized controlled trials appearing in main oncology congresses or in PubMed as of 1 November 2021 were used according to the Preferred Reporting Items for Systematic Review and Meta-Analyses statement. Primarily PFS according to smoking status, and secondarily overall survival (OS) were of interest. Pooled and interaction hazard ratios (HRs) were estimated by fixed or random effects models, depending on the detected degree of heterogeneity. Bias was assessed using the revised Cochrane tool for randomized controlled trials (RoB 2). RESULTS: Information by smoking was available for 1291 patients for PFS (seven studies) and 678 patients for OS (four studies). The risk of bias was low for all studies. Combination treatment significantly prolonged PFS for smokers [n = 502, HR = 0.55, 95% confidence interval (CI): 0.44-0.69] but not for nonsmokers (n = 789, HR = 0.92, 95% CI: 0.66-1.27; treatment-by-smoking interaction P = 0.02). Similarly, a significant OS benefit was found for smokers (n = 271, HR = 0.66, 95% CI: 0.47-0.93) but not for nonsmokers (n = 407, HR = 1.07, 95% CI: 0.82-1.42; treatment-by-smoking interaction P = 0.03). CONCLUSION: In advanced EGFR-non-small-cell lung cancer patients, the addition of an angiogenesis inhibitor to EGFR-tyrosine kinase inhibitor therapy provides a statistically significant PFS and OS benefit in smokers, but not in non-smokers. The biological basis for this observation should be pursued and could determine whether this might be due to a specific co-mutational pattern produced by tobacco exposure.

Malignant pleural mesothelioma: Treatment patterns and outcomes from the Spanish Lung Cancer Group.

BACKGROUND: Malignant mesothelioma is a rare but aggressive tumor arising from the pleura, typically associated with exposure to asbestos. The purpose of this investigation was to describe mesothelioma patient characteristics, treatment patterns, and outcomes in Spain. MATERIAL AND METHODS: Patients diagnosed with malignant mesothelioma of the pleura were recorded in an anonymous online database (BEMME, Epidemiologic Spanish Malignant Mesothelioma Database) from June 2008 through May 2013. Patient and tumor characteristics at time of diagnosis, as well as subsequent treatments (surgery, radiation, and chemotherapy), were collected. Among patients treated with chemotherapy, we explored type of chemotherapy regimen and outcomes by treatments. RESULTS: A total of 560 malignant pleural mesothelioma (MPM) patients were recorded. The median age at diagnosis was 68 years, mainly with epithelioid histology (62 %), and any asbestos exposure was noted in 45 % of patients. Nearly two-thirds of patients (71 %) received chemotherapy, mainly platinum-pemetrexed combination, as part of their treatment. Surgery and radiotherapy were given in 36 % and 17 % of patients, respectively. The median overall survival (OS) in the whole cohort was 13.0 months (95 % confidence interval (CI), 11.1-14.8 months) with 1-year OS of 53.2 % (95 % CI, 48.7-57.7 %). In patients receiving first-line chemotherapy (N = 315), the median OS was 13.4 months (95 % CI, 10.8-16.0 months), reaching 20.2 months (95 % CI, 17.2-23.2 months) for those 68 patients receiving maintenance chemotherapy. Results of multivariate analyses showed significant association of ECOG-performance status, histology and treatment response with improved OS in MPM patients treated with palliative chemotherapy. CONCLUSIONS: Despite multimodal therapeutic intervention, survival of patients with mesothelioma in Spain remains poor. Although it did not reach significance in the multivariate analysis, a meaningful additional survival benefit was observed among those patients receiving maintenance chemotherapy.

Histopathological changes in the placentas and fetuses of mice infected with Trypanosoma cruzi isolated from the Myotis nigricans nigricans bat.

