Phase II study of pembrolizumab and lenvatinib in advanced well-differentiated neuroendocrine tumors.

BACKGROUND: Immune checkpoint inhibitors (CPIs) have not been shown to be active in well-differentiated neuroendocrine tumors (NETs), with response rates <5%. Lenvatinib is a multitargeted tyrosine kinase inhibitor which binds to vascular endothelial growth factor and fibroblast growth factor receptors and has demonstrated efficacy in pancreatic and gastrointestinal NETs [44% and 16% objective radiographic response rate (ORR), respectively]. The combination of antiangiogenic and CPI therapies can be synergistic. We therefore evaluated the combination of lenvatinib and pembrolizumab in well-differentiated gastrointestinal (GI) and thoracic NETs. PATIENTS AND METHODS: A prospective, phase II trial evaluated patients with advanced GI/thoracic NETs (pancreatic NETs were excluded due to high response rate of lenvatinib monotherapy in this patient population), with evidence of progression within 8 months of study entry and at least two prior lines of systemic therapy. Patients received lenvatinib 20 mg daily and pembrolizumab 200 mg intravenously every 3 weeks until unacceptable toxicity or progression of disease. Primary endpoint was objective response rate, and an interim analysis was planned once 20 patients were enrolled. Four ORRs were required to continue enrollment. RESULTS: Twenty patients were enrolled on protocol from April 2021 to January 2022 (nine small intestine, five lung, two thymic, two unknown primary, one cecal, one presacral primaries). Two patients (10%) achieved a partial response (atypical lung and small intestinal primaries). Median progression-free survival (PFS) was 8 months (95% confidence interval 5.8-10.2 months). Twelve (60%) patients experienced probably or definitely associated grade 3 adverse events (10 hypertension). Fourteen patients (70%) required dose reductions or discontinued one of the medications. Two patients discontinued treatment before radiographic assessment. CONCLUSIONS: The combination of pembrolizumab and lenvatinib did not show sufficient response in patients with NETs to warrant continued enrollment on trial.

Neurodevelopmental model of long-term outcomes of adult survivors of childhood brain tumors.

Childhood brain tumors and related treatments disrupt the developing brain and have a cascading impact on core cognitive skills and intellectual (intelligence quotient [IQ]) and academic achievement outcomes. Theoretical models for this cascade have been developed based on the literature, but no studies thus far have empirically evaluated the models. The current study aimed to empirically test the two extant models and generate a new data-driven model of the relationships among neurodevelopmental risk factors, core cognitive skills (i.e., processing speed, attention span, working memory), and IQ and achievement outcomes. Fifty-seven adult survivors of childhood brain tumors and fifty-seven demographically matched neurotypical individuals were included in the current study. The average age at brain tumor diagnosis was 8 years, and the average time since diagnosis was 17 years. Three a priori path models tested the hypothesized relationships among variables. Results of the path analyses revealed that the hybrid model best fit the data for both survivors and controls based on all statistical criteria. For survivors, processing speed was the core cognitive skill most widely associated with neurodevelopmental risk factors and outcomes. However, working memory and attention span also had unique contributions to IQ and academic achievement. Processing speed appears to be the central cognitive skill that disrupts the other core cognitive skills of attention span and working memory, and all three make a unique contribution to IQ and academic achievement. This is best demonstrated by a novel neurodevelopmental model that combines components of two earlier untested theoretical models.

On-chip free beam optics on a polymer-based photonic integration platform.

This paper presents on-chip free beam optics on polymer-based photonic components. Due to the circumstance that waveguide-based optics allows no direct beam access we use Gradient index (GRIN) lenses assembled into the chip to collimate the beam from the waveguides. This enables low loss power transmission over a length of 1432 µm. Even though the beam propagates through air it is possible to create a resonator with a wavelength shift of 0.002 nm/°C, hence the allowed deviations from the ITU-T grid (100 GHz) are met for ± 20 °C. In order to guarantee reliable laser stability, it is necessary to implement optical isolators at the output of the laser. This requires the insertion of bulk material into the chip and is realized by a 1050 µm thick coated glass. Due to the large gap of the free-space section, it is possible to combine different resonators together. This demonstrates the feasibility of an integrated wavelength-meter.

