Oncolytic virus TG6002 safety and activity after intrahepatic artery administration in patients with liverdominant metastatic colorectal cancer

The TG6002.03 trial is a dose-escalation phase 1 clinical trial of TG6002 infusion via the hepatic artery in patients with liver-dominant colorectal cancer metastases. TG6002 is an engineered Copenhagen strain oncolytic Vaccinia virus, deleted of thymidine kinase and ribonucleotide reductase to enhance tumor selective viral replication and expressing FCU1, an enzyme converting the non-cytotoxic prodrug 5-fluorocytosine (5-FC) into the chemotherapeutic compound 5-fluorouracil (5-FU). In this trial, patients with advanced unresectable liver-dominant metastatic colorectal cancer who had failed previous oxaliplatin and irinotecan-based chemotherapy were treated with up to 2 cycles of TG6002 infusion 6 weeks apart via the hepatic artery on day 1 combined with oral 5-FC on days 5 to 14 (where day 1 = TG6002 infusion). TG6002 infusion was performed over 30 minutes via selective catheterization of the hepatic artery proper. 5-FC oral dosing was 50mg/kg x4 daily. Blood was sampled for TG6002 pharmacokinetics and 5-FC and 5-FU measurements. Sampling of liver metastases was performed at screening and on day 4 or day 8 for virus detection and 5-FC and 5-FU quantification. In total, 15 patients (median age 61 years, range 37-78) were treated in 1 UK centre and 2 centres in France and received a dose of TG6002 of 1 x 106 (n=3), 1 x 107 (n=3), 1 x 108 (n=3), or 1 x 109 pfu (n=6). Fourteen of the 15 patients received a single cycle of treatment, including one patient who did not received 5-FC, and one patient received two cycles. TG6002 was transiently detected in plasma following administration, suggesting a strong tissue selectivity for viral replication. In the highest dose cohort, a virus rebound was observed on day 8, concordant with replication time of the virus. In serum samples, 5-FU was present on day 8 in all patients with a high variability ranging from 0.8 to 1072 ng/mL and was measurable over several days after initiation of therapy. Seven of the 9 patients evaluable showed the biodistribution of the virus in liver lesions by PCR testing on day 4 or day 8. Translational blood samples showed evidence for T-cell activation and immune checkpoint receptor-ligand expression. At 1 x 109 pfu, there was evidence for T-cell proliferation and activation against tumour-associated antigens by ELISpot and for immunogenic cell death. In terms of safety, a total of 34 TG6002-related adverse events were reported, of which 32 were grade 1-2 and 2 were grade 3. The maximum tolerated dose was not reached, and a single dose-limiting toxicity was observed consisting of a myocardial infarction in a context of recent Covid-19 infection in a 78-year-old patient. These results indicate that TG6002 infused via the hepatic artery in combination with oral 5-FC was well tolerated, effectively localized and replicated in the tumor tissues, expressed its therapeutic payload and showed anti-tumoral immunological activity.

Deviation from standard cancer treatment during the first wave of the COVID-19 pandemic in India: A cross-sectional study

Background: During the coronavirus disease 2019 (COVID-19) pandemic, established best practices in cancer care were modified to diminish the risk of COVID-19 infection among patients and health-care workers. Objective(s): We aimed to study the modifications in cancer-directed therapy during the first wave of the COVID-19 pandemic. Material(s) and Method(s): A cross-sectional study of patients with cancers of the head and neck, thoracic, urologic, and central nervous systems who visited the medical oncology department of the Tata Memorial Hospital, Mumbai, India, between April 22, 2020 and June 01, 2020, was conducted. Data were prospectively collected in an online pro forma and supplemented from the electronic medical records. Result(s): Of a total of 514 patients, 363 (71%) were men. The most common malignancy was lung cancer in 234 patients (46%). Cancer-directed therapy was modified in 83 patients (16%). Deviations consisted of modification of the chemotherapy regimen (48%), temporary discontinuation of chemotherapy in 37%, and interim chemotherapy to delay surgery in 5%. Changes in the chemotherapy regimen included a shift to a less intensive regimen in 45%, changing from intravenous to oral in 40%, and less frequent dosing of immunotherapy in 7%. Considering missed appointments as a deviation from planned cancer therapy, 68% of patients had a deviation in the standard planned cancer care. Conclusion(s): Almost two-thirds of the patients could not reach the hospital during the COVID-19 pandemic lockdown in India. Of those who could reach the hospital, one of out every six patients with cancer had a change in their cancer-directed treatment, half of which consisted of a modification in the standard chemotherapy regimens. The effects of these therapy deviations are likely to be long-lasting. (Clinical Trials Registry-India, CTRI/2020/07/026533).Copyright © 2023 Neurology India, Neurological Society of India Published by Wolters Kluwer - Medknow.

