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Background: Radio-chemotherapy remains the mainstay of glioblastoma first-line treatment after extended surgery, but the prognosis is still poor. PARP inhibitors like olaparib may improve glioblastoma outcomes. We implemented a phase 1-2a trial to assess the safety and efficacy of olaparib combined with standard radio-chemotherapy as a first-line treatment in unresected glioblastoma patients. We herein present results of phase 1., Methods: Based on the Stupp regimen, two sequential dose escalations of olaparib were performed to distinguish the radiotherapy period and the maintenance period for assessing the maximum tolerated dose (MTD) of olaparib separately for each treatment period. Dose escalations were performed by a TITE-CRM (TIme-To-Event Continual Reassessment Method)., Results: A total of 30 pts were enrolled: 20 (66.7%) men, median age 59 years [range 25-70], 12 (42.9%) Eastern Cooperative Oncology Group (ECOG) performance status of 0. Among them, 16 and 11 pts were assessable for determining MTD in each period. Hematological dose-limiting toxicities were experienced by 4 and 1 patients in each sequential dose escalation, respectively. MTD was olaparib 100 mg twice daily for 3 days a week in concomitant during both the radio-chemotherapy and maintenance periods of the standard treatment. Median progression-free and overall survival was 6.2 and 19.8 months, respectively. The 2-year survival rate was 36.7% [22.9-58.7]., Conclusions: Intermittent dosing of olaparib at radiosensitizing concentrations in concomitant with the Stupp protocol has an acceptable safety profile with promising outcomes in unresectable glioblastoma patients. Further efficacy determination is ongoing in the phase 2a step.

Background: Cemiplimab is a monoclonal antibody targeting the PD-1, and phase II trials have shown its efficacy in the treatment of advanced cutaneous squamous cell carcinoma in patients who are not candidates for curative surgery or radiation therapy as a first- or later-line treatment. A synergistic antitumoral response has been demonstrated with concurrent radiotherapy and PD1-immunotherapy. However, no real-life study has demonstrated this effect in advanced cutaneous squamous cell carcinoma., Methods: We conducted a real-life retrospective cohort study to investigate the benefit of concomitant therapy in 33 patients treated with cemiplimab at the University Hospital of Caen, alone (C group) or concomitant to radiotherapy (C/RT group). Our primary objectives were to evaluate the best overall response and objective response rate. Our secondary objectives were the disease control rate, median time to response, progression-free survival, overall survival, clinical benefit of radiotherapy, and safety data. After stopping cemiplimab administration, we performed a follow-up of our patients and performed a descriptive study., Results: We reported an objective response rate of 45.5%, including 47.6% in the cemiplimab group versus 41.6% in the concomitant group. The addition of radiotherapy to cemiplimab enables an earlier clinico-radiological response, with a median duration of 5.5 months in the cemiplimab group versus 3 months in the concomitant therapy group. The response to treatment was prolonged despite discontinuation of cemiplimab, with 91.6% ( n = 11/12) and 83.3% ( n = 10/12) patients in complete or partial remission at 6 months and 1 year after cessation of cemiplimab and no switch to another oncological treatment, respectively. Radiation therapy also provided a therapeutic effect in 83.3% of the patients in the concomitant group, without increasing the occurrence of adverse events., Conclusions: Our study confirms the efficacy of cemiplimab and radiotherapy in the management of advanced cutaneous squamous cell carcinoma. Concomitant therapy permitted to obtain an earlier radiological response, a beneficial local therapeutic effect of radiotherapy, without any safety alert.

Purpose: Proton therapy (PT) can be a good option to achieve tumor control while reducing the probability of radiation induced toxicities compared to X-ray-based radiotherapy. However, there are still uncertainties about the effects of PT on the organs in direct contact with the irradiated volume. The aim of this prospective series was to report 6-month follow-up of clinical and functional optic neuropathy rates of patients treated by proton therapy using a standardized comprehensive optic examination., Methods and Materials: Standardized ophthalmological examinations were performed to analyze subclinical anomalies in a systematic way before treatment and 6 months after the end of proton therapy with: Automatic visual field, Visual evoked potential (VEP) and optic coherence of tomography (OCT)., Results: From October 2018 to July 2020 we analyzed 81 eyes. No significant differences were found in the analysis of the clinical examination of visual functions by the radiation oncologist. However, considering VEP, the impairment was statistically significant for both fibers explored at 30'angle (p:0.007) and 60'angle (p <0.001). In patients with toxicity, the distance of the target volume from the optical pathways was more important with a p-value for 30'VEP at 0.035 and for 60'VEP at 0.039., Conclusions: These results confirm uncertainties concerning relative biological effectiveness of proton therapy, linear energy transfer appears to be more inhomogeneous especially in areas close to the target volumes. The follow-up of patients after proton therapy is not an easy process to set up but it is necessary to improve our knowledges about the biological effects of proton therapy in real life. Our study which will continue during the coming years, suggests that follow-up with in-depth examinations such as VEP as a biomarker could improve the detection of early abnormalities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Lecornu, Lesueur, Salleron, Balosso, Stefan, Kao, Plouhinec, Vela, Dutheil, Bouter, Marty, Thariat and Quintyn.)

