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BackgroundThe treatment of congenital curvatures (bowing) of the tibia still represents a challenging problem for all pediatric orthopedic surgeons because of its unpredictable course, especially if pseudoarthrosis occurs after a pathologic fracture of the tibia.Case presentationWe describe the case of a child affected by an isolated curvature of his left leg. The congenital malformation was discovered at birth and no other pathological clinical finding was present. The first x-ray showed the presence of a congenital curvature of the tibia of the antero-lateral type. He was born in another country (Romania) and when he first came to our clinical observation at the Orthopedic and Traumatology Department, Pediatric Hospital “Bambino Gesu’”, Rome, the child was 14 months of age and had already started walking. Only a leg discrepancy of about 2 cm was present with consequent pelvis obliquity. At the beginning, we prescribed external lower limb orthoses and a simple shoe rise to prevent a tibial pathologic fracture and reduce pelvic obliquity. At periodical clinical follow-up visits and despite the external lower limb orthoses prescribed, a progressive worsening of the severe congenital tibial curvature was observed together with signs and symptoms, such as pain and limping, that suggested an objective “pre-fracture stage” of the tibial curvature; we decided to perform surgery. At the time of surgery, the child was three and a half years old. Surgery consisted of a double osteotomy, both of the fibula and of the tibia. Subtraction of the distal meta-diaphyseal portion of the fibula and tibial osteotomy in Correspondence: of the major anterolateral curvature. The tibial osteotomy was then stabilized by an internal Rush rod inserted proximally to the tibia under the cartilage growth plate and made it end inside the distal tibial epiphysis, crossing the distal tibial cartilage growth plate, preserving the ankle joint.ResultsThe patient had an immediately excellent outcome. The tibial osteotomy site healed perfectly. At periodical orthopedic follow-up visits, the child was found to be always better. No clinical significative evidence of growth disturbances, due to the Rush rod that crossed the distal tibial cartilage growth plate, were noted. X-rays showed that the Rush rod progressively migrated with tibial growth together with the tibial bone growth, always getting further away from the distal tibial cartilage growth plate. Moreover, even the leg-length discrepancy and the pelvic obliquity improved. After an eight-year follow up, the patient, now a young boy of 11 and a half years, has an excellent outcome.ConclusionsOur case report undoubtedly provides further important information for the treatment of these rare congenital disorders. In particular, it highlights the management of the “pre-fracture stage” in a severe congenital tibial antero-lateral curvature in a very young child and describes the surgical technique performed.

Abstract The expanding targeted therapy landscape requires combinatorial biomarkers for patient stratification and treatment selection. This requires simultaneous exploration of multiple genes of relevant networks to account for the complexity of mechanisms that govern drug sensitivity and predict clinical outcomes. We present the algorithm, Digital Display Precision Predictor (DDPP), aiming to identify transcriptomic predictors of treatment outcome. For example, 17 and 13 key genes were derived from the literature by their association with MTOR and angiogenesis pathways, respectively, and their expression in tumor versus normal tissues was associated with the progression-free survival (PFS) of patients treated with everolimus or axitinib (respectively) using DDPP. A specific eight-gene set best correlated with PFS in six patients treated with everolimus: AKT2, TSC1, FKB-12, TSC2, RPTOR, RHEB, PIK3CA, and PIK3CB (r = 0.99, p = 5.67E−05). A two-gene set best correlated with PFS in five patients treated with axitinib: KIT and KITLG (r = 0.99, p = 4.68E−04). Leave-one-out experiments demonstrated significant concordance between observed and DDPP-predicted PFS (r = 0.9, p = 0.015) for patients treated with everolimus. Notwithstanding the small cohort and pending further prospective validation, the prototype of DDPP offers the potential to transform patients’ treatment selection with a tumor- and treatment-agnostic predictor of outcomes (duration of PFS).

