Fabrication and Characterization of PDMS Waveguides for Flexible Optrodes.

With the growth of optogenetic research, the demand for optical probes tailored to specific applications is ever rising. Specifically, for applications like the coiled cochlea of the inner ear, where planar, stiff, and nonconformable probes can hardly be used, transitioning from commonly used stiff glass fibers to flexible probes is required, especially for long-term use. Following this demand, polydimethylsiloxane (PDMS) with its lower Young's modulus compared to glass fibers can serve as material of choice. Hence, the long-term usability of PDMS as a waveguide material with respect to variations in transmission and refractive index over time is investigated. Different manufacturing methods for PDMS-based flexible waveguides are established and compared with the aim to minimize optical losses and thus maximize optical output power. Finally, the waveguides with lowest optical losses (-4.8 dB cm-1 ± 1.3 dB cm-1 at 472 nm) are successfully inserted into the optogenetically modified cochlea of a Mongolian gerbil (Meriones unguiculatus), where optical stimuli delivered by the waveguides evoked robust neuronal responses in the auditory pathway.

Identification of characteristics predictive of long-term survival with durvalumab or durvalumab plus tremelimumab in metastatic urothelial carcinoma.

BACKGROUND: This retrospective analysis of data from clinical trials in metastatic urothelial carcinoma (mUC) was conducted to determine baseline patient characteristics associated with long-term survival (LTS) following treatment with immune checkpoint inhibitors. METHODS: Data for this analysis were from patients with platinum-refractory mUC who received durvalumab or durvalumab plus tremelimumab in phase 1/2 studies. The primary outcome measure was LTS. Patients were categorised as overall survival (OS) ≥ 2 years (from first dose) or OS < 2 years. A univariable analysis assessed independent associations with LTS and multivariable logistic regression was employed including each variable with P ≤ 0.05 as covariates. RESULTS: Among 360 patients, 88 (24.4%) had OS ≥ 2 years and 272 (75.6%) had OS < 2 years. In univariable analysis, several baseline characteristics and laboratory measurements were associated with LTS including sex, ECOG PS, PD-L1 expression, prior surgery, time from initial diagnosis, lymph node-only involvement, visceral disease, haemoglobin level, absolute neutrophil count, neutrophil-lymphocyte ratio and lactate dehydrogenase level. In multivariable analysis, LTS was significantly associated with ECOG PS, PD-L1 expression, haemoglobin level and absolute neutrophil count. CONCLUSIONS: Several baseline clinical characteristics and laboratory measurements were associated with LTS for patients with platinum-refractory mUC treated with durvalumab or durvalumab plus tremelimumab.

Impact of the COVID-19 Pandemic on the Wellbeing of International Oncology and Hematology Fellows at the Princess Margaret Cancer Center (PMCC).

BACKGROUND: The COVID-19 pandemic has led to significant disruptions across all levels of medical training. International fellows in subspecialty training programs are essential members of the frontline physician workforce, but may face additional and unique challenges as a result of being away from their home country. In this study, we aimed to understand the impact of the COVID-19 pandemic on the wellbeing of international fellows in the Hematology and/or Oncology fellowship program at the PMCC. METHODS: In collaboration with our staff psychiatrist, we conducted an online survey of hematology and/or oncology fellows at the PMCC from July 6 to August 10, 2020. The survey consisted of 60 questions divided into 4 sections: demographics, wellbeing assessment using the validated Short Warwick Edinburgh Mental Wellbeing Scale (SWEMWBS), fellowship specific questions (personal and professional) and coping strategies using the validated brief COPE scale. RESULTS: Overall 24/52 (46%) fellows completed the survey: 21/24 were international fellows with 48% from Asia, 3/24 were Canadian fellows but away from home; 54% were male; 48% were aged 31-35 years; 65% were married, 48% had children. Mean SWEMWBS score was 21, indicating lower overall wellbeing than the general population who had a score of 23.6. Compared to their pre-COVID status, many reported a decline in their wellbeing (63%), sense of guilt for not being with their family (45%) or helping their country (41%), stress in personal relationships (26%), fatigue (50%), sleep disorders (38%) and loss of interest in daily activities (38%). Personal events were altered by almost 80%; and 20% planned to extend their fellowship. According to the Brief-COPE scale, during the pandemic, most fellows used more adaptive coping mechanisms (mean score 39.2) as opposed to maladaptive ones (mean score 21.8). CONCLUSIONS: The ongoing COVID-19 pandemic has negatively affected the overall wellbeing of international fellows. Understanding the specific challenges and coping mechanisms used by international fellows may help institutions develop better targeted strategies to promote wellbeing, professional development and ensure high-quality patient care during unprecedented times like the COVID pandemic.

