62 research outputs found
Safety and preliminary activity results of the GATTO study, a phase Ib study combining the anti-TA-MUC1 antibody gatipotuzumab with the anti-EGFR tomuzotuximab in patients with refractory solid tumors
Colorectal cancer; Lung cancer; Monoclonal antibodyCáncer colorrectal; Cáncer de pulmón; Anticuerpo monoclonalCà ncer colorectal; Cà ncer de pulmó; Anticòs monoclonalBackground
The phase I GATTO study (NCT03360734) explored the feasibility, tolerability and preliminary activity of combining gatipotuzumab, a novel humanized monoclonal antibody binding to the tumor-associated epitope of mucin 1 (TA-MUC1) and an anti-epidermal growth factor receptor (anti-EGFR) antibody in refractory solid tumors.
Patients and methods
Initially the study enrolled primary phase (PP) patients with EGFR-positive metastatic solid tumors, for whom no standard treatment was available. Patients received gatipotuzumab administered at 1400 mg every 2 weeks, 6 weeks after the start of the glyco-optimized anti-EGFR antibody tomuzotuximab at 1200 mg every 2 weeks. As this regimen was proven safe, enrollment continued in an expansion phase (EP) of patients with refractory metastatic colorectal cancer, non-small-cell lung cancer, head and neck cancer and breast cancer. Tomuzotuximab and gatipotuzumab were given at the same doses and gatipotuzumab treatment started 1 week after the first dose of the anti-EGFR antibody. Additionally, investigators could use a commercial anti-EGFR antibody in place of tomuzotuximab.
Results
A total of 52 patients were enrolled, 20 in the PP and 32 in the EP. The combined treatment was well tolerated and no dose-limiting toxicity was observed in the whole study, nor related serious adverse event or death. Preliminary activity of the combination was observed, with one and four RECIST partial responses in the PP and EP, all in colorectal cancer patients. The trial was accompanied by a comprehensive translational research program for identification of biomarkers, including soluble TA-MUC1 (sTA-MUC1) in serum. In the EP, patients with baseline sTA-MUC1 levels above the median appeared to have improved progression-free survival and overall survival.
Conclusions
Combination of a TA-MUC1-targeting antibody and an EGFR-targeting antibody is safe and feasible. Interesting antitumor activity was observed in heavily pretreated patients. Future studies should test this combination together with chemotherapy and explore the potential of sTA-MUC1 as a companion biomarker for further development of the combination.This work was supported by Glycotope GmbH (no grant number)
A maChine and deep Learning Approach to predict pulmoNary hyperteNsIon in newbornS with congenital diaphragmatic Hernia (CLANNISH): Protocol for a retrospective study
Introduction Outcome predictions of patients with congenital diaphragmatic hernia (CDH) still have some limitations in the prenatal estimate of postnatal pulmonary hypertension (PH). We propose applying Machine Learning (ML), and Deep Learning (DL) approaches to fetuses and newborns with CDH to develop forecasting models in prenatal epoch, based on the integrated analysis of clinical data, to provide neonatal PH as the first outcome and, possibly: Favorable response to fetal endoscopic tracheal occlusion (FETO), need for Extracorporeal Membrane Oxygenation (ECMO), survival to ECMO, and death. Moreover, we plan to produce a (semi)automatic fetus lung segmentation system in Magnetic Resonance Imaging (MRI), which will be useful during project implementation but will also be an important tool itself to standardize lung volume measures for CDH fetuses. Methods and analytics Patients with isolated CDH from singleton pregnancies will be enrolled, whose prenatal checks were performed at the Fetal Surgery Unit of the Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (Milan, Italy) from the 30th week of gestation. A retrospective data collection of clinical and radiological variables from newborns' and mothers' clinical records will be performed for eligible patients born between 01/01/2012 and 31/12/2020. The native sequences from fetal magnetic resonance imaging (MRI) will be collected. Data from different sources will be integrated and analyzed using ML and DL, and forecasting algorithms will be developed for each outcome. Methods of data augmentation and dimensionality reduction (feature selection and extraction) will be employed to increase sample size and avoid overfitting. A software system for automatic fetal lung volume segmentation in MRI based on the DL 3D U-NET approach will also be developed. Ethics and dissemination This retrospective study received approval from the local ethics committee (Milan Area 2, Italy). The development of predictive models in CDH outcomes will provide a key contribution in disease prediction, early targeted interventions, and personalized management, with an overall improvement in care quality, resource allocation, healthcare, and family savings. Our findings will be validated in a future prospective multicenter cohort study
Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling
Within the gastrointestinal stem cell niche, nerves help to regulate both normal and neoplastic stem cell dynamics. Here, we reveal the mechanisms underlying the cancer-nerve partnership. We find that Dclk1+ tuft cells and nerves are the main sources of acetylcholine (ACh) within the gastric mucosa. Cholinergic stimulation of the gastric epithelium induced nerve growth factor (NGF) expression, and in turn NGF overexpression within gastric epithelium expanded enteric nerves and promoted carcinogenesis. Ablation of Dclk1+ cells or blockade of NGF/Trk signaling inhibited epithelial proliferation and tumorigenesis in an ACh muscarinic receptor-3 (M3R)-dependent manner, in part through suppression of yes-associated protein (YAP) function. This feedforward ACh-NGF axis activates the gastric cancer niche and offers a compelling target for tumor treatment and prevention
Germinal BRCA1-2 pathogenic variants (gBRCA1-2pv) and pancreatic cancer: epidemiology of an Italian patient cohort
Objective: Germline BRCA1-2 pathogenic variants (gBRCApv) increase the risk of pancreatic cancer and predict for
response to platinating agents and poly(ADP-ribose) polymerase inhibitors. Data on worldwide gBRCApv incidence
among pancreatic ductal adenocarcinoma (PDAC) patients are sparse and describe a remarkable geographic
heterogeneity. The aim of this study is to analyze the epidemiology of gBRCApv in Italian patients.
