Two Clinical Cases of Metastatic Merkel Cell Carcinoma Illustrating Avelumab Tolerability in Elderly Patients

We present two cases of primary cutaneous Merkel cell carcinoma in a 80-year and a 95-year old patient. Both patients had a wide local excision, but early recurrences occurred. Case 1 required palliative radiotherapy. He did not receive chemotherapy but case 2 did. They then proceeded to have immunotherapy with sustained responses lasting greater than 2 and 3 years. This report highlights an important new class of drug for the treatment of advanced Merkel cell carcinoma. Furthermore, our case report demonstrates that avelumab immunotherapy can be safely delivered to elderly patients, including 80- and 95-year-old patients. This report parallels the high and durable response rates to avelumab (including complete responses) that were shown in the JAVELIN phase II trials.

Juxtacellular Labeling of Stellate, Disk and Basket Neurons in the Central Nucleus of the Guinea Pig Inferior Colliculus

We reconstructed the intrinsic axons of 32 neurons in the guinea pig inferior colliculus (IC) following juxtacellular labeling. Biocytin was injected into cells in vivo, after first analyzing physiological response properties. Based on axonal morphology there were two classes of neuron: (1) laminar cells (14/32, 44%) with an intrinsic axon and flattened dendrites confined to a single fibrodendritic lamina and (2) translaminar cells (18/32, 56%) with axons that terminated in two or more laminae in the central nucleus (ICc) or the surrounding cortex. There was also one small, low-frequency cell with bushy-like dendrites that was very sensitive to interaural timing differences. The translaminar cells were subdivided into three groups of cells with: (a) stellate dendrites that crossed at least two laminae (8/32, 25%); (b) flattened dendrites confined to one lamina and that had mainly en passant axonal swellings (7/32, 22%) and (c) short, flattened dendrites and axons with distinctive clusters of large terminal boutons in the ICc (3/32, 9%). These terminal clusters were similar to those of cortical basket cells. The 14 laminar cells all had sustained responses apart from one offset response. Almost half the non-basket type translaminar cells (7/15) had onset responses while the others had sustained responses. The basket cells were the only ones to have short-latency (7–9 ms), chopper responses and this distinctive temporal response should allow them to be studied in more detail in future. This is the first description of basket cells in the auditory brainstem, but more work is required to confirm their neurotransmitter and precise post-synaptic targets.

Insight Into the Hispanic Paradox: The Language Hypothesis

Hispanics have a lower burden of heart disease than would be predicted from their risk factors. Explanations for this phenomenon, the Hispanic paradox, focus on specific characteristics of the culture that affect stress appraisal and accumulation, including social connections. Features of culture evolve in the context of language, which influences the way emotions are appraised and expressed. The Spanish language, a unifying component defining Hispanic cultures, has unique features that may promote emotional expression, expand the emotional concepts implicated in the construction of emotion, and influence the appraisal of stress. Under chronic stress conditions, sustained responses can become maladaptive, leading to disease. Features of the Spanish language allow its speakers a wide range of emotion schemas by virtue of its emotion lexicon, the ability to easily minimize or exaggerate expressions, and ease in considering hypothetical situations with the use of the subjunctive. The hypothesis here proposes that the Spanish language is directly and indirectly (via culture) responsible for mitigating some of the effects of acute stress responses in Hispanics and, therefore, limits stress accumulation and is partly responsible for the Hispanic paradox.

Mutation and Microsatellite Burden Predict Response to PD-1 Inhibition in Children with Germline DNA Replication Repair Deficiency

Cancers arising from germline DNA mismatch-repair or polymerase-proofreading deficiencies (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion/deletion (MS-indel) burden in humans and are lethal due to inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICI) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI in these patients. ICI treatment of 45 progressive/recurrent tumours from 38 patients revealed durable objective responses in the majority, culminating in 3-year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations/Mb) enriched for combined MMRD+PPD, while MS-indels predicted response in MMRD tumours with lower mutation burden (10-100 mutations/Mb). Further, both mechanisms were associated with increased immune infiltration even in “immunologically-cold” tumours such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and associated with immune activation in both the tumour microenvironment and systemically. Further, patients with flare continuing ICI treatment achieved durable responses. Our study demonstrates improved survival for patients with tumours not previously known to respond to ICI, including CNS and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained responses to immunotherapy.