Phase I trial of copanlisib, a selective PI3K inhibitor, in combination with cetuximab in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.

Background The phosphatidylinositol-3 kinase pathway is often altered in head and neck squamous cell carcinoma (HNSCC), and is involved in the resistance to EGFR inhibitors. Objective We investigated the dose-limiting toxicities (DLTs), maximum tolerated dose, pharmacokinetics, and preliminary efficacy of the combination of copanlisib, an intravenous, pan-class I PI3K inhibitor, with the anti-EGFR monoclonal antibody cetuximab in recurrent and/or metastatic HNSCC patients in a phase I dose-escalation trial. Patients and methods Copanlisib was given intravenously on days 1, 8, and 15 of 28-day cycles at the dose of 45 mg and 30 mg, in combination with standard doses of weekly cetuximab (400 mg/m2 loading dose followed by 250 mg/m2 on days 8, 15, and 22, and weekly thereafter). Results Three patients received copanlisib 45 mg, of whom two experienced grade 3 hyperglycemia during Cycle 1 that met the DLT criteria. Eight patients were then treated with copanlisib at the dose of 30 mg. Because of the occurrence of hyperglycemia, a premedication with metformine was introduced on the day of the injections. No DLTs were reported at this dose level. The trial was stopped early because of the unfavourable toxicity profile of the combination. Among eight evaluable patients for response, four patients (50%) had disease stabilization according to RECIST1.1 as best response. Conclusion Copanlisib combined with cetuximab demonstrated unfavorable toxicity and limited efficacy in heavily pretreated recurrent and/or metastatic HNSCC patients.Trial registration NCT02822482, Date of registration: June 2016.

Recent Advances in the Management of Penile Cancer: A Contemporary Review of the Literature.

Penile cancer is a rare condition, which mostly affects men in their sixth decade of life. The most common histology is squamous cell carcinoma (SCC), with about half of the cases linked to human papilloma virus (HPV) infection. The lack of awareness and significant social and psychological stigma associated with penile cancer often leads to delays in presentation, diagnosis and management. Timely multidisciplinary care at experienced centers is therefore critical for improving outcomes. For patients with advanced disease, treatment options are limited and prognosis remains poor. Large international efforts are underway to further define the optimal standards of care. Targeted therapies and immune checkpoint inhibitors could potentially play a role in advanced disease and are under evaluation in clinical trials. In this review, we discuss the current management of penile cancer and future directions.

Enfortumab Vedotin in urothelial cancer.

The treatment landscape for metastatic urothelial cancer (mUC) beyond first-line platinum-based chemotherapy has changed significantly over the last 5 years with the recent approvals of the immune checkpoint inhibitors (ICIs), fibroblast growth factor receptor (FGFR) inhibitors and most recently Enfortumab Vedotin (EV). EV is a novel antibody-drug conjugate (ADC), that delivers monomethyl auristatin E (MMAE), a microtubule-disrupting agent, inside cells harboring the cell surface nectin-4 receptor. In mUC, EV has shown encouraging response rates and received accelerated approval from the Food and Drug Administration (FDA) in December 2019 in the post-platinum and ICI setting. EV is generally well tolerated, with the main toxicities being neuropathy, skin rash, alopecia and fatigue. Notably EV can also be administered to patients with renal dysfunction, which is commonly a concern in this patient population. EV is now being tested in combination strategies and in earlier disease settings in urothelial cancers. In this review, we will discuss its mechanism of action, clinical trials leading to FDA approval as well as ongoing trials and future directions.

