BEECH: a dose-finding run-in followed by a randomised phase II study assessing the efficacy of AKT inhibitor capivasertib (AZD5363) combined with paclitaxel in patients with estrogen receptor-positive advanced or metastatic breast cancer, and in a PIK3CA mutant sub-population.

BACKGROUND: BEECH investigated the efficacy of capivasertib (AZD5363), an oral inhibitor of AKT isoforms 1-3, in combination with the first-line weekly paclitaxel for advanced or metastatic estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer, and in a phosphoinositide 3-kinase, catalytic, alpha polypeptide mutation sub-population (PIK3CA+). PATIENTS AND METHODS: BEECH consisted of an open-label, phase Ib safety run-in (part A) in 38 patients with advanced breast cancer, and a randomised, placebo-controlled, double-blind, phase II expansion (part B) in 110 women with ER+/HER2- metastatic breast cancer. In part A, patients received paclitaxel 90 mg/m2 (days 1, 8 and 15 of a 28-day cycle) with capivasertib taken twice daily (b.i.d.) at two intermittent ascending dosing schedules. In part B, patients were randomly assigned, stratified by PIK3CA mutation status, to receive paclitaxel with either capivasertib or placebo. The primary end point for part A was safety to recommend a dose and schedule for part B; primary end points for part B were progression-free survival (PFS) in the overall and PIK3CA+ sub-population. RESULTS: Capivasertib was well tolerated, with a 400 mg b.i.d. 4 days on/3 days off treatment schedule selected in part A. In part B, median PFS in the overall population was 10.9 months with capivasertib versus 8.4 months with placebo [hazard ratio (HR) 0.80; P = 0.308]. In the PIK3CA+ sub-population, median PFS was 10.9 months with capivasertib versus 10.8 months with placebo (HR 1.11; P = 0.760). Based on the Common Terminology Criteria for Adverse Event v4.0, the most common grade ≥3 adverse events in the capivasertib group were diarrhoea, hyperglycaemia, neutropoenia and maculopapular rash. Dose intensity of paclitaxel was similar in both groups. CONCLUSIONS: Capivasertib had no apparent impact on the tolerability and dose intensity of paclitaxel. Adding capivasertib to weekly paclitaxel did not prolong PFS in the overall population or PIK3CA+ sub-population of ER+/HER2- advanced/metastatic breast cancer patients.ClinicalTrials.gov: NCT01625286.

Early ctDNA dynamics as a surrogate for progression-free survival in advanced breast cancer in the BEECH trial.

BACKGROUND: Dynamic changes in circulating tumour DNA (ctDNA) levels may predict long-term outcome. We utilised samples from a phase I/II randomised trial (BEECH) to assess ctDNA dynamics as a surrogate for progression-free survival (PFS) and early predictor of drug efficacy. PATIENTS AND METHODS: Patients with estrogen receptor-positive advanced metastatic breast cancer (ER+ mBC) in the BEECH study, paclitaxel plus placebo versus paclitaxel plus AKT inhibitor capivasertib, had plasma samples collected for ctDNA analysis at baseline and at multiple time points in the development cohort (safety run-in, part A) and validation cohort (randomised, part B). Baseline sample ctDNA sequencing identified mutations for longitudinal analysis and mutation-specific digital droplet PCR (ddPCR) assays were utilised to assess change in ctDNA abundance (allele fraction) between baseline and 872 on-treatment samples. Primary objective was to assess whether early suppression of ctDNA, based on pre-defined criteria from the development cohort, independently predicted outcome in the validation cohort. RESULTS: In the development cohort, suppression of ctDNA was apparent after 8 days of treatment (P = 0.014), with cycle 2 day 1 (4 weeks) identified as the optimal time point to predict PFS from early ctDNA dynamics. In the validation cohort, median PFS was 11.1 months in patients with suppressed ctDNA at 4 weeks and 6.4 months in patients with high ctDNA (hazard ratio = 0.20, 95% confidence interval 0.083-0.50, P < 0.0001). There was no difference in the level of ctDNA suppression between patients randomised to capivasertib or placebo overall (P = 0.904) nor in the PIK3CA mutant subpopulation (P = 0.071). Clonal haematopoiesis of indeterminate potential (CHIP) was evident in 30% (18/59) baseline samples, although CHIP had no effect on tolerance of chemotherapy nor on PFS. CONCLUSION: Early on-treatment ctDNA dynamics are a surrogate for PFS. Dynamic ctDNA assessment has the potential to substantially enhance early drug development. CLINICAL REGISTRATION NUMBER: NCT01625286.