Combined therapy in children and adolescents with classical Hodgkin's lymphoma: A report from the SFCE on MDH-03 national guidelines.

Hodgkin's lymphoma (HL) in children and adolescents is highly curable, but children are at risk of long-term toxicity. The MDH-03 guidelines were established in order to decrease the burden of treatment in good-responder patients, and this report should be considered a step toward further optimization of treatment within large collaborative trials. We report the therapy and long-term outcomes of 417 children and adolescents treated according to the national guidelines, which were applied between 2003 and 2007 in France. The patients were stratified into three groups according to disease extension. Chemotherapy consisted of four cycles of VBVP (vinblastine, bleomycin, VP16, prednisone) in localized stages (G1/95 pts/23%), four cycles of COPP/ABV (cyclophosphamide, vincristine, procarbazine, prednisone, adriamycin, bleomycin, vinblastine) cycles in intermediate stages (G2/184 pts/44%) and three cycles of OPPA (vincristine, procarbazine, prednisone, adriamycin) plus three cycles of COPP in advanced stages (G3/138 pts/33%). Radiation therapy of the involved field was given to 97% of the patients, with the dose limited to 20 Gy in good responders (88%). With a median follow-up of 6.6 years, the 5-year event-free survival (EFS) and overall survival (OS) were 86.7% (83.1-89.7%) and 97% (94.5-98.1%), respectively. EFS and OS for G1, G2, and G3 were 98% and 100%, 81% and 97%, and 87% and 95%, respectively. Low-risk patients treated without alkylating agents and anthracycline had excellent outcomes and a low expected incidence of late effects. Intensification with a third OPPA cycle in high-risk group patients, including stage IV patients, allowed for very good outcomes, without increased toxicity.

Phase II clinical trial of pasireotide long-acting repeatable in patients with metastatic neuroendocrine tumors.

Pasireotide long-acting repeatable (LAR) is a novel somatostatin analog (SSA) with avid binding affinity to somatostatin receptor subtypes 1, 2, 3 (SSTR1,2,3) and 5 (SSTR5). Results from preclinical studies indicate that pasireotide can inhibit neuroendocrine tumor (NET) growth more robustly than octreotide in vitro. This open-label, phase II study assessed the clinical activity of pasireotide in treatment-naïve patients with metastatic grade 1 or 2 NETs. Patients with metastatic pancreatic and extra-pancreatic NETs were treated with pasireotide LAR (60 mg every 4 weeks). Previous systemic therapy, including octreotide and lanreotide, was not permitted. Tumor assessments were performed every 3 months using Response Evaluation Criteria in Solid Tumors (RECIST) criteria. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), overall radiographic response rate (ORR), and safety. Twenty-nine patients were treated with pasireotide LAR (60 mg every 4 weeks) and 28 were evaluable for response. The median PFS was 11 months. The most favorable effect was observed in patients with low hepatic tumor burden, normal baseline chromogranin A, and high tumoral SSTR5 expression. Median OS has not been reached; the 30-month OS rate was 70%. The best radiographic response was partial response in one patient (4%), stable disease in 17 patients (60%), and progressive disease in ten patients (36%). Although grade 3/4 toxicities were rare, pasireotide LAR treatment was associated with a 79% rate of hyperglycemia including 14% grade 3 hyperglycemia. Although pasireotide appears to be an effective antiproliferative agent in the treatment of advanced NETs, the high incidence of hyperglycemia raises concerns regarding its suitability as a first-line systemic agent in unselected patients. SSTR5 expression is a potentially predictive biomarker for response.

[Pediatric palliative care: a national survey of French pediatric residents' knowledge, education, and clinical experience]. / Soins palliatifs pédiatriques : connaissances, expérience clinique et formation des internes de pédiatrie français. Résultats d'une enquête nationale.