Background: High Body mass index (BMI) is a risk factor for breast cancer among postmenopausal women and an adverse prognostic factor in early-stage. Little is known about its impact on clinical outcomes in patients with metastatic breast cancer (MBC). Methods: The National ESME-MBC observational cohort includes all consecutive patients newly diagnosed with MBC between Jan 2008 and Dec 2016 in the 18 French comprehensive cancer centers. Results: Of 22 463 patients in ESME-MBC, 12 999 women had BMI data available at MBC diagnosis. Median BMI was 24.9 kg/m2 (range 12.1–66.5); 20% of women were obese and 5% underweight. Obesity was associated with more de novo MBC, while underweight patients had more aggressive cancer features. Median overall survival (OS) of the BMI cohort was 47.4 months (95% CI [46.2–48.5]) (median follow-up: 48.6 months). Underweight was independently associated with a worse OS (median OS 33 months; HR 1.14, 95%CI, 1.02–1.27) and first line progression-free survival (HR, 1.11; 95%CI, 1.01; 1.22), while overweight or obesity had no effect. Conclusion: Overweight and obesity are not associated with poorer outcomes in women with metastatic disease, while underweight appears as an independent adverse prognostic factor.

Objectives: HERmione study was conducted to assess, in human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (eBC), the safety profile of subcutaneous (SC) formulation of trastuzumab in real-life in France. Materials and methods: This prospective, non-interventional study included 511 patients planned to be treated in both neoadjuvant and adjuvant settings with a follow-up of 12 months maximum in 101 sites. The safety analyses concerned 505 patients. Primary endpoint was the description of systemic safety and local tolerability of the SC trastuzumab. Results: The median age of patients was 58 years. Over the study, 2449 adverse events (AEs) occurred in 422 (83.6%) patients (asthenia, arthralgia, radiation skin injury, myalgia, hot flush and diarrhea in ≥10% of patients): 92 AEs (3.8%) were grade ≥3 (radiation skin injury in 1.8% of patients and febrile neutropenia in 1.4% of patients), 76 (3.1%) were serious (mainly febrile neutropenia in 1.4% of patients) and 336 (13.7%) were treatment-related (mainly injection site pain in 9.1% of patients). Congestive Heart Failure occurred in 58 (11.5%) patients and was related to treatment in 4.6% of patients. Only 34 AEs (1.4%) in 27 (5.4%) patients led to permanent treatment discontinuation. One death was assessed as not treatment-related. Quality of life (QoL) analyses showed no deterioration of global health status. Conclusion: The HERmione study showed that, in a real-life setting, the safety of SC trastuzumab administered in HER2-positive eBC patients is consistent with data reported from previous clinical trials, without new safety concerns or QoL deterioration.

BackgroundMost cancer-related deaths result from disseminated diseases that develop resistance to anticancer treatments. Inappropriate communication in this challenging situation may result in unmet patient information and support needs. Patient communication aids such as question prompt lists (QPLs) may help. ObjectiveThis study aims to develop and pilot-test a specific QPL in the following two contrasting clinical contexts in France after cancer resistance has developed: triple-negative and luminal B metastatic breast cancer (MBC) and metastatic uveal melanoma (MUM). MethodsA sequential study design with a mixed methods collaborative approach will be applied. The first step aims to build a specific QPL. Step 1a will explore oncologist-patient communication issues from oncology professionals’ interviews (n=20 approximately). Step 1b will appraise information and support needs experienced by patients with MBC or MUM both quantitatively (n=80) and qualitatively (n=40 approximately). These data will be used to develop and pilot-test a QPL specific to patients with cancer experiencing initial or acquired resistance to treatment. We expect to obtain a core QPL that comprises questions and concerns commonly expressed by patients with resistant cancer and is complemented by specific issues for either MBC or MUM cancer sites. In step 1c, 2 focus groups of patients with any type of metastatic cancer (n=4) and health care professionals (n=4) will be conducted to revise the content of a preliminary QPL and elaborate an acceptable and feasible clinical implementation. In step 1d, the content of the QPL version 1 and implementation guidance will be validated using a Delphi process. Step 2 will pilot-test the QPL version 1 in real practice with patients with MBC or MUM (n=80). Clinical utility will be assessed by comparing responses to questionnaires administered in step 1b (QPL-naive historical control group) and step 2 (QPL intervention group). ResultsThis study received grants in March and December 2019 and was approved by the French national ethics committee in July 2019. As of October 2021, interviews with oncology professionals have been conducted and analyzed (N=26 to reach saturation), and 39 and 27 patients with MBC and MUM, respectively, have been recruited. ConclusionsA clinically and culturally tailored QPL is expected to facilitate patients’ participation in consultations, improve oncologists’ responses to patients’ information and support needs, and thus foster patients’ psychological adjustment to the diagnosis and follow-up of cancer resistance to treatment. Trial RegistrationClinicalTrials.gov NCT04118062; http://clinicaltrials.gov/ct2/show/NCT04118062 International Registered Report Identifier (IRRID)DERR1-10.2196/26414