Pharmacometric Modeling of Liver Metastases' Diameter, Volume, and Density and Their Relation to Clinical Outcome in Imatinib-Treated Patients With Gastrointestinal Stromal Tumors.

Three-dimensional and density-based tumor metrics have been suggested to better discriminate tumor response to treatment than unidimensional metrics, particularly for tumors exhibiting nonuniform size changes. In the developed pharmacometric modeling framework based on data from 77 imatinib-treated gastrointestinal patients, the time-courses of liver metastases' maximum transaxial diameters, software-calculated actual volumes (Vactual ) and calculated ellipsoidal volumes were characterized by logistic growth models, in which imatinib induced a linear dose-dependent size reduction. An indirect response model best described the reduction in density. Substantial interindividual variability in the drug effect of all response assessments and additional interlesion variability in the drug effect on density were identified. The predictive ability of longitudinal tumor unidimensional and three-dimensional size and density on overall survival (OS) and progression-free survival (PFS) were compared using parametric time-to-event models. Death hazard increased with increasing Vactual . This framework may guide early clinical interventions based on three-dimensional tumor responses to enhance benefits for patients with gastrointestinal stromal tumors (GIST).

Cetuximab rechallenge in metastatic colorectal cancer patients: how to come away from acquired resistance?

BACKGROUND: Scientific data provide the evidence that secondary K-RAS mutations do not occur during anti-epidermal growth factor receptor therapy in colorectal cancer patients. This multicenter phase II prospective study aims to investigate the activity of a retreatment with a cetuximab-based therapy. PATIENTS AND METHODS: We enrolled 39 irinotecan-refractory patients who had a clinical benefit after a line of cetuximab- plus irinotecan-based therapy and then a progression of disease for which underwent a new line chemotherapy and finally, after a clear new progression of disease, were retreated with the same cetuximab- plus irinotecan-based therapy. RESULTS: Median number of therapeutic lines before accrual was 4. Median interval time between last cycle of first cetuximab-based therapy and first cycle of the retreatment was 6 months. Overall response rate was 53.8% with 19 partial responses (48.7%) and 2 complete responses (5.1%). Disease stabilization was obtained in 35.9% of patients and progression in four patients (10.2%). Median progression-free survival was 6.6 months. The correlation between skin toxicity during first cetuximab therapy and during cetuximab rechallenge was significant (P = 0.01). CONCLUSION: Rechallenge with the same cetuximab-based therapy may achieve a new important clinical benefit further delaying the progression of disease and improving the therapeutic options.

[Treatment of gastrointestinal bleeding in neonates: a case report]. / Scelta terapeutica nelle emorragie intestinali pediatriche: un controverso caso neonatale.

Gastrointestinal bleeding in infants and children is an uncommon and potentially serious problem, but fortunately is usually limited and most cases resolve with close medical attention. The therapeutic criteria is often difficult particularly in neonates. In this work we examine the case of a neonate with serious gastrointestinal bleeding and the delayed treatment for diagnostic difficulties.

Iatrogenic traumas by nasogastric tube in very premature infants: our cases and literature review.

OBJECTIVE: The nasogastric tube is the chosen nutritional technique in premature infants. However, it is not without complications. The aim of this study is to compare our experience in iatrogenic complications caused by nasogastric tube (especially in very low birth weight infants) to a review of the most recent literature. METHODS: From january to december of 2008, in the Department of Neonatal Pathology at the Hospital of Treviso, 118 premature patients were treated. 110 of them had a body weight less than 1,500gr: serious complications caused by nasogastric tube occurred in two of these very low birth weight infants. The first case relates an injury of the esophagus, while the second case is about a perforation of the posterior wall of the stomach, left lobe of the liver and the spleen hilus. RESULTS: The surgical treatment was limited to the second case ending in splenectomy and repair of the posterior gastric wall and liver lobe. DISCUSSION AND CONCLUSIONS: Among all the iatrogenic injuries described in the literature, this last case is the most serious. It is important to verify always the position of the gastric tube and to doubt for a dislocation in any case of deviation of the tube from the normal course. In those cases in which a patient suddenly goes from a full well-being to a critical state without a precise contingent cause it is imperative to check the nasogastric tube place. In addition those cases have guided us to change our habits for managing these critical patients: we are then oriented toward the usage of silastic gastric probes, which are softer, less dangerous for ulcer damages, and long term replaceable, thus reducing the possibility of a iatrogenic injury.