Implantable Glass Waveguides and Coating Materials for Chronic Optical Medical Applications.

An innovative fabrication process of glass waveguides on silicon substrates for miniaturized implants is presented. Thin glass was bonded on oxidized silicon wafers and patterned using wet etching. Multimode waveguides with different shapes and a low surface roughness as well as low scattering of light were successfully fabricated. For efficient coupling of light and accurate alignment, KOH-grooves were etched in the silicon with respect to the glass waveguides to attach optical fibers from external light sources. Towards higher biostability, several coating materials were evaluated in accelerated in vitro tests in 60°C PBS for the first time over a long period of time regarding their optical properties. Ti02, SiC, polyimide, Parylene C and SU-8 showed a very stable optical transmittance after 320 days in accelerated aging while PECVDSi3N4 showed significant changes within the first days.

Relevance of a molecular tumour board (MTB) for patients' enrolment in clinical trials: experience of the Institut Curie.

BACKGROUND: High throughput molecular screening techniques allow the identification of multiple molecular alterations, some of which are actionable and can be targeted by molecularly targeted agents (MTA). We aimed at evaluating the relevance of using this approach in the frame of Institut Curie Molecular Tumor Board (MTB) to guide patients with cancer to clinical trials with MTAs. PATIENTS AND METHODS: We included all patients presented at Institut Curie MTB from 4 October 2014 to 31 October 2017. The following information was extracted from the chart: decision to perform tumour profiling, types of molecular analyses, samples used, molecular alterations identified and those which are actionable, and inclusion in a clinical trial with matched MTA. RESULTS: 736 patients were presented at the MTB. Molecular analyses were performed in 442 patients (60%). Techniques used included next-generation sequencing, comparative genomic hybridisation array and/or other techniques including immunohistochemistry in 78%, 51% and 58% of patients, respectively. Analyses were performed on a fresh frozen biopsy in 91 patients (21%), on archival tissue (fixed or frozen) in 326 patients (74%) and on both archival and fresh frozen biopsy in 25 patients (6%). At least one molecular alteration was identified in 280 analysed patients (63%). An actionable molecular alteration was identified in 207 analysed patients (47%). Forty-five analysed patients (10%) were enrolled in a clinical trial with matched MTA and 29 additional patients were oriented and included in a clinical trial based on a molecular alteration identified prior to the MTB analysis. Median time between date of specimen reception and molecular results was 28 days (range: 5-168). CONCLUSIONS: The implementation of an MTB at Institut Curie enabled the inclusion of 10% of patients into a clinical trial with matched therapy.

Immunotherapy in head and neck cancers: A new challenge for immunologists, pathologists and clinicians.

Cancer occurrence can be understood as the result of dysfunctions in immune tumoral microenvironment. Here we review the recent understandings of those microenvironment changes, regarding their causes and prognostic significance in head and neck (HN) carcinoma. We will focus on HN squamous cell cancer (SCC) and nasopharyngeal carcinomas (NPC). Their overall poor prognosis may be improved with immunotherapy in a subset of patients, as supported by current clinical trials. However, finding reliable markers of therapeutic response is crucial for patient selection, due to potential severe adverse reactions and high costs. Half of HNSCC exhibit PD-L1 expression, this expression being higher in HPV-positive tumors. In recent clinical trials, a better therapeutic response to anti-PD-1 was obtained in patients with higher PD-L1 expression. The Food and Drug Administration (FDA) approved the use of these therapeutics without stating a need for patient selection regarding PD-L1 status. Activation status, density and localization of TIL as well as PD-L2, γ-interferon, inflammatory cytokines, epithelial-mesenchymal transition phenotype and mutational burden may all be potential therapeutic response markers. In Epstein-Barr Virus (EBV)-induced nasopharyngeal non-keratinizing cancer, PD-L1 is over-expressed compared to EBV-negative tumors. A 22% response rate has been observed under anti-PD-1 treatment among PD-L1-positive NPC patients. A better understanding of immune checkpoint regulation processes may allow patients to benefit from these promising immunotherapies.