Drug-induced pericarditis

Though not common, drug-induced pericarditis is a serious condition, since pericardial tamponade, should it develop, may be life-threatening. As the number of drugs is constantly expanding, so does the proportion of those capable of causing pericarditis. The authors reviewed the relevant literature in the PubMed database and complemented it with information from the VigiBase database. In their article, the authors present current knowledge about the mechanisms of origin and level of risk of drug-induced pericarditis and discuss relevant information on individual drugs divided into 7 classes. Some medicines are associated with a high risk of developing pericarditis, a fact to be taken into account when treating patients with these agents. © 2022 Czech Society of Cardiology Z.S. All rights reserved.

Transcriptome in Human Mycoses

Mycoses are infectious diseases caused by fungi, which incidence has increased in recent decades due to the increasing number of immunocompromised patients and improved diagnostic tests. As eukaryotes, fungi share many similarities with human cells, making it difficult to design drugs without side effects. Commercially available drugs act on a limited number of targets and have been reported fungal resistance to commonly used antifungal drugs. Therefore, elucidating the pathogenesis of fungal infections, the fungal strategies to overcome the hostile environment of the host, and the action of antifungal drugs is essential for developing new therapeutic approaches and diagnostic tests. Large-scale transcriptional analyses using microarrays and RNA sequencing (RNA-seq), combined with improvements in molecular biology techniques, have improved the study of fungal pathogenicity. Such techniques have provided insights into the infective process by identifying molecular strategies used by the host and pathogen during the course of human mycoses. This chapter will explore the latest discoveries regarding the transcriptome of major human fungal pathogens. Further we will highlight genes essential for host–pathogen interactions, immune response, invasion, infection, antifungal drug response, and resistance. Finally, we will discuss their importance to the discovery of new molecular targets for antifungal drugs. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2014, 2022.

Self-medication Practices for COVID-19 Prevention: A Study among Medical Students in Yogyakarta, Indonesia

The corona virus disease 2019 (COVID-19) pandemic has increased the interest in self-care strategies, including self-medication. Medical students, as future health practitioners, learn more about medications than other students. This study aimed to describe self-medication practices for preventing COVID-19 among medical students at Universitas Islam Indonesia. This observational study used a cross-sectional design and was undertaken in November- December 2020. The study sample included 336 undergraduate medical students determined using a consecutive sampling technique based on inclusion and exclusion criteria. Data were collected using an online questionnaire about self-medication practices in the preceding 3 months. Among a total of 336 students, 137 (41%) reported using self-medication intending to prevent COVID-19, and 126 (92%) of these 137 took preventive supplements, mainly vitamins C, D, and E, and omega-3. Seven students reported the use of zinc, mainly in combination with other vitamins. Students who practiced self-medication lived closer to people confirmed with COVID-19, washed their hands more often, and desinfected their belongings more frequently than their counterparts (p<0.05). The mean duration for consuming vitamins was 11-16 days. Forty students (29%) used herbal medicine to prevent COVID-19;ginger, turmeric, honey, black seed, cutcherry, and Curcuma were the most often consumed herbal remedies. Fourteen students (10%) reported taking over-the-counter medications to relieve symptoms related to COVID-19, including antipyretic, analgesic, antiseptic, antihistamine, decongestant, antitussive, and expectorant medications. Most respondents (82%) purchased their medications at pharmacies, and 11 (9%) obtained them from online shops. These findings show the high rate of self-medication using vitamins and herbal remedies for COVID-19 prevention among university medical students. Further studies are needed to explore students' knowledge about the risks of self-medication including the use of herbal medicines.Copyright © 2022 Marmara University Press.