[Foreign body ingestion: a common problem in paediatric age]. / L'ingestione di corpi estranei in età pediatrica: una costante realtà.

Foreign body (F.B.) ingestion occurs very frequently in paediatric age. The kind of ingested foreign bodies depends on the patient's age. Children between 1 and 3 years of age mostly swallow coins, toy parts, stones and small batteries; instead, older children typically ingest boluses of meat. The aim of this study is to review our case histories according to the latest literature, focusing on some events that needed a therapeutic emergency treatment.

Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy.

The primary end point of the study was the analysis of associations between polymorphisms with putative influence on 5-fluorouracil/irinotecan activity and progression-free survival (PFS) of patients with advanced colorectal cancer treated with first-line FOLFIRI chemotherapy. Peripheral blood samples from 146 prospectively enrolled patients were used for genotyping polymorphisms in thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), excision repair cross-complementation group-1 (ERCC 1) xeroderma pigmentosum group-D (XPD), X-ray cross-complementing-1 (XRCC 1), X-ray cross-complementing-3 (XRCC 3) and uridine diphosphate-glucuronosyltransferases-A1 (UGT1 A1). TS 3'-UTR 6+/6+ and XRCC3-241 C/C genotypes were associated with adverse PFS. Hazard ratio for PFS achieved 2.89 (95% confidence interval=1.56-5.80; P=0.002) in 30 patients (20%) with both risk genotypes. Risk for Grade III-IV neutropenia was significantly associated with UGT1A1*28 7/7 genotype. These promising findings deserve further investigations and their validation in independent prospective studies.

New developments of aminobisphosphonates: the double face of Janus.

BACKGROUND: Bisphosphonate (BP) therapy has become a standard of therapy for patients with malignant bone disease. In vivo preclinical and preliminary clinical data indicate that BPs may prevent cancer treatment-induced bone loss and the onset of malignant bone disease in patients with early-stage cancer. DESIGN: This review will describe the preclinical evidences of action of BPs on osteoclasts and tumor cells. In addition, the effects of principal BPs on skeletal disease progression in patients with breast cancer, prostate cancer, non-small-cell lung cancer and other cancers will be reported. The preliminary clinical data from retrospective trials on the effect of zoledronic acid (ZA) on survival will be described and the ongoing adjuvant phase III trial will be analyzed. CONCLUSIONS: This review will describe the preliminary clinical evidences from prospective studies on the effect of ZA treatment on the prevention of bone metastasis.

Cell cycle alterations and lung cancer.

It is now widely accepted that human carcinogenesis is a multi-step process and phenotypic changes during cancer progression reflect the sequential accumulation of genetic alterations in cells. The recent progress of scientific research has notably increased knowledge about biological events involved in lung cancer pathogenesis and progression, thanks to the use of molecular biology and immunohistochemistry techniques. Lots of the genetic alteration found in small cells lung cancer (SCLC) and in not small cells lung cancer (NSCLC) concern the expression of cell cycle genes, actually recognized as onco-suppressor genes and the lack of equilibrium between oncogenes and oncosuppressor genes. The present review of literature widely describes the cell cycle control, the lung cancer molecular pathogenesis, the catalog of known genetic alterations and the recent advances in global expression profiles in lung tumors, on the basis of the various hystological types too. Such data suggest the potential use of this knowledges in clinical practice both as prognostic factors and innovative therapeutic possibilities and they impose the necessity of new studies about cell cycle control and lung carcinogenesis.

Electrospray ionization mass spectrometric study of the hydrolysis-polycondensation process of Sn(OBu(t))(4).

The oligomerization of Sn(OBu(t))(4) in the sol-gel process has been studied by several different analytical approaches. Electrospray ionization (ESI) mass spectrometry was highly effective in describing the first species produced by the hydrolysis-polycondensation reactions. Mössbauer spectroscopy has elucidated the fast behavior of the hydrolytic oligomerization process, while calorimetric data have demonstrated the high enthalpy of the reaction in the presence of different solvents.

