Citations

Summary: Prognostication following cardiorespiratory arrest relies on the neurological examination, which is supported by neuroimaging and neurophysiological testing. Acute posthypoxic myoclonus (PHM) is a clinical entity that has prognostic significance and historically has been considered an indicator of poor outcome, but this is not invariably the case. “Malignant” and more “benign” forms of acute PHM have been described and differentiating them is key in understanding their meaning in prognosis. Neurophysiological tests, electroencephalogram in particular, and clinical phenotyping are crucial in defining subtypes of acute PHM. This review describes the neurophysiological and phenotypic markers of malignant and benign forms of acute PHM, a clinical approach to evaluating acute PHM following cardiorespiratory arrest in determining prognosis, and gaps in our understanding of acute PHM that require further study.

The treatment landscape of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has significantly evolved in recent years. Targeted therapy with Bruton’s tyrosine kinase (BTK) inhibitors and BCL-2 inhibitors has emerged as an effective chemotherapy-free option for patients with previously untreated or relapsed/refractory CLL/SLL. Undetectable minimal residual disease after the end of treatment is emerging as an important predictor of progression-free and overall survival for patients treated with fixed-duration BCL-2 inhibitor-based treatment. These NCCN Guidelines Insights discuss the updates to the NCCN Guidelines for CLL/SLL specific to the use of chemotherapy-free treatment options for patients with treatment-naïve and relapsed/refractory disease.

Abstract INTRODUCTION: HER2/neu is a potent biomarker for which anti-HER2/neu antibodies offer significant responses. However, many cancers, such as melanoma, have less than 5% expression of HER2/neu. The purpose of this study was to determine whether induced expression of erbb2 (mouse HER2/neu analogue) could function as a neoantigen target for anti-erbb2 antibody. METHODS: RT-PCR was used to construct a rat erbb2-encoding vector using the live, non-replicating lentivirus pLenti6.3. erbb2-encoding pLenti6.3 was transfected in vitro into the B16 mouse melanoma cell line, which has less than 5% endogenous expression of erbb2. The generated erbb2+ B16 cell line was designated B16/neu. Anti-erbb2 antibody (7.16.4) was used to treat C57Bl/6 male and female mice bearing B16/neu (200 ug intraperitoneally three times per week for 3 weeks). To confirm activity of 7.16.4, this antibody (100 ug per T75 flask) was co-cultured with B16/neu in vitro, and cell growth/confluence was measured. RESULTS: The novel B16/neu cell line expressed approximately 50% erbb2 in vitro on flow cytometry analysis, compared to 2% errb2 expression in naïve B16. Erbb2/neu expression was confirmed on fluorescent Western blot. Anti-erbb2 antibody (7.16.4) slowed the growth of B16/neu in vitro, confirming the suppressive effects of 7.16.4. In B16/neu-bearing mice, 7.16.4 resulted in effective control of tumor growth and a complete tumor response rate of 35.7%, (5/14 mice) compared to placebo controls (p < 0.01). Interestingly, B16/neu tumors demonstrated slower growth kinetics compared to naïve B16 tumors (p = 0.013), suggesting immune recognition of erbb2 in naïve C57Bl/6 mice as a neoantigen target. No adverse reactions were observed with 7.16.4. In vivo inoculation of erbb2-encoding pLenti6.3 in naïve B16 tumors and treatment of in vivo transfected B16/neu tumors with 7.16.4 comprise ongoing experiments. CONCLUSIONS: erbb2 expression on B16 melanoma was successfully achieved using a novel erbb2-encoding lentivirus. Induced erbb2 served as a neoantigen target for anti-erbb2 antibody. This preclinical study provides translational evidence that induced HER2/neu expression may be utilized to repurpose anti-HER2 antibodies for human malignancies that do not normally express high levels of HER2/neu. Citation Format: Emmanuel M. Gabriel, Brian Necela, Deborah Bahr, Jamie Kaplan, Kristopher Attwood, Keith Knutson. Repurposing erbb2 (HER2/neu) as a neoantigen target for neu-negative tumors using a novel erbb2-encoding lentivirus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5371.

Abstract INTRODUCTION: Intratumoral phenylephrine (α1 vasoconstrictor) combined with chemotherapy has been used for cutaneous malignancies with modest local response. The purpose of this study was to improve the efficacy of intratumoral melphalan using sustained-release, liposomal nanoparticles containing phenylephrine in a mouse model of melanoma. METHODS: A modified ethanol injection method was used to develop the liposomal phenylephrine nanoparticles. These were injected peri-tumorally to generate a local vasoconstrictive effect intended to “entrap” intratumorally injected melphalan. Drug exposure/dwell time was measured with fluorescent imaging. Mice bearing B16 (subclone F10) melanoma tumors were treated with intratumoral melphalan (20 ug/50 ul) with or without peri-tumoral liposomal phenylephrine (10 ug/50-100 ul x 4-5 injections around the tumor periphery) twice weekly x 3 weeks. RESULTS: UV-Absorbance spectroscopy confirmed encapsulation of phenylephrine within the liposomal nanoparticles with an expected absorbance of 275 nm. The modified ethanol injection method produced liposomal phenylephrine encapsulation of approximately 25%. Peri-tumoral, liposomal phenylephrine caused vasoconstriction of normal surrounding vessels with an approximate 10% decrease in vessel diameter. Our liposomal phenylephrine nanoparticles also led to increased retention of intratumorally injected fluorescently-labeled (FITC) liposomes 24-48 hours after inoculation, using both melanoma (B16) and breast (TUBO/4T1) cell lines orthotopically grown within mice (C57Bl/6 and BALB/c, respectively). The combination of intratumoral melphalan with peri-tumoral phenylephrine resulted in more effective control of tumor growth and a complete tumor response rate of 44.4%, compared to phenylephrine/melphalan only controls (p < 0.01, n=18 per group). However, there was significant adverse reaction with the combination therapy, resulting in ulceration of the injection/tumor site. Ulcers healed about 14 days after completion of treatment. Immunohistochemistry demonstrated increased infiltration of CD11b+ cells into the tumors, suggesting an immune-mediated response in addition to direct chemotoxicity. CONCLUSIONS: Liposomal nanoparticles containing phenylephrine increased retention/dwell time of intratumorally administered melphalan and resulted in superior anti-tumor response. Our preclinical model holds innovative, translational promise for the clinical advancement of intralesional therapies in cutaneous/subcutaneous malignancies. Citation Format: Emmanuel M. Gabriel, Vijay Madamsetty, Deborah Bahr, Jamie Kaplan, Kristopher Attwood, Sanjay Bagaria, Keith Knutson, Debabrata Mukhopadhyay. Novel approach to intra- and peri-tumoral delivery of sustained-release chemotherapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5071.