Early detection of recurrent HPV+ hypopharyngeal squamous cell carcinoma by circulating tumor DNA

Circulating tumor DNA is a liquid biomarker that offers a highly specific method to assess HPV-associated tumor burden via a blood draw. It has the potential for many clinical applications in cancer care, including prognostication, monitoring treatment response, and surveillance for disease recurrence. In this case report, we present a case of recurrent HPV-associated hypopharyngeal squamous cell carcinoma first detected by circulating tumor HPV DNA that demonstrates the role of circulating tumor HPV DNA tests in posttreatment surveillance and the utility of HPV testing in all HPV-mediated tumors, regardless of subsite.Copyright © 2023 Elsevier Inc.

A Case Report Of The Effects Of Chemotherapy On Post-heart-transplant Gene Expression Profiling

Introduction: Malignancies are a major complication of heart transplant (HT). Noninvasive surveillance after HT using gene expression (GEP) profiling and donor derived cell free DNA (dd-cfDNA) are noninferior to biopsy and are widely utilized. The interpretation of % dd-cfDNA, is not well understood in malignancies with a conceptual increase in the recipient fraction. The effect of chemotherapy on GEP in the setting of post-HT surveillance has not been described to the best of our knowledge. Hypothesis: Induction of chemotherapy will cause global transcriptional reduction in GEP. Method(s): GEP was performed with AlloMap (AM, CareDx), which evaluates expression levels of 11 mononuclear cell genes, involved in lymphocyte activation, T-cell priming, cell migration, hematopoietic proliferation, steroid sensitivity, and platelet activation. Scores range from 0-40, higher scores have a stronger correlation with rejection. At our center a total of 995 draws were analyzed from 2019-2022. In parallel dd-cfDNA, which informs about graft injury was analyzed using AlloSure (AS, CareDx). Case Events: A 71-year-old male HT recipient for nonischemic cardiomyopathy and no rejection history was diagnosed with metastatic gastric adenocarcinoma at 16 months post-HT. Following diagnosis, mycophenolic acid was stopped, prednisone 5 mg was started, and tacrolimus trough goal was gradually lowered to 4-6 given infectious complications. Palliative chemotherapy with folinic acid, fluorouracil (5-FU), oxaliplatin (FOLFOX) was initiated at 18 months post-HT with planned dose reduction of oxaliplatin and holding of 5-FU bolus to reduce risk of myelosuppression given comorbidities. Oxaliplatin was stopped at 18 months post HT. Due to COVID he last received 5-FU at 33 months post-HT. Graft function remained stable and DSA negative. At 36 months post-HT, he developed a bowel obstruction without surgical options for interventions and expired shortly thereafter. Result(s): With initiation of prednisone and following chemotherapy there was a drastic decrease in AM scores (Fig. A). Steroid therapy led to an 18% decline in AM scores, the greatest decrease occurred with chemotherapy, with 67% decline from the mean when compared to all center patients (Fig B). Dd-cfDNA levels remained stable during the course aside from one early elevation. Conclusion(s): To the best of our knowledge this is the first published case on the effect of chemotherapy on GEP profiling in the setting of post-HT surveillance. This case advises caution when interpreting GEP in the setting of chemotherapy showing great reduction in GEP scores. While dd-cfDNA levels remained relatively stable after malignancy diagnosis and treatment initiation further studies will need to inform on the use of both GEP and dd-cfDNA in these patients.Copyright © 2022