Histopathological changes and placental transmission were studied in the late stages of pregnancy in mice infected with a strain of Trypanosoma cruzi, isolated from a Myotis nigricans nigricans bat. Large amastigote nests were observed in uterine muscles, as well as in decidual and endothelial placental cells. In addition, persistent coagulative and fibrotic vascular degeneration was observed. Large amastigote burdens were found in giant cells, spongioblasts and endothelial cells within the labyrinthine layer. Transplacental transmission was confirmed in 30% of the fetuses examined, in which amastigote nests were seen only in striated muscle. During the acute phase, intrauterine development was impaired as the result of parasitic invasion of the placenta, and fetal mortality rose to 10%.

A morphometric study of maternal smoking on apoptosis in the syncytiotrophoblast.

OBJECTIVES: To study syncytiotrophoblast apoptosis in the placenta of smoking and non-smoking pregnant women. METHODS: Twelve neonates, pregnancies and placentas were available for study. Eight mothers smoked during pregnancy and the remaining four were non-smokers used as control subjects. The main outcome measure was the apoptotic syncytiotrophoblast index for each group. Apoptosis was detected by immunohistochemistry using the TUNEL method and quantitatively measured using a Merz grid. The apoptotic syncytiotrophoblast index was calculated as the ratio of mean apoptotic labeling to percent terminal villus area using high-power field microscopy. RESULTS: Significant differences in apoptotic syncytiotrophoblast index were observed between the control group (15.06+/-3.72) and the smoker group (1.66+/-1.74) (P < 0.0001, Mann-Whitney test), but no differences were detected in clinical or morphometric data between groups. CONCLUSIONS: The human placental syncytiotrophoblast undergoes apoptosis and this process is associated with inhibition of apoptosis by the smoking habit. The same way as the presence of trophoblast apoptosis is associated with modifications of the maternal-fetal exchange, the inhibitory effect of the smoking habit on syncytiotrophoblast could be responsible for the poor prognosis of pregnancy in the presence of maternal smoking.

Effect of hyperthermia on rat fetus palate epithelium.

Maternal hyperthermia during gestation induces delayed cellular growth and differentiation in fetal rat palate epithelium, with increased nuclear, cytoplasmic and cellular volumes, increased epithelial thickness, decreased keratin and cellular numerical density.

Alcohol-induced alterations in the palate epithelium of the rat fetus.

Maternal alcoholism (ethanol and sugar cane brandy) during gestation induces delayed cellular growth and differentiation in fetal rat palate epithelium, with increased nuclear, cytoplasmic and cellular volumes, increased epithelial and keratin thickness and decreased cellular numerical density.

Effect of acyclovir on rat fetus palate mucosa.

Five pregnant rats were treated during organogenesis with sc injections of acyclovir (50 mg/kg body weight) on days 9, 10 and 11 of pregnancy. The fetuses (N=62) were evaluated on day 20 of gestation and presented decreased body weight as well as delayed differentiation of fetal rat palate epithelium, with increased nuclear volume, decreased cytoplasmic and cellular volumes, decreased epithelial and keratin thicknesses, and increased cellular numerical density.

Teratogenic effects of the interaction acetylsalicylic acid (ASA) and ethanol: morphologic and morphometric evaluation of the lingual epithelium in rat fetuses.

The objective of the present work was to evaluate the teratogenic effects of the interaction between acetylsalicylic acid (ASA) and ethanol on the epithelium of the lingual mucosa in rat fetuses. On the 10th pregnancy day, a single intraperitoneal ethanol dose (2.96 g/kg body weight) (Group I), ASA (200 mg/kg body weight) (Group II) and ASA plus ethanol, in the same doses (Group III), or saline (Group IV - control), were administrated. The epithelial alterations were assessed by means of histological and morphometric methods, on posterior dorsal, anterior dorsal and ventral regions of the tongue. ASA reduced, in rat fetuses, the ethanol deleterious effects on nuclear size in the epithelial prickle cell of the lingual mucosa. On the other hand, ASA did not influence the effects of ethanol in both epithelial layers of the lingual mucosa, when the nuclear shape, cell volume or epithelial layers thickness were evaluated.

Regional variation of the vasculo-syncytial membranes in the human full-term placenta.