Materials and methods: Patients of any age with pancreatic adenocarcinoma, screened within 3 months from diagnosis
for gBRCApv in Italian oncologic centers systematically performing tests without any selection. For the purposes of our
analysis, breast, ovarian, pancreas, and prostate cancer in a patient’s family history was considered as potentially BRCAassociated. Patients or disease characteristics were examined using the c2 test or Fisher’s exact test for qualitative
variables and the Student's t-test or ManneWhitney test for continuous variables, as appropriate.
Results: Between June 2015 and May 2020, 939 patients were tested by 14 Italian centers; 492 (52%) males, median
age 62 years (range 28-87), 569 (61%) metastatic, 273 (29%) with a family history of potentially BRCA-associated
cancers. gBRCA1-2pv were found in 76 patients (8.1%; 9.1% in metastatic; 6.4% in non-metastatic). The gBRCA2/
gBRCA1 ratio was 5.4 : 1. Patients with gBRCApv were younger compared with wild-type (59 versus 62 years,
P ¼ 0.01). The gBRCApv rate was 17.1% among patients <40 years old, 10.4% among patients 41-50 years old,
9.2% among patients 51-60 years old, 6.7% among patients aged 61-70 years, and 6.2% among patients >70 years
old (none out of 94 patients >73 years old). gBRCApv frequency in 845 patients <74 years old was 9%. Patients
with/without a family history of potentially BRCA-associated tumors had 14%/6% mutations.
Conclusion: Based on our findings of a gBRCApv incidence higher than expected in a real-life series of Italian patients
with incident PDAC, we recommend screening all PDAC patients <74 years old, regardless of family history and stage,
due to the therapeutic implications and cancer risk prevention in patients' relatives.
Key words: germline BRCA, epidemiology, pancreatic cancer genetics, familial cance
Recent Innovations & Daily Problems. A new prosthesis in inguinal hernia repair:preliminary results of a pilot study.
Introduction: Elective surgery for inguinal hernia is affected by very
low mortality « 1 per 10000 operation); in contrast, when surgery
is carried out for complicated inguinal hernia, risks of postoperative
complication are higher. TAPP is a world-wide accepted surgical practice
in the treatment of elective bilateral or recurrent inguinal hernia,
above all in young patients. Few exploratory studies were published on
laparoscopic approach in the treatment of urgent complicated inguinal
hernia. Aim of this study was to analyze feasibility (operative time,
conversion rate), safety (postoperative morbidity, length of hospital
stay) and quality of life (acute and chronic pain, return to work) of
trans-abdominal pre-peritoneal laparoscopic hernia repair in acute
incarcerated inguinal hernia. Rationale of laparoscopic trans-abdominal
approach is the easier hernia reduction under vision and a better
exploration of the abdominal cavity.
Methods: from September 2012 to September 2013, 15 consecutive
patients admitted in emergency at the Division of General Surgery of
University "Sapienza", Polo Pontino, for acute incarcerated inguinal
hernia were submitted to TAPP using 3 trocars (1 of 10 mm and 2 of
5mm) and polyester prosthesis fixed by fibrin glue. Exclusion criteria
for laparoscopic approach were age III, previous
abdominal surgery, signs of strangulated hernia. All of them were
evaluated for operative time, conversion rate, postoperative morbidity,
organ resection or other surgery required. All patients were scored for
pain by Visual Analogic Scale (VAS) during postoperative in hospital
stay at 7 days, 1,6 and 12 months after surgery.