Contact allergy to Efudix cream: a reminder and review

5-Fluorouracil (Efudix) cream is established as a topical treatment for superficial malignant and premalignant skin lesions. Its method of action involves the irreversible binding of the pyrimidine analogue fluorouracil to thymidylate synthetase within a cell. This prevents the incorporation of uracil into nuclear RNA, which destroys abnormal cancer cells (https://dermnetnz.org/topics/5-fluorouracil-cream). The expected sequelae of its use involves the development of a marked inflammatory response. We present a case of a severe, disproportionate reaction to Efudix cream, secondary to contact allergy to the excipients. A 61-year-old man attended the cutaneous allergy clinic with a history of severe, florid, inflammatory and ulcerative skin reactions affecting the lower limbs at sites of application of Efudix cream. This had been used as directed, to treat areas of Bowen disease, at intervals between December 2019 and February 2021. Contact allergy to Efudix cream was suspected and patch testing was performed to the British Standard and Cosmetic series, as well as the excipients of Efudix cream, including stearyl alcohol, propylene glycol (PG), methylparahydroxybenzoate, propylparahydroxybenzoate and white soft paraffin. While the patch tests were applied in the department on day 0, subsequent appointments on days 2, 4 and 7 were performed virtually with photographs as the patient developed COVID-19 symptoms, with positive lateral flow and polymerase chain reaction tests. He was patch test positive on days 4 and 7 to stearyl alcohol and propylene glycol, both being excipients of Efudix cream. A review of our database over a period of 17 years revealed 53 other cases with positive patch test to PG (n = 53/8000;0.66%), none of which were attributable to the use of Efudix cream, and only six cases of a positive patch test to stearyl alcohol (n = 6/8000;0.075%), of which one was attributable to the use of Efudix cream. Allergic contact dermatitis to Efudix cream and its excipients stearyl alcohol and propylene glycol is rare, although it has previously been described in the literature with the earliest reports in 1992, and the most recent being 15 years ago [Meijer B, de Waardvan der Spek F. Allergic contact dermatitis because of topical use of 5-fluorouracil (Efudix cream). Contact Dermatitis 2007;57: 58-60]. This case adds to the existing literature and is a reminder to clinicians that, although inflammation is expected with the use of Efudix cream, severe or disproportionate reactions should raise suspicion of possible contact allergy. Furthermore, this case highlights the challenges of patch testing in the current COVID-19 climate and highlights the importance of teledermatology as a novel option for assessment in cutaneous allergy services facing these conditions.

Successful treatment of viral warts with topical and intralesional cidofovir in an immunocompromised paediatric patient

Cidofovir is well described as an effective antiviral agent. It is reported to treat viral warts successfully in immunocompetent and immunocompromised individuals. Unfortunately, its use may be limited by the high cost and pain of treatment. We here report the successful treatment of multiple palmoplantar warts in an 8-year old male undergoing chemotherapy for relapsed acute lymphoblastic leukaemia. His most significant lesion was a 3 x 3 x 1.5 cm tumorous lesion on the central plantar forefoot that interfered with weight bearing. It had been resistant to over-the-counter treatments, cryotherapy, silver nitrate cautery, curettage and cautery, cantharadin and topical 5-fluorouracil. He was developing multiple satellite lesions and they had spread to the toes, the other foot and both hands, totalling more than 30 lesions. The first treatment session was during sedation for intrathecal chemotherapy. One millilitre of cidofovir (diluted to 15 mg mL-1) was instilled to the largest lesion (although solution was seen visibly escaping from the surface). The remainder of the vial was compounded to topical cidofovir 1% in Eucerin, which he applied once daily to remaining lesions. His postprocedure recovery was unremarkable, with no analgesia requirements or other complications. By the time of review 4 weeks later, the verruca that had received one session of intralesional treatment had completely resolved. Some of the smaller warts had shrunk in size. Despite reports of pain associated with intralesional cidofovir injections, our patient was keen for a repeated treatment to more lesions without sedation/anaesthetic. He tolerated the treatment of a number of remaining lesions without the need for topical or local anaesthesia. Treatments continued at 4-weekly intervals (to coincide with his chemotherapy regimen) with good response and no side-effects. After three treatment sessions most lesions had resolved with only some smaller lesions remaining. Unfortunately, his next treatments were suspended as he contracted COVID-19. In summary, we report the successful eradication of significant and widespread viral warts in an immunocompromised paediatric patient. Reports in patients under 10 years of age are scarce. We also confirm excellent tolerance of the procedure. Although the high cost of cidofovir may seem prohibitive, given that one vial could generate around 25 mL solution and 0.2-1 mL is needed per lesion, we would argue that it may be more costeffective than multiple sessions of other less/ineffective modalities. Furthermore, its antiviral mechanism of action is particularly beneficial in immunocompromised patients in comparison with other modalities, which require an efficient immune response in order to be successful.

