COVID-19 Outcomes in Stage IV Cancer Patients Receiving Immune Checkpoint Inhibitors.

Cancer patients are a vulnerable population in the current coronavirus disease 2019 (COVID-19) outbreak. The impact of immune checkpoint inhibitors (ICIs) on the outcomes of COVID-19 infection in cancer patients remains largely unclear. We retrospectively investigated all solid cancer patients who received at least one cycle of ICIs at a single institution between August 2020 and August 2021. All stage IV solid cancer patients who were on or ceased ICI treatment when diagnosed with COVID-19 were eligible. All COVID-19 infections were confirmed by RT-PCR. Risk factors for hospitalization, severe symptoms, and death were analyzed. A total of 56 patients were included in our study. Twenty (35.7%) patients require hospitalization, 12 (21.4%) developed severe symptoms, and 10 (17.9%) died from COVID-19 infection. ICI treatment was interrupted in 37 patients (66.1%), 24 of whom (64.9%) had treatment resumed. Eight (80%) COVID-19-related death occurred in unvaccinated individuals. Reinfection occurred in seven patients (12.5%), and three of them died from their second COVID-19 infection. Factors associated with hospitalization were high Charlson comorbidity score (OR 1.56, 95% CI 1.10-2.23, p = 0.01) and lymphocyte ≤ 1500 mm3 (OR 10.05, 95% CI 2.03-49.85, p = 0.005). Age, chemoimmunotherapy, and ICI treatment duration were not associated with increased risk of hospitalization, severe symptoms, or COVID-19-related mortality. ICI therapy does not impose an increased risk for severe COVID-19 infection in stage IV cancer patients. Vaccination should be encouraged among this population. Clinicians should be cognizant of a potential worse outcome in COVID-19-reinfected patients.

Nitric Oxide Production by Myeloid-Derived Suppressor Cells Plays a Role in Impairing Fc Receptor-Mediated Natural Killer Cell Function.

Purpose: mAbs are used to treat solid and hematologic malignancies and work in part through Fc receptors (FcRs) on natural killer cells (NK). However, FcR-mediated functions of NK cells from patients with cancer are significantly impaired. Identifying the mechanisms of this dysfunction and impaired response to mAb therapy could lead to combination therapies and enhance mAb therapy.Experimental Design: Cocultures of autologous NK cells and MDSC from patients with cancer were used to study the effect of myeloid-derived suppressor cells (MDSCs) on NK-cell FcR-mediated functions including antibody-dependent cellular cytotoxicity, cytokine production, and signal transduction in vitro Mouse breast cancer models were utilized to study the effect of MDSCs on antibody therapy in vivo and test the efficacy of combination therapies including a mAb and an MDSC-targeting agent.Results: MDSCs from patients with cancer were found to significantly inhibit NK-cell FcR-mediated functions including antibody-dependent cellular cytotoxicity, cytokine production, and signal transduction in a contact-independent manner. In addition, adoptive transfer of MDSCs abolished the efficacy of mAb therapy in a mouse model of pancreatic cancer. Inhibition of iNOS restored NK-cell functions and signal transduction. Finally, nonspecific elimination of MDSCs or inhibition of iNOS in vivo significantly improved the efficacy of mAb therapy in a mouse model of breast cancer.Conclusions: MDSCs antagonize NK-cell FcR-mediated function and signal transduction leading to impaired response to mAb therapy in part through nitric oxide production. Thus, elimination of MDSCs or inhibition of nitric oxide production offers a strategy to improve mAb therapy. Clin Cancer Res; 24(8); 1891-904. ©2018 AACR.

Monocular diplopia-associated migraine-like headache induced by nicotine withdrawal.

We describe an extremely rare case of migraine-associated monocular diplopia developed in a 23-year-old man after sudden cessation of smoking. The physical examination and brain MRI scan were unremarkable. The symptoms resolved after starting nicotine patch. We reviewed the literature and discussed the diagnosis and possible mechanism of this phenomenon.

Efficacy of Nd:YAG laser therapy for the treatment of verrucae: a literature review.

Verrucae are benign epithelial proliferations, characteristically 1-20 mm in diameter, caused by human papilloma virus (HPV) infection occurring on the skin and mucosa (Photomed Laser Surg 33(6):338-42, 2015; Lasers Med Sci 29(3):1111-6, 2014). Prevalence of verrucae is 5-20% in children and young adults with peak incidence reported during teenage years (Lasers Med Sci 29(3):1111-6, 2014; J Am Acad Dermatol 22(4):547-66, 1990; J Korean Med Sci 24(5):889-93, 2009). Patients often express significant displeasure with quality of life due to this cosmetic insecurity, as well as functional problems and physical discomfort when they occur on palms of hands and soles of feet. Traditional therapeutic options for warts, such as topical salicyclic acid, topical imiquimod, bleomycin injections, cryotherapy, surgical excision, and electrocautery, have proven somewhat effective but often lead to high recurrence rates or scarring (Photomed Laser Surg 33(6):338-42, 2015). Laser therapy offers an alternative solution by employing selective tissue destruction with minimal risks. We performed a broad literature search in PubMed to obtain all available published articles that studied the treatment of verrucae on the skin with 1064-nm neodymium-doped yttrium aluminum garnet laser. This laser is specifically suited for verruca treatment due to its deeply penetrating 1064-nm wavelength and relatively low risk of pigmentation changes in dark skin types (Photomed Laser Surg 33(6):338-42, 2015). Laser therapy is effective in the treatment of verrucae and has enabled clinicians to provide direct, targeted treatment of warts.

Targeting myeloid-derived suppressor cells using a novel adenosine monophosphate-activated protein kinase (AMPK) activator.

