BioHabana 2022: Preventive and Immunotherapeutic Strategies Against COVID-19 and Cancer in Cuba.

The convergence of life sciences with neurosciences, nanotechnology, data management, and engineering has caused a technological diversification of the biotechnology, pharmaceutical, and medical technology industries, including the phenomenon of digital transformation, which has given rise to the so-called Fourth Industrial Revolution (Industry 4.0). Confronting the COVID-19 pandemic revealed the outstanding response capacity of the scientific community and the biopharmaceutical industry, based on a multidisciplinary and interinstitutional approach that has achieved an unprecedented integration in the history of biomedical science. Cuba, a small country, with scarce material resources, has had remarkable success in controlling the disease, which also highlights the impact of social factors. This report presents a summary of the most relevant presentations of selected topics during the scientific meeting, "BioHabana 2022: Cancer Immunotherapy and the COVID-19 Pandemic," which was held in Havana Cuba in April 2022.

Combinación de interferones en pacientes con tumores cerebrales de alto grado de malignidad sin opciones terapéuticas / Combination of interferons in patients with high-grade brain tumors without therapeutic options

Introducción: La escasa supervivencia de pacientes con tumores cerebrales de alto grado de malignidad, pese a la existencia de algunas opciones de tratamiento, conduce a la búsqueda de nuevas modalidades terapéuticas. La combinación cubana de interferones alfa y gamma es novedosa y existen evidencias de que aumenta la supervivencia de pacientes con tumores sólidos. Método: Se realizó una investigación clínica para determinar la eficiencia de la combinación en pacientes con tumores cerebrales de alto grado sin opciones terapéuticas. Se incluyeron 40 pacientes tratados en el Hospital “Arnaldo Milián Castro” en el período 2009-2020, se evaluó seguridad y eficacia. Resultados: No se produjeron efectos adversos graves, fueron leves o moderados, y los pacientes se recuperaron. Al año habían fallecido el 8,7 % de los casos del grupo experimental, frente al 70,6 % en el grupo control. La supervivencia global en estadio III fue similar en ambos escenarios y en estadio IV fue superior para el grupo experimental. La posibilidad de sobrevivir para los pacientes que se trataron con la combinación de interferones fue 0,887 veces superior a los casos control. Se produjeron diferencias significativas en la capacidad funcional entre ambos grupos de pacientes. Conclusiones: Se evidenció que la combinación cubana de interferones es segura y eficaz para el tratamiento de tumores cerebrales de alto grado de malignidad sin opciones terapéuticas, lo que la convierte en una opción eficiente en este escenario clínico. (AU)

Introduction: The poor survival of patients with high-grade malignancy brain tumors, despite the existence of some treatment options, leads to the search for new therapeutic modalities. The cuban combination of alpha and gamma interferons is novel and there is evidence that it increases the survival of patients with solid tumors. Method: A clinical investigation was conducted to determine the efficiency of the combination in patients with high-grade brain tumors without therapeutic options. 40 patients treated at the “Arnaldo Milián Castro” Hospital in the period 2009-2020 were included, safety and efficacy were evaluated. Results: No serious adverse events occurred, events were mild or moderate, expected, and patients recovered. After one year, 8.7 % of the cases in the experimental group had died, compared to 70.6 % in the control group. Overall survival in stage III was similar in both scenarios and in stage IV it was higher for the experimental group. The chance of survival for the patients who were treated with the combination of interferons was 0.887 times higher than the control cases. There were significant differences in functional capacity between both groups of patients. Conclusions: It was evidenced that the Cuban combination of interferons is safe and effective for the treatment of high-grade malignancy brain tumors without therapeutic options, which makes it an efficient option in this clinical scenario. (AU)

Carcinoma basocelular de la piel cabelluda tratado con HeberFERON. Seguimiento clínico, ecográfico e histopatológico

Fundamento: El carcinoma basocelular es infrecuente en la piel cabelluda. Es un tumor de invasión local y crecimiento lento, puede ser agresivo, destruir tejidos vecinos, causar ulceración e invadir en profundidad cartílago y hueso. Objetivo: Evaluar los resultados de la aplicación del HeberFERON y el seguimiento con ecografía cutánea en pacientes con carcinoma basocelular en la piel cabelluda. Metodología: Se realizó un estudio observacional, descriptivo y longitudinal en una serie de casos con diagnóstico de carcinoma basocelular de la piel cabelluda en el Policlínico Centro de la ciudad Sancti Spíritus, durante el período de 10 de julio del 2018 a 29 de julio del 2022. Se incluyeron 6 casos. Las variables estudiadas fueron la respuesta al tratamiento mediante la clínica, la ecografía cutánea e histopatología y presencia de eventos adversos. Resultados: Predominó el sexo masculino, subtipo histológico sólido, subtipo clínico nódulo ulcerativo, tamaño del tumor mayor de 30 mm y tiempo de evolución de más de 12 meses; la respuesta al tratamiento en la mayoría de los casos fue parcial. Los eventos adversos fueron dolor y ardor en el sitio de inyección, fiebre, edema y eritema perilesional. Conclusiones: El HeberFERON resultó de utilidad en los pacientes con carcinoma basocelular del cuero cabelludo ya que redujo el tumor en unos casos y en otros lo eliminó. La ecografía permitió la evaluación en tiempo real de la neoplasia; los eventos adversos más frecuentes fueron la fiebre y el dolor en el sitio de inyección, a pesar de ello ningún paciente abandonó el tratamiento.