Theoretical Investigation of 5-Fluorouracil and Tamoxifen Complex - Structural, Spectrum, DFT, ADMET and Docking Simulation

Combination of FDA approved drugs may be more effective in biological activities by targeting different protein mechanism at a same time and less toxic. A combination of 5-Fluorouracil and tamoxifen may cause a synergistic effect and induce cancer cell death and more effective against corona virus. In this study, constructed 5-Fluorouracil with tamoxifen structure was optimized through DFT/B3LYP approach with the basis set 6-311 G. Theoretical, ultraviolet-visible spectrum was calculated, and electronic transitions were examined. The energy gap between HOMO and LUMO was used to study the combined structure's structural stability and reactivity and the computed energy gap (Delta E) was 4.3023825 eV. The Mulliken charge distribution was assessed and the atomic charges were calculated. The molecular docking simulation was performed with breast cancer and SARS-CoV-19 target proteins. The docking scores showed that the complex compound's binding affinity was higher, that confirms better synergistic effect of 5-Fluorouracil and tamoxifen. The complex compound's maximum binding affinity was -8.0 Kcal/mol against caspase 6 and -8.1 Kcal/mol against furin, that showed inhibitory potential against cancer and corona virus. The pharmacokinetic properties and toxicity of the complex structure was studied, and the results showed the safety profile of the complex lead compound and can be utilized as an effective anticancer and antiviral drug.

ONE MORE FEATHER IN THE CAP (DECITABINE): YET ANOTHER CASE OF CHEMOTHERAPY-INDUCED LUNG INJURY

SESSION TITLE: Drug-Induced and Associated Critical Care Cases Posters 2 SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Lung toxicity due to antineoplastic therapy is reported with both cytotoxic and molecularly targeted agents [1]. We present one such case of lung injury induced by capecitabine. CASE PRESENTATION: A 79-year-old female with history of triple negative infiltrating duct carcinoma of the right breast (status post mastectomy and adjuvant chemotherapy with docetaxel and cyclophosphamide 3 years prior) presented to the hospital with dyspnea on exertion following her fourth cycle of capecitabine therapy for breast cancer recurrence. Patient developed nausea, vomiting, and malaise with cycles 1, 2, and 3 of capecitabine therapy with onset of severe dyspnea on exertion, cough, and hypoxia following cycle 4. Computed tomography (CT) scan of the chest on admission showed consolidative opacities in the right upper, right middle, and anterior right lower lobe along with smaller opacities in the left lung apex and small subcentimeter nodules;no pulmonary embolism. Antibiotics were given for a short duration for suspected pneumonia without improvement. Capecitabine was held on discharge. She presented again to the emergency room with worsening shortness of breath, diarrhea, fatigue, and dizziness. COVID test was negative. Chest x-ray redemonstrated patchy airspace disease involving the right apical, lateral, mid lower lung field. Oral steroids were recommended for suspected organizing pneumonia, but the patient refused due to concerns about side effects. Her hospital course was complicated by Clostridium difficile infection (treated with oral vancomycin) and left lower extremity deep venous thrombosis (treated with anticoagulation). Subsequently she followed up with pulmonology outpatient. Repeat imaging showed evolving infiltrates in the same areas with elevated aspergillus IgG level (18.0 mcg/ml) and IgE (178 kU/L) but negative galactomannan and sputum bacterial/fungal/acid fast cultures. Oral steroids were initiated with clinical and symptomatic improvement. DISCUSSION: Capecitabine is a prodrug of fluorouracil (antimetabolite). It is used as a chemotherapy agent in multiple types of cancer including breast cancer. Respiratory side effects include cough (<7%) and bronchitis (<5%). Lung injury/pneumonitis is a rare complication with only a few cases reported to date [2,3]. The timing of symptoms with chemotherapy administration and the negative infectious work-up supports capecitabine as the inciting etiology of lung injury. Withholding chemotherapy and starting systemic steroids were effective treatments in this case of chemotherapy induced lung toxicity. CONCLUSIONS: Capecitabine induced lung injury is a rare but important entity and should always be kept in mind while evaluating dyspnea in cancer patients. Reference #1: Capri G, Chang J, et al. An open-label expanded access study of lapatinib and capecitabine in patients with HER2-overexpressing locally advanced or metastatic breast cancer. Ann Oncol. 2010;21(3):474. Epub 2009 Oct 8. DOI: 10.1093/annonc/mdp373 Reference #2: C. J. Benthin, G. Allada. Capecitabine-Induced Lung Injury. American Journal of Respiratory and Critical Care Medicine 2016;193:A1653. Reference #3: Andrew K Chan, Bok A Choo, John Glaholm. Pulmonary toxicity with oxaliplatin and capecitabine/5-Fluorouracil chemotherapy: a case report and review of the literature. Onkologie. 2011;34(8-9):443-6. doi: 10.1159/000331133. Epub 2011 Aug 19. DISCLOSURES: No relevant relationships by William Karkowsky No relevant relationships by Chahat Puri No relevant relationships by Sahib Singh