BACKGROUND: The need for educational training of healthcare professionals in palliative care is an important issue. Training and practice of pediatric residents in the field of pediatric palliative care (PPC) has never been assessed, although the organization of the medical curriculum in France is currently being revised. MATERIALS AND METHODS: This study presents a national survey of pediatric residents, using a computerized anonymous questionnaire. Four different areas were studied: epidemiological data, theoretical and practical knowledge, education, and clinical experience in PPC. RESULTS: The response rate was 39% (n=365/927). Whatever their age or regional location, 25% of residents did not know any details of the French law concerning patients' rights and the end of life. Experience with PPC starts very early since 77% of the first-year pediatric residents experienced at least one child in a palliative care and/or end-of-life situation. During their entire residency, 87% of the residents had experience with PPC and nearly all (96%) end-of-life care. Furthermore, 76% had participated in announcing palliative care (cancer, ICU, etc.) or a serious illness, and 45% had met and discussed with bereaved parents. Furthermore, while 97% of the pediatric residents received training in adult palliative care, mainly before their residency, only 60% received specific PPC training. DISCUSSION AND CONCLUSION: Ninety-six percent of all French pediatric residents encountered a PPC situation during their residency. That 77% of them had experienced PPC during their first year of residency shows the importance of early training in PPC for pediatric residents. Furthermore, this study points out that there is a significant lack in PPC training since 40% of all residents in the study received no specific PPC training. Progress in education remains insufficient in the dissemination of knowledge on the legal framework and concepts of palliative medicine: while the medical curriculum is being revised, we suggest that training in medical ethics and PPC should be introduced very early and systematically.

Race/ethnicity affects the probability of finding an HLA-A, -B, -C and -DRB1 allele-matched unrelated donor and likelihood of subsequent transplant utilization.

Factors relevant to finding a suitable unrelated donor and barriers to effective transplant utilization are incompletely understood. Among a consecutive series of unrelated searches (n=531), an 8/8 HLA-A, -B, -C and -DRB1-matched unrelated donor was available for 289 (54%) patients, 7/8 for 159 (30%) and no donor for 83 (16%). Patients of Caucasian race (P<0.0001) were more likely to find a donor. Younger age (P=0.01), Caucasian race (P=0.03), lower CIBMTR (Center for International Blood and Marrow Transplantation Research) risk (P=0.005), and 8/8 HLA matching (P=0.005) were associated with higher odds of reaching hematopoietic cell transplantation (HCT). In a univariate analysis of OS, finding a donor was associated with hazard ratio (HR) of 0.85 (95% CI 0.63-1.2), P=0.31. Karnofsky performance status (KPS) accounted for interaction between having a donor and survival. Patients with KPS 90-100 and a donor had significantly reduced hazard for death (HR 0.59, 95% CI 0.38-0.90, P=0.02). These data provide estimates of the probability to find an unrelated donor in the era of high-resolution HLA typing, and identify potentially modifiable barriers to reaching HCT. Further efforts are needed to enhance effective donor identification and transplant utilization, particularly in non-Caucasian ethnic groups.

Polarization rotator for InP rib waveguide.

A polarization rotator, suitable for integration in a polarization diversity optical receiver fabricated in InP technology, is proposed. The device, based on a two steps waveguide rotator, includes tapered input and output ports that provide very low insertion loss (<0.04 dB). An extinction ratio of 40 dB at 1550 nm wavelength is calculated, comparable or even superior to other state of the art polarization converters. The main advantage of the proposed design is the capability of implementation using a standard fabrication process with only two dry etch steps, significantly reducing complexity and cost.

A phase II clinical trial of sunitinib following hepatic transarterial embolization for metastatic neuroendocrine tumors.