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of early myeloid cells that accumulate in the blood and tumors of patients with cancer. MDSC play a critical role during tumor evasion and promote immune suppression through variety of mechanisms, such as the generation of reactive oxygen and nitrogen species (ROS and RNS) and cytokines. AMPactivated protein kinase (AMPK) is an evolutionarily conserved serine/threonine kinase that regulates energy homeostasis and metabolic stress. However, the role of AMPK in the regulation of MDSC function remains largely unexplored. This study was designed to investigate whether treatment of MDSC with OSU-53, a PPAR-inactive derivative that stimulates AMPK kinase, can modulate MDSC function. Our results demonstrate that OSU-53 treatment increases the phosphorylation of AMPK, significantly reduces nitric oxide production, inhibits MDSC migration, and reduces the levels of IL-6 in murine MDSC cell line (MSC2 cells). OSU53 treatment mitigated the immune suppressive functions of murine MDSC, promoting T-cell proliferation. Although OSU-53 had a modest effect on tumor growth in mice inoculated with EMT-6 cells, importantly, administration of OSU53 significantly (p < 0.05) reduced the levels of MDSC in the spleens and tumors. Furthermore, mouse MDSC from EMT-6 tumor-bearing mice and human MDSC isolated from melanoma patients treated with OSU-53 showed a significant reduction in the expression of immune suppressive genes iNOS and arginase. In summary, these results demonstrate a novel role of AMPK in the regulation of MDSC functions and provide a rationale of combining OSU-53 with immune checkpoint inhibitors to augment their response in cancer patients.

The picosecond laser for tattoo removal.

The prevalence of tattoos continues to grow as modern society's stigma towards this form of body art shifts towards greater acceptance. Approximately one third of Americans aged 18-25 and 40 % of Americans aged 26-40 are tattooed. As tattoos continue to rise in popularity, so has the demand for an effective method of tattoo removal such as lasers. The various colors of tattoo inks render them ideal targets for specific lasers using the principle of selective photothermolysis. Traditional laser modalities employed for tattoo removal operate on pulse durations in the nanosecond domain. However, this pulse duration range is still too long to effectively break ink into small enough particles. Picosecond (10-12) lasers have emerged at the forefront of laser tattoo removal due to their shorter pulse lengths, leading to quicker heating of the target chromophores, and consequently, more effective tattoo clearance. Recent studies have cited more effective treatment outcomes using picosecond lasers. Future comparative studies between picosecond lasers of various settings are necessary to determine optimal laser parameters for tattoo clearance.

Myeloid-Derived Suppressor Cells Express Bruton's Tyrosine Kinase and Can Be Depleted in Tumor-Bearing Hosts by Ibrutinib Treatment.

Myeloid-derived suppressor cells (MDSC) are a heterogeneous group of immature myeloid cells that expand in tumor-bearing hosts in response to soluble factors produced by tumor and stromal cells. MDSC expansion has been linked to loss of immune effector cell function and reduced efficacy of immune-based cancer therapies, highlighting the MDSC population as an attractive therapeutic target. Ibrutinib, an irreversible inhibitor of Bruton's tyrosine kinase (BTK) and IL2-inducible T-cell kinase (ITK), is in clinical use for the treatment of B-cell malignancies. Here, we report that BTK is expressed by murine and human MDSCs, and that ibrutinib is able to inhibit BTK phosphorylation in these cells. Treatment of MDSCs with ibrutinib significantly impaired nitric oxide production and cell migration. In addition, ibrutinib inhibited in vitro generation of human MDSCs and reduced mRNA expression of indolamine 2,3-dioxygenase, an immunosuppressive factor. Treatment of mice bearing EMT6 mammary tumors with ibrutinib resulted in reduced frequency of MDSCs in both the spleen and tumor. Ibrutinib treatment also resulted in a significant reduction of MDSCs in wild-type mice bearing B16F10 melanoma tumors, but not in X-linked immunodeficiency mice (XID) harboring a BTK mutation, suggesting that BTK inhibition plays an important role in the observed reduction of MDSCs in vivo Finally, ibrutinib significantly enhanced the efficacy of anti-PD-L1 (CD274) therapy in a murine breast cancer model. Together, these results demonstrate that ibrutinib modulates MDSC function and generation, revealing a potential strategy for enhancing immune-based therapies in solid malignancies. Cancer Res; 76(8); 2125-36. ©2016 AACR.

Effects of a predictive preventive model for prevention of Clostridium difficile infection in patients in intensive care units.

BACKGROUND: Health care-acquired Clostridium difficile infection (HACDI) is associated with adverse outcomes at both the organization and patient level. Factors that increase risk for development of HACDI have been identified. Objectives of this study were to develop a predictive screening tool to identify patients at risk for HACDI and implement a bundle of mitigation interventions. METHODS: A predictive screening tool was developed based on risk factors identified in the literature and validated by retrospective analysis of all HACDI cases occurring in critically ill patients during 2013. The tool was used to screen all patients admitted to an intensive care unit. Evidence-based interventions (bundle) were implemented for patients identified as being at high risk for HACDI. Effectiveness of the model was measured by reduction of HACDI rate during the intervention period compared with the preintervention period. RESULTS: During the 12-month intervention period 217 high-risk patients were identified as infected with Clostridium difficile. Sixty-two of these met exclusion criteria, resulting in a study population of 157 patients. During the preintervention phase, 10 cases of HACDI occurred (overall incidence rate, 14.7). During the 12-month study period, 2 cases of HACDI were identified (incidence rate, 3.12). The reduction was statistically significant. CONCLUSION: A strategy for identifying patients at increased risk and implementation of multidisciplinary risk-mitigation strategies is effective in reducing incidence of HACDI.