Co-existence of Head and Neck Squamous Cell Carcinoma with Sinonasal Mucormycosis: Therapeutical Challenges

Pandemic was new experience for entire humanity. Medical fraternity was no exception. The cases of mucormycosis were on the rise during the second wave of the pandemic. Presented here are two cases which were combination of two diseases, one of which was squamous cell carcinoma of head and neck region and other one was sinonasal mucormycosis. Both patients were diabetics and had history of Coronavirus Disease-2019 (COVID-19) infection in past. Our literature search doesn't reveal any previously reported cases of this rare combination. There were certain challenges in management. Both diseases were lethal and treatment of one cannot be prioritised over other. Challenges in managing those cases were, reconstruction planning, perioperative management and postsurgery adjuvant therapy. In absence of previous experience to treat this combination or any literature available new treatment protocol were formulated. Cases were discussed in multidisciplinary team meetings and treatment plans were formulated. Mucormycosis and oral squamous cell carcinoma both were operated and reconstructed in same sitting. In one patient revision endoscopic debridement had to be done. Amphotericin B was started once diagnosis was confirmed. Patients were followed-up on weekly basis during first month and imaging was done every 15 days. Both patients had satisfactory recovery without any sign of progression of mucormycosis. Adjuvant radiation was given in both cases at appropriate time. At follow-up both patients were free from disease for six months. From these unique experiences it can be recommended that combination of sinonasal mucormycosis and squamous cell carcinoma of head and neck is very rare. Both diseases can be treated simultaneously. Excision and reconstruction can be done in single sitting. There is no need to delay or avoid adjuvant radiation. Multidisciplinary team approach is the key for treatment.

Versatile use of Carmofur: A comprehensive review of its chemistry and pharmacology.

Carmofur, 1-hexylcarbamoyl-5-fluorouracil (HCFU) is an antineoplastic drug, which has been in clinics in Japan since 1981 for the treatment of colorectal cancer. Subsequently, it was also introduced in China, Korea, and Finland. Besides colorectal cancer, it has also shown antitumor activity in other cancers such as breast, head and neck, pancreatic, gastrointestinal, and solid brain tumors. A prodrug of 5-fluorouracil (5-FU), carmofur has shown better gastrointestinal stability and superior antiproliferative activity compared to its active counterpart 5-FU. Recently, carmofur has gained attention as an acid ceramidase inhibitor and as a potential lead compound against several noncancerous diseases such as coronavirus disease 2019, Krabbe disease, acute lung injury, Parkinson's disease, dementia, childhood ependymoma etc. Carmofur has also been reported to have antifungal, and antimicrobial properties. Nevertheless, no comprehensive review is available on this drug. Herein, we summarized the chemistry, pharmacokinetics, and pharmacology of carmofur based on the literature published between January 1976 and March 2022 as identified from PubMed and Google Scholar search engines.