BACKGROUND: The liver is the predominant site of metastases among patients with advanced neuroendocrine tumors (NETs). Prior retrospective studies have reported high response rates in patients treated with transarterial embolization (TAE). NETs are highly vascular and are known to express vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR). We hypothesized that administration of sunitinib, a VEGFR inhibitor, following TAE would extend progression-free survival (PFS). PATIENTS AND METHODS: Patients with metastatic NETs to the liver underwent a series of selective TAEs followed by sunitinib (until disease progression or maximum of 12 months). Radiographic response (by RECIST), survival, and safety parameters were monitored. RESULTS: Thirty-nine patients were enrolled. The overall response rate was 72% [95% confidence interval (CI), 0.58-0.86]. Median PFS was 15.2 months. Rates of overall survival (OS) at 1 and 4 years were 95% (95% CI, 0.88-1.00) and 59% (95% CI, 0.38-0.80), respectively. A significant 34% rise in serum VEGF was observed following the initial TAE (P = 0.03). CONCLUSIONS: Hepatic TAE is a highly active treatment option for patients with metastatic NETs to the liver. Embolization stimulates release of VEGF into the circulation. Sunitinib, an oral VEGFR inhibitor, can be safely administered following embolization. The high rates of PFS and OS associated with this sequence of therapies are encouraging.

Next generation 1.5 microm terahertz antennas: mesa-structuring of InGaAs/InAlAs photoconductive layers.

Mesa-structuring of InGaAs/InAlAs photoconductive layers is performed employing a chemical assisted ion beam etching (CAIBE) process. Terahertz photoconductive antennas for 1.5 microm operation are fabricated and evaluated in a time domain spectrometer. Order-of-magnitude improvements versus planar antennas are demonstrated in terms of emitter power, dark current and receiver sensitivity.

In situ protein expression of RRM1, ERCC1, and BRCA1 in metastatic breast cancer patients treated with gemcitabine-based chemotherapy.

Ribonucleotide reductase 1 (RRM1) is a determinant of gemcitabine efficacy in non-small-cell lung cancer and pancreatic cancer. We investigated the protein levels of RRM1 and two other DNA repair enzymes, ERCC1 and BRCA1, in 55 metastatic breast cancer (MBC) patients undergoing gemcitabine-based chemotherapy. With automated in situ protein quantification (AQUA v1.6), the average scores for RRM1, ERCC1, and BRCA1 ranged from 245.6-2774.1, 74.0-410.3, and 54.4-1833.1, respectively. They were significantly associated with each other (Spearman's rho > or = .36; p < or = .007). Given their pattern of distribution, RRM1 and BRCA1 are potentially suitable markers for clinical decision making in MBC.

Voriconazole provides effective prophylaxis for invasive fungal infection in patients receiving glucocorticoid therapy for GVHD.

Patients on systemic glucocorticoids for GVHD after hematopoietic cell transplant are susceptible to invasive fungal infections (IFI), which greatly contribute to morbidity and mortality. We evaluated the efficacy of prophylactic treatment options (voriconazole or fluconazole vs itraconazole) for IFI by performing a retrospective review of patients on glucocorticoids for GVHD who were administered voriconazole (n=97), fluconazole (n=36) or itraconazole (n=36). IFI developed in 7/72 (10%) patients on fluconazole/itraconazole vs 2/97 (2%) on voriconazole (P=0.03) within the first 100 days of glucocorticoids. Five (7%) patients developed Aspergillus IFI on fluconazole/itraconazole, compared with none on voriconazole (0%) (P=0.008); Aspergillus IFI resulted in death in all five patients. We found that IFI occurred in patients who received an initial dose of at least 2 mg/kg/day of prednisone or equivalent; when the analysis was restricted to these patients, the hazard ratio (0.39; 95% confidence interval: 0.08-1.86) was consistent with a protective effect of voriconazole compared with fluconazole/itraconazole, although this subset analysis did not reach significance. OS at 100 days after start of glucocorticoids was 77% in patients administered fluconazole/itraconazole and 85% in those administered voriconazole (P=0.22). Our results suggest that voriconazole is more effective than fluconazole/itraconazole in preventing IFI, especially aspergillosis, in patients receiving glucocorticoids post transplant.