Background: Basal cell carcinoma is uncommon in the scalp. It is a slow-growing locally invasive tumor, it can be aggressive in destroying neighboring tissues, cause ulceration and invade deep into the cartilage and bone. Objective: To evaluate the results of HeberFERON application and follow-up with cutaneous echographical in patients with scalp basal cell carcinoma. Methodology: An observational, descriptive and longitudinal study was conducted in a series of cases diagnosed with scalp basal cell carcinoma at the Center Polyclinic in Sancti Spíritus city during the period from July 10, 2018 to July 29, 2022. Six clinical cases were included. The studied variables were the answer to the treatment by clinical, cutaneous echographical and histopathology and the presence of adverse events. Results: Male sex predominated, solid histologic subtype, clinical subtype ulcerative nodule, tumor size greater than 30 mm and evolution time of over 12 months; the treatment response in most cases was partial; adverse events were pain and burning at the injection site, fever, edema and perilesional erythema. Conclusion: It was observed that in patients with scalp basal cell carcinoma, the HeberFERON treatment reduced in some cases and eliminated the tumor in others. Echography allowed real-time evaluation of the neoplasm, fever and pain at the injection site were the most frequent adverse events. In spite of this, none of the patients abandoned the therapy.

HeberFERON en el tratamiento del carcinoma basoescamoso / HeberFERON in Treating Basosquamous Carcinoma

Introducción: El carcinoma basoescamoso es un subtipo agresivo de carcinoma basocelular compuesto por células basaloides y áreas de células escamosas con una zona de transición intermedia, con tendencia a la recurrencia y metástasis. Objetivo: Describir el caso clínico de una paciente con un carcinoma basoescamoso en región temporal cerca del canto externo del ojo izquierdo. Presentación de caso: Se presentó el caso de una paciente con un carcinoma basoescamoso en región temporal cerca del canto externo del ojo izquierdo de 30 mm de diámetro. Se aplicó HeberFERON con respuesta completa al eliminar el tumor. Conclusiones: El HeberFERON es una opción no quirúrgica de tratamiento que puede ser usada en el carcinoma basoescamoso de localización facial que por su tamaño puede provocar mutilaciones o deformidades en esta zona(AU)

Introduction: Basal squamous cell carcinoma is an aggressive subtype of basal cell carcinoma composed of basaloid cells and areas of squamous cells with an intermediate transition zone, with a tendency to recur and metastasize. Objective: To describe the clinical case of a patient with a basal squamous cell carcinoma in the temporal region near the external canthus of the left eye. Case report: This paper reports a case of a female patient with a basal squamous cell carcinoma in the temporal region near the external canthus of her left eye with 30 mm diameter. HeberFERON was used with complete response when eliminating the tumor. Conclusions: HeberFERON is a non-surgical treatment option that can be used in facial basal squamous cell carcinoma that, due to its size, can cause mutilations or deformities in this area(AU)

HeberFERON en el tratamiento de pacientes con carcinoma basocelular en zona de alto riesgo / HeberFERON in the Treatment of Patients with Basal Cell Carcinoma on a High-Risk Zone

Introducción: El carcinoma basocelular es un tumor de invasión local de crecimiento; se origina en las células epidérmicas de los folículos pilosos o las células basales de la epidermis, cuando se localizan en zona de alto riesgo en la cara tienen un mayor índice de recurrencia tumoral y de invasión a estructuras adyacentes y subyacentes. Objetivo: Evaluar los resultados de la aplicación del HeberFERON en pacientes con carcinoma basocelular en zona de alto riesgo. Métodos: Se realizó un estudio observacional, descriptivo y prospectivo en pacientes con diagnóstico clínico, dermatoscópico e histopatológico de carcinoma basocelular en zona de alto riesgo, tratados con HeberFERON en la consulta del Policlínico Centro de Sancti Spíritus desde el 12 de enero de 2016 hasta el 25 de marzo de 2022. La muestra quedó conformada por 62 pacientes Las principales variables estudiadas fueron la respuesta al tratamiento y los eventos adversos. Resultados: Predominó el sexo masculino, el área urbana, fototipocutáneo III y la edad mayor de 40 años. La localización más frecuente fue la nasal; el subtipo clínico el nódulo ulcerativo; el histológico, el sólido; el tumor primitivo y menor de 2 cm; la respuesta al tratamiento fue completa en la mayoría de los pacientes. Los eventos adversos más comunes fueron dolor y ardor en el sitio de inyección, edema y eritema perilesional, fiebre y cefalea. Conclusiones: La mayoría de los pacientes tratados con HeberFERON tuvieron una respuesta completa, los eventos adversos fueron los descritos en la literatura por el uso de interferones, sin cambio en la actitud farmacológica(AU)