Durvalumab (D) and PET-directed chemoradiation (CRT) after induction FOLFOX for esophageal adenocarcinoma: Final results

Background: Induction FOLFOX followed by PET-directed CRT prior to surgery demonstrated positive results in the CALGB 80803 study. We investigated the safety and efficacy of adding D, an anti-PD-L1 antibody, to PET-directed CRT. Methods: Patients (pts) with locally advanced esophageal/GEJ adenocarcinoma were enrolled. Pts received 2 cycles of mFOLFOX6 prior to repeat PET/CT. PET responders (≥35% reduction in SUV (PETr)) received 5-FU/capecitabine and oxaliplatin with RT to 50.4Gy, while induction PET non-responders (PETnr) received carboplatin/paclitaxel with RT. All Pts received D 1,500 mg q4W ×2 starting 2 weeks prior to CRT. Esophagectomy was planned 6-8 weeks after CRT. Pts with R0 resections received adjuvant D 1,500mg q4W ×6. The primary endpoint was the pathologic complete response (pCR) rate. Results: 36 pts were enrolled. Clinical ≥T3 disease was seen in 32 pts (88.9%, cT4 = 3) and ≥N1 in 23 (63.9%) pts. PD-L1 CPS was ≥1 in 25 (71.4%) of 35 tested with 14 (40%) ≥5. Microsatellite instability (MSI) was identified in 3 (8.3%) pts. 25 (70%) pts were PETr. Preop treatment was well tolerated with no new safety signals. Three pts had disease progression prior to surgery. pCR was identified in 8 (22.2%) pts and 22 (64.7%) had major pathologic response (MPR;ypTanyN0 + ≥90% response). Those with MSI tumors had ≥90% treatment response (1 pCR, 1: ypT1aN0 99% response, 1: ypT2N0, 90% response). 17 (73.9%) of 23 cN+ pts had ypN0 disease. MPR was associated with PD-L1 ≥1 (p = 0.03) and with a higher tumor mutational burden (TMB;p = 0.016) on MSK-IMPACT testing. Adjuvant D was commenced in 27 pts, with a median number of 6 cycles. Early discontinuation was due to risks of visits due to COVID19 (4, 15%), progressive disease (3, 11%), late surgical complications (2, 7%) and immune toxicity (1, 4%). With a median follow-up of 30 months, OS rates were 92% [95%CI: 83%-100%] and 85 % [95%CI: 74%-98%] at 12 and 24 months post induction. 12 and 24-month PFS rates were 81% [95%CI: 69%-95%] and 71% [95%CI: 58%-88%] respectively. In the 33 operated pts, 12 and 24-month disease free survival was 82% [95%CI: 70%-96%] and 78% [95%CI: 65%-94%], respectively. In addition to SUV on PET, total lesion glycolysis (TLG) was correlated with pathologic response. In cases with borderline change in SUV, TLG could predict response to treatment. One PETnr with 30.8% reduction in SUV had 88.1% reduction in TLG and pCR. Conversely, a PETr (-36.3%) who had an increase in TLG (39.3%) had only 40% treatment response on pathology. Conclusions: The addition of D to induction FOLFOX and PETdirected CRT prior to surgery is safe and appears effective with a high rate of pathologic response, as well as encouraging survival data. PD-L1 CPS≥1 and higher TMB may be associated with MPR. TLG is a novel PET variable that should be studied prospectively. Additional correlatives and comparison to a cohort treated with standard PET-directed CRT will be presented.

In silico Drug Repurposing of Anticancer Drug 5-FU and Analogues Against SARS-CoV-2 Main Protease: Molecular Docking, Molecular Dynamics Simulation, Pharmacokinetics and Chemical Reactivity Studies.

Background: Since the last COVID-19 outbreak, several approaches have been given a try to quickly tackle this global calamity. One of the well-established strategies is the drug repurposing, which consists in finding new therapeutic uses for approved drugs. Following the same paradigm, we report in the present study, an investigation of the potential inhibitory activity of 5-FU and nineteen of its analogues against the SARS-CoV-2 main protease (3CLpro). Material and Methods: Molecular docking calculations were performed to investigate the binding affinity of the ligands within the active site of 3CLpro. The best binding candidates were further considered for molecular dynamics simulations for 100 ns to gain a time-resolved understanding of the behavior of the guest-host complexes. Furthermore, the profile of druggability of the best binding ligands was assessed based on ADMET predictions. Finally, their chemical reactivity was elucidated using different reactivity descriptors, namely the molecular electrostatic potential (MEP), Fukui functions and frontier molecular orbitals. Results and Discussion: From the calculations performed, four candidates (compounds 14, 15, 16 and 18) show promising results with respect to the binding affinity to the target protease, 3CLpro, the therapeutic profile of druggability and safety. These compounds are maintained inside the active site of 3CLpro thanks to a variety of noncovalent interactions, especially hydrogen bonds, involving important amino acids such as GLU166, HIS163, GLY143, ASN142, HIS172, CYS145. Molecular dynamics simulations suggest that the four ligands are well trapped within the active site of the protein over a time gap of 100 ns, ligand 18 being the most retained. Conclusion: In line with the findings reported herein, we recommend that further in-vitro and in-vivo investigations are carried out to shed light on the possible mechanism of pharmacological action of the proposed ligands.