Exploitation of Precision Medicine Trials Data: Examples of Long Responders From the SHIVA01 Trial.

PURPOSE: Precision medicine trials constitute a precious source of molecular data with prospective clinical annotations allowing the exploration of patients' subpopulations according to specific clinical or biological questions. Using the SHIVA01-the first randomized trial comparing molecularly targeted therapy on the basis of tumor molecular profiling versus conventional chemotherapy in metastatic cancer patients who failed standard of care therapy-annotated database, we report cases of patients treated in the trial with targeted therapy who experienced an objective response or prolonged disease stabilization in light of patients' molecular alterations. PATIENTS AND METHODS: We selected all patients included in SHIVA01 treated with a molecularly targeted agent (MTA) who experienced an objective response or disease stabilization that lasted longer than 6 months according to Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: Among the 170 patients who received MTAs in the SHIVA01 trial, 15 patients (9%) experienced an objective response (n = 3) or disease stabilization that lasted longer than 6 months (n = 12). The most frequent histologic subtypes were breast cancer (27%) and cervical cancer (20%). Six patients, including three patients with breast cancer, were treated with abiraterone on the basis of androgen receptor protein overexpression. Five patients were treated with everolimus on the basis of a PTEN heterozygous deletion with loss of protein expression, PIK3CA mutation, or both alterations. The remaining four patients were treated with tamoxifen, erlotinib, imatinib, and vemurafenib on the basis of progesterone receptor expression, EGFR amplification, KIT mutation, and BRAF mutation, respectively. TP53 mutations were absent in responder patients. CONCLUSION: Analysis of patients who experienced objective responses or disease stabilization that lasted longer than 6 months allowed the identification of potential biomarkers of sensitivity and resistance to MTAs.

First-in-Human Phase I Study of Single-agent Vanucizumab, A First-in-Class Bispecific Anti-Angiopoietin-2/Anti-VEGF-A Antibody, in Adult Patients with Advanced Solid Tumors.

Purpose: Vanucizumab is an investigational antiangiogenic, first-in-class, bispecific mAb targeting VEGF-A and angiopoietin-2 (Ang-2). This first-in-human study evaluated the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of vanucizumab in adults with advanced solid tumors refractory to standard therapies.Experimental Design: Patients received escalating biweekly (3-30 mg/kg) or weekly (10-30 mg/kg) intravenous doses guided by a Bayesian logistic regression model with overdose control.Results: Forty-two patients were treated. One dose-limiting toxicity, a fatal pulmonary hemorrhage from a large centrally located mediastinal mass judged possibly related to vanucizumab, occurred with the 19 mg/kg biweekly dose. Arterial hypertension (59.5%), asthenia (42.9%), and headache (31%) were the most common toxicities. Seventeen (41%) patients experienced treatment-related grade ≥3 toxicities. Toxicity was generally higher with weekly than biweekly dosing. A MTD of vanucizumab was not reached in either schedule. Pharmacokinetics were dose-linear with an elimination half-life of 6-9 days. All patients had reduced plasma levels of free VEGF-A and Ang-2; most had reductions in KTRANS (measured by dynamic contrast-enhanced MRI). Two patients (renal cell and colon cancer) treated with 30 mg/kg achieved confirmed partial responses. Ten patients were without disease progression for ≥6 months. A flat-fixed 2,000 mg biweekly dose (phamacokinetically equivalent to 30 mg/kg biweekly) was recommended for further investigation.Conclusions: Biweekly vanucizumab had an acceptable safety and tolerability profile consistent with single-agent use of selective inhibitors of the VEGF-A and Ang/Tie2 pathway. Vanucizumab modulated its angiogenic targets, impacted tumor vascularity, and demonstrated encouraging antitumor activity in this heterogeneous population. Clin Cancer Res; 24(7); 1536-45. ©2017 AACR.