Purpose: Correct tandem implantation for cervix cancer intracavitary brachytherapy may be challenging. We investigated whether suboptimal implantation can be related to patient and disease characteristics and may result in subsequent underutilization of brachytherapy in cervical cancer., Methods and Materials: Consecutive cervix cancer patients referred for intracavitary brachytherapy after external beam radiation therapy performed in several general hospitals from 2013 to 2017 were included., Results: In 172 patients having 301 procedures, 95 implantations were suboptimal (15% inadequate tandem insertions, 10% subserosal insertion, and 6% uterine perforation on postimplant CT scan). Risk factors were age, myometrium invasion, and uterine retroversion. Median followup was 21 months. Three-year local control and survival rates were 72% and 85%, respectively. Forty-seven patients (27%) failed to receive brachytherapy. Failure to perform brachytherapy was associated with poorer local control (OR = 0.34 [0.17-0.67], p = 0.001). By contrast, suboptimal implantation did not increase local failure or toxicity rates in patients undergoing brachytherapy. No peritoneal carcinomatosis occurred after uterine perforation in our cohort., Conclusions: Suboptimal implantation was frequent. In the absence of image guidance during implantation, conversion to other treatment modalities (including external beam radiation therapy) due to insertion difficulties resulted in worse local control. With optimization, however, suboptimal brachytherapy implantation did not result in suboptimal dose coverage or poorer local control. Failure to perform a brachytherapy boost correlates with increased local failure risk in patients with cervix cancer, whereas tandem malposition does not. Real-time intraoperative ultrasound guidance may be useful to reduce uterine perforation rates and thus increase brachytherapy use., (Copyright © 2019 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.)

Introduction: The aims of this study were to analyze 3-dimensional skeletal changes in subjects with Class II malocclusion treated with the Herbst appliance and to compare these changes with treated Class II controls using 3-dimensional superimposition techniques., Methods: Seven consecutive Herbst patients and 7 Class II controls treated with Class II elastics who met the inclusion criteria had cone-beam computed tomographs taken before treatment, and either after Herbst removal or at posttreatment for the control subjects. Three-dimensional models were generated from the cone-beam computed tomography images, registered on the anterior cranial bases, and analyzed using color maps and point-to-point measurements., Results: The Herbst patients demonstrated anterior translation of the glenoid fossae and condyles (right anterior fossa, 1.69 ± 0.62 mm; left anterior fossa, 1.43 ± 0.71 mm; right anterior condyle, 1.20 ± 0.41 mm; left anterior condyle, 1.29 ± 0.57 mm), whereas posterior displacement predominated in the controls (right anterior fossa, -1.51 ± 0.68 mm; left anterior fossa, -1.31 ± 0.61 mm; right anterior condyle, -1.20 ± 0.41 mm; left anterior condyle, -1.29 ± 0.57 mm; P <0.001). There was more anterior projection of B-point in the Herbst patients (2.62 ± 1.08 mm vs 1.49 ± 0.79 mm; P <0.05). Anterior displacement of A-point was more predominant in the controls when compared with the Herbst patients (1.20 ± 0.53 mm vs -1.22 ± 0.43 mm; P <0.001)., Conclusions: Class II patients treated with the Herbst appliance demonstrated anterior displacement of the condyles and glenoid fossae along with maxillary restraint when compared with the treated Class II controls; this might result in more anterior mandibular projection., (Copyright © 2013 American Association of Orthodontists. Published by Mosby, Inc. All rights reserved.)