Index-based Approach to Evaluate City Resilience in Flooding Scenarios

Intense rainfall events combined with high tide levels frequently result in urban floods in riverine or coastal cities. Their increasing variability and uncertainty demand urgent but sustained responses. Thus, resilience-driven approaches are emerging in contrast to the traditional technical-economic frameworks, as urban resilience reflects the overall capacity of a city to survive, adapt and thrive when experiencing stresses and shocks. This paper presents a simplified index-based methodology for the evaluation and quantification of urban resilience to flooding, based on the works developed in the EU H2020 RESCCUE project. A set of five indicators are proposed to compute the Integrated Urban Resilience Index (IURI), allowing to classify resilience according to a proposed range of rankings. This methodology considers simultaneously a multisectoral approach, reflecting services interdependences, and a sectorial approach, applying 1D/2D computational modelling of the urban drainage network. It was applied to the study case of Lisbon downtown, involving the analysis of interdependencies between 124 infrastructures of 10 urban services. Two scenarios were considered, respecting the current and future situations, considering climate changes. Results enhance the usefulness, practicability, and potential of the proposed approach, and improvement opportunities were also identified for future developments. Doi: 10.28991/cej-2021-03091647 Full Text: PDF

A Phase II Study to Assess the Sustained Response Off Treatment in Patients with ITP Receiving Eltrombopag, Who Had a Previous Insufficient Response to Corticosteroids (TAPER): A Recruitment Update