Polyaminoacid Based Core@shell Nanocarriers of 5-Fluorouracil: Synthesis, Properties and Theranostics Application.

Cancer is one of the most important health problems of our population, and one of the common anticancer treatments is chemotherapy. The disadvantages of chemotherapy are related to the drug's toxic effects, which act on cancer cells and the healthy part of the body. The solution of the problem is drug encapsulation and drug targeting. The present study aimed to develop a novel method of preparing multifunctional 5-Fluorouracil (5-FU) nanocarriers and their in vitro characterization. 5-FU polyaminoacid-based core@shell nanocarriers were formed by encapsulation drug-loaded nanocores with polyaminoacids multilayer shell via layer-by-layer method. The size of prepared nanocarriers ranged between 80-200 nm. Biocompatibility of our nanocarriers as well as activity of the encapsulated drug were confirmed by MTT tests. Moreover, the ability to the real-time observation of developed nanocarriers and drug accumulation inside the target was confirmed by fluorine magnetic resonance imaging (19F-MRI).

Treating Melanoma in Situ During a Pandemic with Telemedicine and a Combination of Imiquimod, 5-Fluorouracil, and Tretinoin.

The recent coronavirus disease 2019 (COVID-19) pandemic has created a quandary for the physician in terms of evaluating and treating cutaneous skin cancers, particularly melanomas. At the onset of the pandemic, many planned medical and surgical visits for skin cancers were postponed. Physicians and patients have had to balance the risk of exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with that of worsening morbidity and mortality due to delays in skin cancer treatments. We present a male patient who had two melanoma-in-situs (MISs) that were treated during the COVID-19 pandemic with a combination of topical imiquimod 5% cream, 5-fluorouracil 2% solution, and tretinoin 0.1% cream. The successful treatments occurred without in-person visits and with the aid of telemedicine. Although surgery is the standard for the treatment of melanoma in situ, this case demonstrates an effective viable treatment modality for MIS during a pandemic situation.

Inhibition of SARS-CoV-2 entry through the ACE2/TMPRSS2 pathway: a promising approach for uncovering early COVID-19 drug therapies.

AIM: The COVID-19 pandemic caused by infection with the novel coronavirus SARS-CoV-2 is urging the scientific community worldwide to intense efforts for identifying and developing effective drugs and pharmacologic strategies to treat the disease. Many of the drugs that are currently in (pre)clinical development are addressing late symptoms of the disease. This review focuses on potential pharmacologic intervention at an early stage of infection which could result in less-infected individuals and less cases with severe COVID-19 disease due to reduced virus entry into the cells. METHOD: We scanned the literature for evidence on drugs that target the virus entry machinery into host cells and consist mainly of ACE2 and TMPRSS2, as well as other cellular molecules regulating ACE2 expression, such as ADAM-17 and calmodulin. RESULTS: Several drugs/drug classes have been identified. Most of them are already used clinically for other indications. They include recombinant soluble ACE2, indirect ACE2 modulators (angiotensin receptor blockers, calmodulin antagonists, selective oestrogen receptor modifiers), TMPRSS2 inhibitors (camostat mesylate, nafamostat mesylate, antiandrogens, inhaled corticosteroids) and ADAM-17 enhancers (5-fluorouracil). CONCLUSION: Several agents have potential for prophylactic and therapeutic intervention at the early stages of SARS-CoV-2 infection and COVID-19 disease and they should be urgently investigated further in appropriate preclinical models and clinical studies.