Purpose: To evaluate patient, tumor, and treatment variables associated with survival in patients with jaw osteosarcoma (JOS) and to compare survival in patients treated before 1991 with those managed with more aggressive treatment protocols since 1992., Patients and Methods: This is a retrospective cohort study of patients with JOS treated at Massachusetts General Hospital from 1967 through 2007. Patients were divided by treatment date into Group 1, 1967 to 1991 (n = 30) and Group 2, 1992 to 2009 (n = 17). Medical records were reviewed to collect the following: demographic, radiographic, tumor-specific, treatment, and survival data. The 2 subgroups were statistically compared., Results: There were 47 patients (32 males, 15 females) with a mean age of 30.9 years (range 4 to 74). Mandibular location showed a trend toward improved survival (P = .06). Average tumor size was 4.38 cm (range 0.5 to 9.0 cm). Larger tumors were associated with decreased overall survival (P = .016). Higher grade tumors had decreased overall survival (P = .01). Clear surgical margins were obtained in 67% of patients. Clear surgical margins correlated with improved survival (P = .002). Maxillary JOS constituted 83% of those with positive margins. Overall, 5-year survival was 68%. Improved 5-year survival was noted in group 2 (77%) compared with group 1 (52%) [P = .0073]. Patients who developed secondary osteosarcomas (n = 10) had 4.5-fold increased risk of death (P = .01). Recurrence was associated with 7-fold increased risk of death (P = .0008). Thirteen patients died of JOS., Conclusions: Improved survival was noted in treatment group 2. This group benefited from improved imaging, earlier diagnosis and more aggressive treatment that included improved surgical clearance. A clear survival advantage for neoadjuvant chemotherapy was not demonstrated., (Copyright © 2011 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: The higher frequency of Hashimoto's thyroiditis in Turner's syndrome compared with the general population is well known. We have attempted to establish clearly the more frequent association of thyroiditis with the X-isochromosome, since previous reports of this aspect have included only small numbers of patients., Design: Retrospective study of patients with Turner's syndrome investigated within the past 12 years., Patients: Sixty-seven cases of Turner's syndrome were reviewed., Measurements: Peripheral blood leucocyte karyotype and screening for thyroid disturbances on the basis of clinical examination and laboratory evaluation (anti-thyroglobulin and anti-microsomal antibodies, basal TSH levels and TSH levels after TRH stimulation) were made for each patient., Results: A diagnosis of thyroiditis, based on the association of positive antibody titres, elevated TSH and an abnormal thyroid gland on clinical examination, was established in 20.9% (14/67) of cases. A significantly higher frequency of thyroiditis was found among the patients presenting with an X-isochromosome (57.3%, 9/16), compared to patients with other karyotypes (9.8%, 5/51) (P = 0.0001)., Conclusions: Our results, obtained by investigation of a larger number of patients with an X-isochromosome karyotype than in previous reports, confirm conclusively that patients with X-isochromosome Turner's syndrome have an increased risk of developing thyroiditis.

Four cases of psychosocial dwarfism are reported. The growth follow-up of these four children does not fit to the classical description of rapid improvement once separated from their defective or careless family. This illustrates the difficulties for some children to adapt themselves to a foster family and the need to refer them to an institutional center in order to solve their different somatic, nutritional and psychological problems, together with those of their family. In such cases the important growth retardation and hormonal changes may hide severe psychopathological troubles such as hyperkinetic syndrome, anxiety and, possibly, depression.

The authors report the case of a 14 year-old-girl presenting with a prolactin-secreting pituitary macroadenoma and followed over one year of bromocriptine therapy. They focus on the specific clinical features, on the medical management as initial therapy at this age, and on the interest of magnetic resonance imaging and spontaneous hormonal secretion studies for the diagnosis and follow-up.

An association between trisomy 11p15 and Beckwith-Wiedemann syndrome is described in two brothers. The first presented at birth with gigantism and macroglossia, umbilical hernia and abdominal distention, hypoglycemia and atresia of the pulmonary artery, leading to the diagnosis of Beckwith-Wiedemann syndrome. Facial dysmorphism also included: a hypoplastic midface, hypertelorism, and a short nose with a flattened bridge. The karyotype showed a trisomy 11p15 with a monosomy 18p11, due to a t(11;18)(p154;p111)pat. His brother, born a year later, showed the same signs. The association between trisomy 11p15 and Beckwith-Wiedemann syndrome is in certain cases well established.

Two patients with Turner's syndrome and Hashimoto's thyroiditis are described. The incidence of the karyotype 46 XX (iq), 45 X is high in this association reported in the literature; thus, 17 patients among 25 with Turner's syndrome and thyroiditis had a structural abnormality of the X chromosome. Routine thyroid antibodies determination should be carried out in patients with gonadal dysgenesis between 10 and 20 years of age, and early replacement therapy should be undertaken in Turner's syndrome with Hashimoto's thyroiditis, since clinical signs of hypothyroidism are usually delayed.

Two probably monozygotic twins with cerebral gigantism are reported. They showed three typical features: pneumo-encephalography demonstrated a fifth anterior ventricular dilatation; in both patients dermatoglyphic findings showed a thenar exit of the Aline and a vertical palmar alignement; Growth hormone and sulfatation factor blood concentration were low but within normal limits.