The authors determined the frequency of vasculo-syncytial membranes in different cotyledonary regions of the full-term placenta. There were significant differences according to the site from which the sample was obtained. The highest frequency (164,3%) corresponds to the central-parabasal region of the cotyledon, close to the point of entry of the maternal blood into the intervillous space, whereas the lowest value (104,5%) corresponds to the lateral-subchorial region. The results of the present study as well as those reported by others suggest that the villi from the central-parabasal region are the best adapted ones for gas transfer between maternal and fetal blood.

Enzymatic histochemistry of the human umbilical vessels.

The enzymatic activities of human umbilical vessels from normal term pregnancies were studied by histochemical methods. The results obtained suggest that oxidative phosphorylation is of little importance, whereas pentose cycle and anaerobic glycolysis are probably the most important sources of energy in the umbilical vessels. The presence of leucine aminopeptidase activity in the venous endothelium probably represents a defensive mechanism inactivating oxytocin.

Measurement of the villus surface area and its regional variation in the human full-term placenta.

The surface/volume ratio and the surface density of the chorionic villi in different cotyledonary regions of the human mature placenta were studied by stereologic methods. The villus surface/volume ratio showed a mean value of 812.3 cm2/cm3 (standard deviation = 89.2 cm2/cm3). There were no significant differences according to the site from which the sample was obtained. The villus surface density in normal mature placentae was (496.3 +/- 49.0) cm2/cm3. The last parameter showed no differences among regions. Despite the absence of significant differences of exchange surface areas among the cotyledonary regions considered, other important parameters, such as trophoblast thickness, frequency of vasculo-syncytial membranes, as well as the maximal gradient of concentration, facilitates the maternal-fetal transfer by simple diffusion mechanism in the central-parabasal region.

Histochemical study of the fetal membranes in the human term pregnancy.

The histochemical distribution of polysaccharides and proteins was studied in the human fetal membranes from term pregnancies. The neutral polysaccharide reactions were stronger in the trophoblast layer of the chorion and in the decidua, whereas the acid mucopolysaccharides were equally intense in the connective layers and in the decidua. The protein reactions were always stronger in the decidua. It was demonstrated the existence of a cover of acid mucopolysaccharides over the apical surface of the amniotic epithelium. The possible participation of this cover in water and electrolytes transfer is discussed.

A mathematical model for the curves of intrauterine growth.

Different mathematical models for a chart of intrauterine growth were tested attempting to employ uncomplicated curves. In this manner, a chart of foetal growth was elaborated by plotting the cube root of neonate weight against the gestational age. Two different regions can be clearly seen in this chart of growth. In the first one, until the 34th week of pregnancy, there is a linear relationship between the two variables. In the second region, for pregnancies above the 34th week, the curve has a quadratic equation, reaching the maximum between the 43rd and 44th week, decreasing posteriorly. The goodness of fit obtained by the present mathematical model is more satisfactory than that obtained by mathematical models with a single linear equation.

The importance of placental examination in newborns with single umbilical artery.

Examination of placentas from newborns with single umbilical artery (SUA) can furnish valuable data to Perinatologists. Thus, 33.3% of the SUA newborns with gross macroscopic alterations of the placenta were malformed. In the other hand, 75% of the malformed SUA newborns had gross placental alterations. It is pointed out the importance of examination of the placenta, even at unaided eye, as a tool to prevent the Perinatologist in search of probable malformations (both apparent or occult).

Placental characteristics in twin transfusion syndrome.

The authors describe the histological features of the placenta in a typical case of twin-to-twin transfusion, with particular attention focused on the stereologic aspects. Villi from the anemic placental portion were slightly edematous, with small and inconspicuous vessels. The stereologic characteristics of this portion were nearer values of normal placentas. The plethoric region appears as a postmature organ, with a very thin trophoblast layer and numerous vasculo-syncytial membranes. The most dramatic alterations of this region were mainly related to the foetal capillary. According to the stereologic results, the consecutive circulatory alterations would facilitate the maternal-fetal exchanges in the plethoric placental territory, thus justifying the greater development of this twin.