[Usefulness of long-term follow-up of patients operated on for cryptorchidism]. / Utilità del follow-up a lungo termine nei pazienti operati per criptorchidismo.

BACKGROUND: Cryptorchidism, testicular ectopia and rectractile testicle are different pathologies with conceivable different prognosis. As a matter of fact spermiogram used in these patients for the prognosis is really worse in bilateral cryptorchid than ectopic patients, because the tubular damage is present in the former than in the latter. It does not mean, anyway, that direct correlation exists between age of the patient at the operation and fertility. METHODS: 171 patients operated on for cryptorchidism or testicular ectopia at the Pediatric Surgery Department of the Regional Hospital of Treviso during the years 1974-1983 under-went follow-up at the age of 18 years with clinical evaluation, hormonal dosage (testosterone and gonadotropin after stimulus as GnRH) and spermiogram. RESULTS AND CONCLUSIONS: The present study does not differ from many other studies about hormonal levels and spermiograms of cryptorchid patients; it underlines long term follow-up utility of patients operated on for cryptorchidism and stresses the need of an eventual psychological evaluation of these patients.

[Steroid therapy of hemangioma in children]. / Considerazioni sulla terapia steroidea degli emangiomi infantili.

Hemangiomata is the more frequent pediatric tumor, absent at birth and usually growing, sometimes very quickly, during the first week of life. It potentially represents a serious problem because of his unforeseeable evolution during the time: is it more useful to use a corticosteroid therapy or to wait for the involution of the tumor? Here we have the results of the treatment on 51 babies who presented with hemangiomas of various sites: 52.6% of the lesions were on the face and head, 13.4% on chest wall, 10% on upper limbs, 4% on abdominal wall, 10% on pelvis region and 10% multiple. Therapy was compression in 10% of patients, corticosteroid injection in 66%, oral administered corticosteroid in 12%, surgery post corticosteroid therapy in 11.5%, others in 2.5%. Best results were obtained on the lesion of the head and face (good in 96%), worst in those of the abdomen (any modification in 100%).

[Phimosis: when does it require surgical intervention?]. / Fimosi: quando è patologia di interesse chirurgico?

One of the most recurrent questions in pediatric age is the phimosis; this is a frequently underestimated problem and its resolution often cause a lot of discomforts in babies and parents. In many countries it has been treated on the roots of ancient sanitary measures (circumcision) whereas in others it's routinely treated with painful and useless maneuvers; instead, until three years of age this don't represents a problem but the normal situation of the baby. Herein the authors report the results of topic corticosteroid treatment of fimosis in 83 patients aged 1-14 years, with good outcome in 86.7% of cases. Therapy and results are discussed.

Potential shifts at electrodes coated with ion-exchange polymeric films.

Voltammetry at electrodes modified with ion-exchange polymers, named "ion exchange voltammetry", has been recently developed for characterizing and determining quantitatively ionic electroactive analytes preconcentrated at the electrode surface. Like for other voltammetric techniques, characterization is based on the position of the response on the potential scale, but an appreciable difference is frequently observed between the formal half-wave potential for redox couples incorporated within ion-exchange polymeric films and those for the same redox couples in solution as measured at bare electrodes. Such a difference has been rationalized here by a generalized equation, inferred from a suitable elaboration of the Nernst equation, whose validity has been tested by a thorough investigation performed at glassy carbon electrodes modified with either cationic (Nafion) or anionic (Tosflex) polymeric films. With this purpose, the effect of both charge and concentration of the analyte and of the loading counterion, this last introduced as the cation or anion of the supporting electrolyte, of the ion-exchange selectivity coefficients of the redox partners and of their stoichiometric coefficients, as well as of the number of electrons involved in the charge transfer has been evaluated. The results obtained agree quite well with theoretical expectations and indicate that the potential shifts found are mainly conditioned by both charge and concentration of the counterion from the supporting electrolyte and by the ratio of the ion-exchange equilibrium constants for the two redox partners involved. Other parameters considered have no influence on the potential shift or lead to negligible effects, provided that the quantities of the redox partners incorporated within the ion-exchange coating represents less than 5% of the film capacity. Again in agreement with theoretical expectations, positive shifts are found for increasing supporting electrolyte concentrations when cationic redox species incorporated within cationic films are involved, while the opposite effect is found for anionic redox species incorporated within anionic films.