3572 Background: Early onset colorectal cancer (eoCRC: disease diagnosed < 50) has been increasing over the past 2 decades. Currently, standard treatment recommendations for eoCRC patients (pts) with metastatic disease does not differ from late-onset CRC (loCRC) pts although outcomes data in eoCRC pts is limited. Methods: Individual patient data on 5,761 treatment-naive metastatic eoCRC pts was pooled from 8 phase II and III randomized EGFRi studies (2000 - 2012) from the ARCAD mCRC database. The distribution of demographics, clinicopathological features, and biomarkers were summarized by age groups. Progression-free survival (PFS) was compared between age groups by stratified Cox models, adjusting for potential confounders. Predictive value of age group was evaluated by testing interaction effect between treatment and age variables based on a subset of trials with concurrent randomizations between regimens with and without EGFRi Results: eoCRC (n=756) were more evenly distributed between gender, had improved performance status (PS), increased likelihood of metastatic resection, and distant lymph node metastasis, but were less likely to have lung metastasis or KRAS mutation compared to loCRC (n=5,005, table 1). eoCRC and loCRC patients had similar distribution of primary tumor sidedness, primary resection, liver and/or peritoneal involvement, number of metastatic sites involved, and BRAF mutations (MT). No difference in PFS for eoCRC versus loCRC pts was noted (7.8 vs. 7.9 months [M], adjusted hazard ratio [HRadj], 1.02, 95% confidence interval [CI], 0.93-1.11). Among pts with KRAS wild type (WT) and left sided primary tumors, univariable analysis of EGFRi demonstrated improved mPFS in loCRC (9.9 vs 8.5M, HR = 0.74, p<0.001), but this benefit was not seen in eoCRC (8.3 vs 8.9 months, HR 1.20, p=0.36). The same pattern was observed upon multivariable analysis (Table). Conclusions: In our pooled analysis, EGFRi + chemotherapy significantly improved PFS in treatment-naïve loCRC patients but not in left sided, KRAS WT, eoCRC patients. Further validation in an independent cohort is warranted. [Table: see text]

INTRODUCTION: Peptic ulcer disease (PUD) is a common cause of hospitalization worldwide. We assessed temporal trends in hospitalization for PUD in 36 Organisation for Economic Co-operation and Development (OECD) countries since the turn of the 21st century. METHODS: The OECD database contains data on PUD-related hospital discharges and mortality for 36 countries between 2000 and 2019. Hospitalization rates for PUD were expressed as annual rates per 100,000 persons. Joinpoint regression models were used to calculate the average annual percent change (AAPC) with 95% confidence intervals (CIs) for each country, which were pooled using meta-analyses. The incidence of PUD was forecasted to 2021 using autoregressive integrated moving average and Poisson regression models. RESULTS: The overall median hospitalization rate was 42.4 with an interquartile range of 29.7–60.6 per 100,000 person-years. On average, hospitalization rates (AAPC = −3.9%; 95% CI: −4.4, −3.3) and morality rates (AAPC = −4.7%; 95% CI: −5.6, −3.8) for PUD have decreased from 2000 to 2019 globally. The forecasted incidence of PUD hospitalizations in 2021 ranged from 3.5 per 100,000 in Mexico to 92.1 per 100,000 in Lithuania. Across 36 countries in the OECD, 329,000 people are estimated to be hospitalized for PUD in 2021. DISCUSSION: PUD remains an important cause of hospitalization worldwide. Reassuringly, hospitalizations and mortality for PUD have consistently been falling in OECD countries in North America, Latin America, Europe, Asia, and Oceania. Identifying underlying factors driving these trends is essential to sustaining this downward momentum.

Fibrodysplasia ossificans progressiva (FOP) is a rare and devastating genetic disease, in which soft connective tissue is converted into heterotopic bone through an endochondral ossification process. Patients succumb early as they gradually become trapped in a second skeleton of heterotopic bone. Although the underlying genetic defect is long known, the inherent complexity of the disease has hindered the discovery of effective preventions and treatments. New developments in the gene therapy field have motivated its consideration as an attractive therapeutic option for FOP. However, the immune system's role in FOP activation and the as-yet unknown primary causative cell, are crucial issues which must be taken into account in the therapy design. While gene therapy offers a potential therapeutic solution, more knowledge about FOP is needed to enable its optimal and safe application.