Bevacizumab Associated with Chemotherapy for Initially Non-resectable Liver Metastases from Colorectal Cancer: a Case-Control Study.

BACKGROUND: The place of bevacizumab in therapy of patients with initially non-resectable liver metastases from colorectal cancer (CRC) remains debated. Bevacizumab may increase the efficacy of chemotherapy but it may also maintain dormant micrometastases in a dormant state, eventually increasing the long-term likelihood of tumor relapse. The aim of this study was to explore this hypothesis. PATIENTS AND METHODS: A retrospective case-control study was performed in patients with initially non-resectable CRC liver metastases. Metastases were rendered resectable after chemotherapy with (cases) or without (controls) bevacizumab. Cases and controls were matched for synchronicity, number and maximal size of metastases. The main objective was the disease-free survival (DFS). RESULTS: A total of 82 patients were enrolled (41 in each group). The median DFS was 12.0 months in the bevacizumab group, and 10.2 months in the group treated with chemotherapy alone (p=0.26). CONCLUSION: We observed no significant effect on DFS for bevacizumab when added to chemotherapy in patients with initially non-resectable liver metastases. Prospective trials on this issue are warranted.

Treatment Algorithms Based on Tumor Molecular Profiling: The Essence of Precision Medicine Trials.

With the advent of high-throughput molecular technologies, several precision medicine (PM) studies are currently ongoing that include molecular screening programs and PM clinical trials. Molecular profiling programs establish the molecular profile of patients' tumors with the aim to guide therapy based on identified molecular alterations. The aim of prospective PM clinical trials is to assess the clinical utility of tumor molecular profiling and to determine whether treatment selection based on molecular alterations produces superior outcomes compared with unselected treatment. These trials use treatment algorithms to assign patients to specific targeted therapies based on tumor molecular alterations. These algorithms should be governed by fixed rules to ensure standardization and reproducibility. Here, we summarize key molecular, biological, and technical criteria that, in our view, should be addressed when establishing treatment algorithms based on tumor molecular profiling for PM trials.

The spectrum of clinical trials aiming at personalizing medicine.

All anticancer molecularly targeted agents on the market today have been approved with one or no companion diagnostic based on a specific genomic molecular alteration. These drugs have followed the same clinical development than chemotherapeutic agents and have been developed in selected tumor types and histologies. Now, some molecular alterations have been described across different tumor types, although with variable prevalence and functional impact. The latter raises the question of whether treatment decision should be mainly based on molecular biology, independently of tumor location and histology. This approach refers to what is commonly named personalized medicine and can today be addressed in clinical trials, since major advances in high throughput technologies allow depicting most druggable molecular alterations for an affordable cost in a timeframe that is compatible with clinical practice. Several studies have been initiated that aim at personalizing medicine in oncology. They include molecular screening programs, as well as personalized medicine trials that can be divided in two categories: (I) stratified clinical trials according to either molecular alterations or tumor types; and (II) algorithm-testing trials evaluating a treatment algorithm instead of drugs efficacy. Multiple challenges are associated with personalized medicine trials, but the main one remains our ability to predict drug efficacy based on molecular alterations. It is expected that taking into account several molecular alterations for the prediction of drug efficacy using systems biology approaches will improve patients' outcome. Bioinformatics research will be an important factor of future progression in this emerging field.