[A positioning pillow to improve lumbar puncture in paediatric haematology-oncology patients: a randomized controlled trial.]. / Coussin de positionnement pour ponctions lombaires en oncohématologie pédiatrique : résultats d'un essai randomisé

ObjectivesLumbar punctures (LPs) are common in children with cancer. Although pain management during the LP has been well standardised, dealing with stress and anxiety is not well addressed yet. Our objective was to evaluate the potential improvement of the LPs success rate using a positioning pillow, to ensure maximum lumbar flexion, and allow paravertebral muscles to relax, in children who are awake, with either conscious sedation or no sedation.Patients and methodsChildren aged 2-18 years undergoing LPs were randomly assigned to a positioning pillow or no intervention. The primary outcome was the rate of success, i.e. achieving the LPs (sampling or injection) at the first attempt, without bleeding (RBC < 50/mm3). The secondary outcomes included: the child's pain, assessed by a self-administered visual analogical scales (VAS) for children over 6 years of age; the parents' and caregivers' perception of the child's pain; the satisfaction of the children, the parents, the caregivers and the physician. The child's cooperation and the occurrence of post-LP syndrome were also evaluated.ResultsOne hundred twenty-four children (62 in each group) were included. The LP pillow tended to increase the success rate of LPs (67 vs 57%; P = 0.23), and decreased the post-LP syndromes (15 vs 24%; P = 0.17) but the differences were not statistically significant. In children over 6-year of age (N = 72), the rate of success was significantly higher in the pillow group (58.5 vs 41.5%; P = 0.031), with a tendency to feel less pain (for less pain and better satisfaction) [median VAS: 25 vs 15 mm; P = 0.39] and being more satisfied (84.4 vs 75.0%; P = 0.34).ConclusionEven if the results presented here are not as optimistic as we might have wished, we can confirm that there is a benefit in using this pillow for LPs. It is especially promising in children over 6-year of age.

[Hodgkin's disease: treatment specificities in childhood]. / Maladie de Hodgkin : spécificités de la prise en charge en pédiatrie.

Paediatric Hodgkin disease presents some particularities when compared to Hodgkin in adults. In this article, we focus on the paediatric particularities, especially in term of current treatment strategy. The aim is to decrease the important rate of late effects while keeping the excellent survival.

Continuous wave terahertz systems exploiting 1.5 microm telecom technologies.

A fiber-assembled CW THz System operating at 1.5 microm is presented. High speed telecom photodiodes integrated with planar THz antennas serve as THz emitters with power up to 10 microW. Photoconductive antennas based on LT InGaAs/InAlAs multi-layer structures allow coherent detection. The system operates in a wide frequency range of 0.1 -1.6 THz.

Chlamydia trachomatis YtgA is an iron-binding periplasmic protein induced by iron restriction.

Chlamydia trachomatis is a Gram-negative obligate intracellular bacterium that is the causative agent of common sexually transmitted diseases and the leading cause of preventable blindness worldwide. It has been observed that YtgA (CT067) is very immunogenic in patients with chlamydial genital infections. Homology analyses suggested that YtgA is a soluble periplasmic protein and a component of an ATP-binding cassette (ABC) transport system for metals such as iron. Since little is known about iron transport in C. trachomatis, biochemical assays were used to determine the potential role of YtgA in iron acquisition. (59)Fe binding and competition studies revealed that YtgA preferentially binds iron over nickel, zinc or manganese. Western blot and densitometry techniques showed that YtgA concentrations specifically increased 3-5-fold in C. trachomatis, when cultured under iron-starvation conditions rather than under general stress conditions, such as exposure to penicillin. Finally, immuno-transmission electron microscopy provided evidence that YtgA is more concentrated in C. trachomatis during iron restriction, supporting a possible role for YtgA as a component of an ABC transporter.

All-fiber terahertz time-domain spectrometer operating at 1.5 microm telecom wavelengths.

The worldwide first all-fiber THz time-domain spectrometer for operation at 1.5 microm is presented. Applications up to 3 THz are demonstrated. Key devices are photoconductive antennas based on novel LT InGaAs/InAlAs multi-layer structures.