The cellular material studied in the urinary sediment mainly obtained from exfoliated cells of the bladder trigone was submitted to hormonal stimulation. These cell changes constitute the basis of a cytological method called urocytogram. The urinary sediment was examined in twenty seven girls with Turner's syndrome. The authors consider the interest of repeat examinations in the follow-up and treatment of these patients.

We studied the height growth of 96 children presenting with acute leukemia or non Hodgkin lymphoma, together with an investigation of GH and TSH in 41 of them. There were 2 groups: group I consisting of 19 patients without brain irradiation and group II consisting of 77 patients with prophylactic brain irradiation. Initial average height was identical in both groups. Growth rate was significantly decreased in group II but not in group I (p less than 0.01). There is a correlation between the decrease of growth rate and the decrease of GH to arginine stimulation test (p less than 0.03). A lack of response to GRF-44 was noted in 4 of 11 investigated patients. TSH and prolactin secretions were unchanged.

In 4 children with celiac disease, aged 7 months to 11 years, serum somatomedin activities (SMA) were consistently low: less than 0.40 U/ml (N greater than 0.50 U/ml). Basal plasma growth hormone (GH) levels were not elevated and increased normally under arginine-insulin stimulation in 3 patients. Human GH administration at a dosage which usually determines an increase of serum SMA in children with GH deficiency (4 mg/day/2 days) did not modify significantly the low serum SMA. However, in 1 child a clear-cut increase of serum SMA (0.22-0.82 U/ml) was noted under a higher dosage of human GH (8 mg/day/2 days). In 3 patients serum SMA was studied 3 weeks to 4 months after starting the gluten-free diet and was found to be normal. A limitation of the somatomedin generation unrelated to a deficit in GH secretion and probably resistant to GH appears therefore to be present in celiac disease. The rapid normalization of serum SMA under gluten-free diet suggests that the low serum SMA is induced through some unknown hormonal or metabolic signal by the protein malabsorption and/or the nutritional deficiency present in celiac disease.

In this French study with recombinant somatropin, the stimulation of growth in 32 prepubertal (age 10.0 +/- 3.5 years; mean +/- SD) and 19 pubertal (age 14 +/- 1.5 years) GH deficient children was compared; the stimulation of growth was similarly good in the two groups. The height velocity SD scores increased from -2.5 +/- 1.7 and -0.9 +/- 1.5 to 2.2 +/- 1.9 and 1.6 +/- 1.6 in prepubertal and pubertal children, respectively. Expressed as cm/year, these correspond to increases from 3.2 +/- 1.3 cm/year and 4.1 +/- 1.2 cm/year to 8.1 +/- 1.5 cm/year and 8.6 +/- 1.9 cm/year in the prepubertal and pubertal patients, respectively. Safety and tolerance were good and the immunogenicity of Genotonorm was low.

In two siblings with male pseudohermaphroditism (ambiguous external genitalia, XY karyotype) and apparently normal glucocorticoid function, plasma concentrations of 10 progestagens or androgens measured by specific RIAs were found to be abnormal under either basal or dynamic conditions. Basal levels of delta 4-androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone sulfate were subnormal and failed to rise after ACTH stimulation both before and after castration. Meanwhile, levels of pregnenolone, pregnenolone sulfate, 17 alpha-hydroxyprogesterone, and 17 alpha-hydroxypregnenolone were extremely high under basal conditions and rose further after ACTH. All of the progestagens and cortisol were suppressed by dexamethasone. After hCG stimulation, either before treatment or during dexamethasone therapy, the rise in testosterone was less than 100 ng/dl, while the progestagens showed an abnormally high rise. The latter were markedly reduced after castration. These findings are consistent with steroid 17--20-desmolase deficiency in both the testes and adrenal glands. In the third brother, who had only slight abnormalities of his genitalia, a mild form of the same defect was suspected. Low androgens, high 17 alpha-hydroxypregnenolone, and 17 alpha-hydroxyprogesterone levels were found in the amniotic fluid and umbilical cord and peripheral blood at birth. The parents, who were not consanguine, had normal baseline levels of all hormones. The familial occurrence of the disease is suggestive of autosomal recessive inheritance.

After a review of the technique of urocytogram the authors report the results obtained in 39 children between the ages of 3 and 12 years. Before the appearance of the first signs of puberty, urocytograms are similar in both girls and boys. Differences were seen in seven cases of male or female precocious puberty. Urocytograms are also different in patients with incomplete precocious puberty but less marked than in those with true precocious puberty. The authors consider the possibility of repeat urocytograms during the supervision or treatment of incomplete and complete precocious puberty.