Background: There is a lack of information as to which molecular processes, present at diagnosis, favor tumour escape from standard-of-care treatments in cervical cancer (CC). RAIDs consortium (www.raids-fp7.eu), conducted a prospectively monitored trial, [BioRAIDs (NCT02428842)] with the objectives to generate high quality samples and molecular assessments to stratify patient populations and to identify molecular patterns associated with poor outcome. Methods: Between 2013 and 2017, RAIDs collected a prospective CC sample and clinical dataset involving 419 participant patients from 18 centers in seven EU countries. Next Generation Sequencing has so far been carried out on a total of 182 samples from 377 evaluable (48%) patients, allowing to define dominant genetic alterations. Reverse phase protein expression arrays (RPPA) was applied to group patients into clusters. Activation of key genetic pathways and protein expression signatures were tested for associations with outcome. Findings: At a median follow up (FU) of 22 months, progression-free survival rates of this FIGO stage IB1-IV population, treated predominantly (87%) by chemoradiation, were65•4% [CI95%: 60•2-71.1]. Dominant oncogenic alterations were seen in PIK3CA (40%), while dominant suppressor gene alterations were seen in KMT2D (15%) and KMT2C (16%). Cumulative frequency of loss-of-function (LOF) mutations in any epigenetic modulator gene alteration was 47% and it was associated with PIK3CA gene alterations in 32%. Patients with tumours harboring alterations in both pathways had a significantly poorer PFS. A new finding was the detection of a high frequency of gains of TLR4 gene amplifications (10%), as well as amplifications, mutations, and non-frame-shift deletions of Androgen receptor (AR) gene in 7% of patients. Finally, RPPA protein expression analysis defined three expression clusters. Interpretation: Our data suggests that patient population may be stratified into four different treatment strategies based on molecular markers at the outset. Fund: European Union's Seventh Program grant agreement No 304810. Keywords: Bioraids study, Prospective database, Cervical cancers, Whole exome sequencing, Reverse phase protein array, Epigenetics pathways, PI3KCA, Patient stratification

PurposeObservational studies using routinely collected data are faced with a number of potential shortcomings that can bias their results. Many methods rely on controlling for measured and unmeasured confounders. In this work, we investigate the use of instrumental variables (IV) and quasi-trial analysis to control for unmeasured confounders in the context of a study based on the retrospective Epidemiological Strategy and Medical Economics (ESME) database, which compared overall survival (OS) with paclitaxel plus bevacizumab or paclitaxel alone as first-line treatment in patients with HER2-negative metastatic breast cancer (MBC).Patients and methodsCausal interpretations and estimates can be made from observation data using IV and quasi-trial analysis. Quasi-trial analysis has the same conceptual basis as IV, however, instead of using IV in the analysis, a "superficial" or "pseudo" randomized trial is used in a Cox model. For instance, in a multicenter trial, instead of using the treatment variable, quasi-trial analysis can consider the treatment preference in each center, which can be informative, and then comparisons of results between centers or clinicians can be informative.ResultsIn the original analysis, the OS adjusted for major factors was significantly longer with paclitaxel and bevacizumab than with paclitaxel alone. Using the center-treatment preference as an instrument yielded to concordant results. For the quasi-trial analysis, a Cox model was used, adjusted on all factors initially used. The results consolidate those obtained with a conventional multivariate Cox model.ConclusionUnmeasured confounding is a major concern in observational studies, and IV or quasi-trial analysis can be helpful to complement analysis of studies of this nature.