Results: median follow-up was 16 months and 12 as minimum. In all
cases reduction of hernia was always possible and none conversion
to open surgery was recorded, median operative time was 89 minutes
(55-137 as range), omental resection was carried out in one patient
(6,6%), no other organ resections needed, whereas contralateral hernia
was diagnosed and repaired at the same time in 4 patients (26,6%). No
major complications were observed, median blood loss was 100 ml,
minor morbidity was contained to 18% represented by fever and
wound infection of surgical umbilical scar. Median in hospital stay
was 1,5 days with 1-5 days as range. Postoperative median acute pain,
measured by visual analogic scale (VAS), was 2 (range:0-4), none
patient referred any pain during follow-up. Median time of return to
work was 6,5 days, ranged between 3 to 15 days. Patients' compliance
to treatment and to follow-up was complete as well their satisfaction. Conclusions: In centres skilled for laparoscopy in emergency, TAPP
could be considered a feasible and safe technique. In well-selected
patients (especially if emolled in controlled clinical trial) TAPP could
represent an alternative surgical approach for complicated incarcerated inguinal hernia to conventional open surgery even in urgency. The
main advantages of laparoscopic approach are the ability to perform
surgical hernia reduction under vision, a better exploration and evaluation
of abdominal cavity and diagnosis and treatment of eventual
contralateral defect of wall, otherwise often missed. Finally, the good
control of acute and chronic pain, faster return to normal activity and
work, better aesthetic results contributed to total satisfaction and compliance
of the patients
Transitional Care for Patients with Congenital Colorectal Diseases: An EUPSA Network Office, ERNICA, and eUROGEN Joint Venture
Background: Transition of care (TOC; from childhood into adulthood) of patients with anorectal malformations (ARM) and Hirschsprung disease (HD) ensures continuation of care for these patients. The aim of this international study was to assess the current status of TOC and adult care (AC) programs for patients with ARM and HD. Methods: A survey was developed by members of EUPSA, ERN eUROGEN, and ERNICA, including patient representatives (ePAGs), comprising of four domains: general information, general questions about transition to adulthood, and disease-specific questions regarding TOC and AC programs. Recruitment of centres was done by the ERNs and EUPSA, using mailing lists and social media accounts. Only descriptive statistics were reported. Results: In total, 82 centres from 21 different countries entered the survey. Approximately half of them were ERN network members. Seventy-two centres (87.8%) had a self-reported area of expertise for both ARM and HD. Specific TOC programs were installed in 44% of the centres and AC programs in 31% of these centres. When comparing centres, wide variation was observed in the content of the programs. Conclusion: Despite the awareness of the importance of TOC and AC programs, these programs were installed in less than 50% of the participating centres. Various transition and AC programs were applied, with considerable heterogeneity in implementation, content and responsible caregivers involved. Sharing best practice examples and taking into account local and National Health Care Programs might lead to a better continuation of care in the future. Level of Evidence: III
Diagnosis and management of Cornelia de Lange syndrome:first international consensus statement
Cornelia de Lange syndrome (CdLS) is an archetypical genetic syndrome that is characterized by intellectual disability, well-defined facial features, upper limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in any one of seven genes, all of which have a structural or regulatory function in the cohesin complex. Although recent advances in next-generation sequencing have improved molecular diagnostics, marked heterogeneity exists in clinical and molecular diagnostic approaches and care practices worldwide. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria, both for classic CdLS and non-classic CdLS phenotypes, molecular investigations, long-term management and care planning
Continence after posterior sagittal anorectoplasty for anorectal malformations: comparison of different scores
Purpose: To evaluate bowel function in patients with anorectal malformations (ARM) comparing existing scoring systems. Methods: Parents of ARM patients treated at our institution were asked to fill in Holschneider, Kricknebeck, and Rintala questionnaires. Scores obtained from the questionnaires were expressed per cent and analyzed depending on the age and type of ARM according to Krickenbeck classification. Patients younger than 3 years of age or with developmental delay were excluded. Results: Eighty patients (42 males: 52%) were included. Median age was 7.6 years (range 3\u201322). Twenty eight patients (35%) had perineal fistula, 13 (16%) bulbar, 7 (9%) prostatic, 5 (6%) rectobladder neck, 15 (19%) vestibular, 7 (9%) had a cloaca and 5 (6%) imperforate anus without fistula. Using Holschneider, Krickenbeck, and Rintala, average scores were respectively 72, 71 and 73 (p = 0.4 with ANOVA). Using the three questionnaires patients with perineal fistula scored 82, 76 and 84 respectively (p = 0.003), with bulbar 70, 71, 73 (p = 0.8), with prostatic 52,69,59 (p = 0.06), with bladder neck 56, 80, 57 (p = 0.004), with vestibular 75,67,75 (p = 0.02), with cloaca 64, 67, 65 (p = 0.9), and with imperforate anus without fistula 61,49, 53 (p = 0.12). Patients from 3 to 6 years of age scored 74,72 and 76 (p = 0.37), from 7 to 12: 70,71 and 71 (p = 0.87), and older than twelve: 74,66 e 73 (p = 0.08). Conclusion: The scores obtained using Holschneider, Rintala, and Krickenbeck questionnaires are significantly lower with increasing severity of the ARM. For each type of ARM there are some differences in the results obtained using the three questionnaires. In general, Krickenbeck and Pe\uf1a questionnaires tend to give lower scores in patients with ARMs that have good prognosis, and higher scores for ARMs with poor prognosis. Age is not significantly related to the score obtained. Level of evidence: III Type of study: Diagnostic stud
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