Challenges for the implementation of high-throughput testing and liquid biopsies in personalized medicine cancer trials.

During recent decades, major advances in the comprehension of biology and in biotechnologies have paved the way for what is commonly named personalized medicine. For cancer therapy, personalized medicine represents a paradigm shift in which patient treatment is based on biology in addition to histology and tumor location. Here, we report the major personalized medicine trials in oncology that are either based on molecular alterations from tumor tissue or from circulating blood markers. We next review important challenges facing the implementation of personalized medicine in daily clinical practice, including tumor heterogeneity, reliability of high-throughput technologies, the key role of bioinformatics and the assessment of biomarkers and synthetic models, in order to use big data in actual cancer biology.

Do anti-angiogenic therapies prevent brain metastases in advanced renal cell carcinoma?

BACKGROUND: We analyzed renal cell carcinoma (RCC) brain metastasis (BM) risk factors and compared BM occurrence in metastatic RCC (mRCC) treated with or without anti-angiogenic agents (AA). METHODS: Data from all consecutive metastatic RCC patients (patients) treated in a french cancer center between 1995 and 2008 were reviewed. Patients had histologically confirmed advanced RCC without synchronous BM at the time of metastasis diagnosis. AA were sorafenib, sunitinib and bevacizumab. We also included patients treated with mTor inhibitors, temsirolimus and everolimus, as they also demonstrated anti-angiogenic activities. Characteristics of the two groups treated with or without AA were compared with a Fisher exact test. Impact of AA on overall survival (OS) and cumulative rate of brain metastasis (CRBM) was explored by Kaplan-Meier method. RESULTS: One hundred and ninety-nine patients with advanced RCC were identified, 51 treated with AA and 148 without AA. The median follow-up duration was 40 months. BM occurred in 35 patients. Characteristics between AA treated and non-AA treated groups were unbalanced and favoring better prognostic factors in AA treated group. Median OS was 24 months. AA treatment was not associated with a lower CRBM (HR = 0.58 [0.26-1.30], P = 0.187). Median survival free of BM was 11.8 months, CI95% (4.95-18.65) in the group without AA treatment and 28.9 months in the AA group, CI95% (18.64-39.16). Alkaline phosphatase (AP) was an independent prognostic factor for BM (P = 0.05). In multivariate Cox model, after adjustment to AP, AA did not improve the CRBM (aHR = 0.53 [0.22-1.32]). CONCLUSION: In this retrospective study, AA did not decrease significantly the CRBM. Elevated AP was a predictive factor for BM in mRCC.

Hybrid surface design for robust superhydrophobicity.

Surfaces may be rendered superhydrophobic by engineering the surface morphology to control the extent of the liquid-air interface and by the use of low-surface-energy coatings. The droplet state on a superhydrophobic surface under static and dynamic conditions may be explained in terms of the relative magnitudes of the wetting and antiwetting pressures acting at the liquid-air interface on the substrate. In this paper, we discuss the design and fabrication of hollow hybrid superhydrophobic surfaces which incorporate both communicating and noncommunicating air gaps. The surface design is analytically shown to exhibit higher capillary (or nonwetting) pressure compared to solid pillars with only communicating air gaps. Six hybrid surfaces are fabricated with different surface parameters selected such that the Cassie state of a droplet is energetically favorable. The robustness of the surfaces is tested under dynamic impingement conditions, and droplet dynamics are explained using pressure-based transitions between Cassie and Wenzel states. During droplet impingement, the effective water hammer pressure acting due to the sudden change in the velocity of the droplet is determined experimentally and is found to be at least 2 orders of magnitude less than values reported in the literature. The experiments show that the water hammer pressure depends on the surface morphology and capillary pressure of the surface. We propose that the observed reduction in shock pressure may be attributed to the presence of air gaps in the substrate. This feature allows liquid deformation and hence avoids the sudden stoppage of the droplet motion as opposed to droplet behavior on smooth surfaces.