Background: Most of the studies regarding the surgical treatment of severe laryngomalacia (LM) have been aimed at describing the efficacy of the treatment in terms of improvement of clinical symptoms or anatomical findings. There are no studies specifically aimed at analyzing the changes in breathing patterns following surgical treatment for severe LM. Objective: To review the breathing pattern changes before and after corrective surgery in infants with severe LM. Study design: A series of retrospective cases at a tertiary referral children’s hospital. Methods: Retrospective chart review of 81 infants who underwent supra-glottoplasty (SGP) for severe laryngomalacia between 2011 and 2020 at Bambino Gesù Children’s Hospital of Rome, Italy. Among the patients, 47 (58%) were male and 34 (42%) were female. Twenty-one patients (26%) had one or more comorbidities condition. The data collected included age, symptoms, a polysomnography/pulse oximetry study, growth rate, the findings from flexible endoscopy, pre- and post-supra-glottoplasty (SGP) pulmonary function tests (PFTs) and, when indicated, 24 h pH-metry. Breathing patterns were studied during restful, normal sleep, using an ultrasonic flow-meter (Exhalyzer, Viasys) which measured: Tidal Volume (Vt), Respiratory Rate (RR), time to peak expiratory flow/expiratory time ratio (tPTEF/Te, an index of the patency of the lower airways) and mean expiratory/mean inspiratory flow ratio (MEF/MIF, an index of the patency of the upper airways) evaluated before surgical procedure (T1) and 3–6 weeks after (T2). Pre- and post-operative mean data were calculated and comparisons made with a Student T-test. Results: The surgical procedure was well tolerated by all infants and no intraoperative or post-operatory long-term complications were noted. In T1, breathing patterns were characterized by low tidal volume and high tPTEF/Te and MEF/MIF ratios, suggesting a severe reduction in the patency of the upper airways in all patients. After surgery (T2), all the previously mentioned variables significantly improved, reaching normal values for the child’s age. Conclusions: Supra-glottoplasty, as already described in several studies, is a safe and efficient procedure to treat severe laryngomalacia during infancy. The improvement in breathing patterns after surgery was reliably confirmed by a lung function test in our study, which showed the diagnostic value of testing respiratory functionality in the laryngomalacia and comparing them to clinical and endoscopic data. Moreover, considering the results obtained, we also propose the use of this available, dependable test to verify its therapeutic effects (post-surgery) and to monitor future respiratory development in these infants. Moreover, we believe that further studies will provide detailed grading guidelines for gravity of the LM, based on these functional lung tests.

Background and purposeFew data are available concerning the safety of bevacizumab (B) in combination with locoregional radiation therapy (RT). The objective of this study was to evaluate the 5-year late toxicity of concurrent B and RT in non-metastatic breast cancer.Materials and methodsThis multicentre prospective study included non-metastatic breast cancer patients enrolled in phase 3 clinical trials evaluating B with concurrent RT versus RT alone. All patients received neoadjuvant or adjuvant chemotherapy and normofractionated breast or chest wall RT, with or without regional lymph node RT. B was administered at an equivalent dose of 5 mg/kg once a week for 1 year. The safety profile was evaluated 1, 3 and 5 years after completion of radiotherapy.ResultsA total of 64 patients were included between November 2007 and April 2010. Median follow-up was 60 months (12-73) and 5-year late toxicity data were available for 46 patients. The majority of tumours were triple-negative (68.8%), tumour size ConclusionConcurrent B and locoregional RT are associated with acceptable 5-year toxicity in patients with non-metastatic breast cancer. No grade ≥3 toxicity was observed.

[This corrects the article DOI: 10.1371/journal.pone.0144359.].