Corticosteriods (CSs) remain the standard of care for immune thrombocytopenia (ITP); however, many patients relapse after initial treatment, and long-term CS use is associated with considerable toxicity and tolerability issues (Provan et al. Blood 2010). Clinically, there is a need for a less toxic regimen that will provide sustained response. Eltrombopag is a thrombopoietin receptor agonist (TPO-RA) currently approved in the United States for the treatment of ITP in patients who have had an insufficient response to CSs, immunoglobulins, or splenectomy. Limited evidence from retrospective studies and the phase II ESTIT study (NCT02402998) suggests that earlier use of TPO-RAs after ITP diagnosis may allow a larger proportion of patients to achieve sustained responses after tapering off drug (Červinek et al. Int J Hematol 2015; Gonzalez-Lopez et al. Am J Hematol 2015; Newland et al. Br J Haematol 2016; Lucchini, et al. Haematologica 2019). TAPER (NCT03524612) is an ongoing phase II, open-label, prospective, single-arm study assessing sustained response off treatment in adult patients with ITP receiving eltrombopag, who had relapsed or failed to respond to initial CS treatment. Eligible patients are adults (≥ 18 years old) with ITP who are not responsive to or are in relapse after first-line CS therapy ± immunoglobulins used as rescue therapy, with platelet counts < 30×109/L, and assessed as needing treatment. Patients receive a starting dose of 50 mg eltrombopag QD (East/Southeast Asian ancestry: 25 mg QD; Japanese patients treated in Japan: 12.5 mg QD per approved starting dose in the Japanese prescribing information). The primary endpoint is the number (%) of patients with sustained responses off treatment by Month 12. Sustained response is defined as a complete response (platelet count ≥ 100×109/L) with platelet counts ≥ 70×109/L maintained for 2 months, followed by dose reduction and treatment discontinuation while maintaining platelet counts ≥ 30×109/L, without bleeding or rescue therapy, until Month 12. Platelet counts are assessed weekly during the first 8 weeks of treatment, and biweekly thereafter, depending on patient response. Rescue therapy is permitted within the first 14 days of study treatment and does not preclude patients from reaching the primary endpoint criteria, if successful discontinuation of eltrombopag is reached and maintained at Month 12. The proportion of patients who reach the primary endpoint will be summarized with the 95% confidence interval (Clopper-Pearson method). A binomial test for one proportion, H0: P = 0.15 vs. H1: P > 0.15 will be performed to test if the proportion of remission patients is greater than 15%, using a target alpha level of 0.05. Patients who meet the primary endpoint at 12 months will be followed up for an additional 12 months.Patients who relapse between Months 12 and 24 will be offered retreatment with eltrombopag until the end of Month 24. Secondary endpoints will include measures of quality of life, and exploratory endpoints will include biomarker assessments of immunomodulation. Here, we report an update on trial recruitment and patient baseline characteristic data from an early data cut (November 15, 2019). An estimated 101 patients across 50 sites will be enrolled; 47 sites are currently active and 3 are pending site initiation visits. As of November 15, 2019, 66 patients had been screened, 53 of whom had been enrolled and had undergone treatment. Of the patients enrolled, 60.4% were female and the mean (± standard deviation) age was 49.4 (± 19.0) years. The majority of patients were White (88.7%). On June 24, 2020, patients from 15 countries worldwide were committed to screening (Figure 1); the number of patients screened had risen to 98, with 82 patients enrolled. The planned study timeline has been disrupted due to the COVID-19 pandemic. Enrollment is expected to complete in November 2020, with final results expected in 2023. Conclusion: The purpose of this trial is to assess sustained response off treatment following eltrombopag therapy in patients with ITP who failed to respond to or have relapsed after initial treatment with steroids. The data generated by TAPER will provide insights into whether eltrombopag could be a viable treatment option after first-line steroid treatment. If this were confirmed, the earlier use of eltrombopag could have the potential to reduce the toxicity from repeated steroid exposure in patients with ITP. Disclosures Cooper: Novartis: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Ghanima:Amgen: Honoraria, Speakers Bureau; Bristol Myers Squibb: Research Funding; Bayer: Research Funding; Novartis: Honoraria, Speakers Bureau; Principia: Honoraria, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau. Haenig:Novartis: Current Employment. Lee:Novartis: Current Employment, Other: Novartis AG equity holder. Rahman:Novartis: Other: Full time employee of IQVIA which provides services to Novartis; IQVIA: Current Employment. Zaja:Kyowa Kirin: Honoraria, Speakers Bureau; Mundipharma: Honoraria, Speakers Bureau; Novartis: Honoraria, Patents & Royalties: Pending patent (No. PAT058521) relating to TAPER trial (NCT03524612), Speakers Bureau; Roche: Honoraria, Speakers Bureau; AbbVie: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Grifols: Honoraria, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Janssen-Cilag: Honoraria, Speakers Bureau.

SQ3370 Activates Cytotoxic Drug via Click Chemistry at Tumor and Elicits Sustained Responses in Injected & Non-injected Lesions

While systemic immuno-oncology therapies have shown remarkable success, only a limited subset of patients benefit from them. Our Click Activated Protodrugs Against Cancer (CAPAC™) Platform is a click chemistry-based approach that activates cancer drugs at a specific tumor with minimal systemic toxicity. CAPAC Platform is agnostic to tumor characteristics that can vary across patients and hence applicable to several types of tumors. We describe the benefits of SQ3370 (lead candidate of CAPAC) to achieve systemic anti-tumor responses in mice bearing two tumors. SQ3370 consists of a biopolymer, injected in a single lesion, followed by systemic doses of an attenuated protodrug of doxorubicin (Dox). SQ3370 was well-tolerated at 5.9-times the maximum dose of conventional Dox, increased survival by 63% and induced a systemic antitumor response against injected and non-injected lesions. The sustained anti-tumor response also correlated with immune activation measured at both lesions. SQ3370 could potentially benefit patients with micro-metastatic lesions.