Introduction: Basal cell carcinoma is a growing and locally invasive tumor; it originates in the epidermal cells of hair follicles or the basal cells of the epidermis. When located in a high-risk facial zone, they present a higher rate of tumor recurrence and invasion to adjacent and underlying structures. Objective: To evaluate the results of HeberFERON application in patients with basal cell carcinoma on a high-risk zone. Methods: An observational, descriptive and prospective study was conducted in patients with a clinical, dermatoscopic and histopathological diagnosis of basal cell carcinoma on a high-risk zone, treated with HeberFERON in the consultation of Policlínico Centro of Sancti Spíritus, from January 12, 2016 to March 25, 2022. The sample was made up of 62 patients. The main variables studied were response to treatment and adverse events. Results: There was a predominance of the male sex, the urban area, skin phototype III and age over 40 years. The most frequent localization was nasal; the clinical subtype, ulcerative nodule; the histological subtype, solid. The response to treatment was complete in most patients. The most common adverse events were pain and burning at the injection site, perilesional erythema and edema, fever and headache. Conclusions: Most patients treated with HeberFERON had a complete response; the adverse events were those described in the literature due to the use of interferons, with no change in pharmacological behavior(AU)

A co-formulation of interferons alpha2b and gamma distinctively targets cell cycle in the glioblastoma-derived cell line U-87MG.

BACKGROUND: HeberFERON is a co-formulation of α2b and γ interferons, based on their synergism, which has shown its clinical superiority over individual interferons in basal cell carcinomas. In glioblastoma (GBM), HeberFERON has displayed promising preclinical and clinical results. This led us to design a microarray experiment aimed at identifying the molecular mechanisms involved in the distinctive effect of HeberFERON compared to the individual interferons in U-87MG model. METHODS: Transcriptional expression profiling including a control (untreated) and three groups receiving α2b-interferon, γ-interferon and HeberFERON was performed using an Illumina HT-12 microarray platform. Unsupervised methods for gene and sample grouping, identification of differentially expressed genes, functional enrichment and network analysis computational biology methods were applied to identify distinctive transcription patterns of HeberFERON. Validation of most representative genes was performed by qPCR. For the cell cycle analysis of cells treated with HeberFERON for 24 h, 48 and 72 h we used flow cytometry. RESULTS: The three treatments show different behavior based on the gene expression profiles. The enrichment analysis identified several mitotic cell cycle related events, in particular from prometaphase to anaphase, which are exclusively targeted by HeberFERON. The FOXM1 transcription factor network that is involved in several cell cycle phases and is highly expressed in GBMs, is significantly down regulated. Flow cytometry experiments corroborated the action of HeberFERON on the cell cycle in a dose and time dependent manner with a clear cellular arrest as of 24 h post-treatment. Despite the fact that p53 was not down-regulated, several genes involved in its regulatory activity were functionally enriched. Network analysis also revealed a strong relationship of p53 with genes targeted by HeberFERON. We propose a mechanistic model to explain this distinctive action, based on the simultaneous activation of PKR and ATF3, p53 phosphorylation changes, as well as its reduced MDM2 mediated ubiquitination and export from the nucleus to the cytoplasm. PLK1, AURKB, BIRC5 and CCNB1 genes, all regulated by FOXM1, also play central roles in this model. These and other interactions could explain a G2/M arrest and the effect of HeberFERON on the proliferation of U-87MG. CONCLUSIONS: We proposed molecular mechanisms underlying the distinctive behavior of HeberFERON compared to the treatments with the individual interferons in U-87MG model, where cell cycle related events were highly relevant.

HeberFERON en el tratamiento de pacientes con carcinoma basocelular de la oreja / HeberFERON in the treatment of patients with basal cell carcinoma of the ear

Fundamento: El carcinoma basocelular de la región auricular es considerado uno de los más agresivos y con peor pronóstico, suele ser destructivo y mutilante por lo que el tratamiento conservador, como es el uso de los interferones, es importante en la práctica médica habitual. Objetivo: Evaluar los resultados de la aplicación del HeberFERON en una serie de pacientes con carcinoma basocelular en la región auricular. Metodología: Se realizó un estudio observacional, descriptivo y longitudinal en una serie de casos con diagnóstico clínico, dermatoscópico e histopatológico de carcinoma basocelular de la oreja que recibieron tratamiento con HeberFERON en el Policlínico Centro de la ciudad Sancti Spíritus, durante el período del 20 de febrero de 2017 a 20 de diciembre de 2022. En total se incluyeron 29 pacientes. Se realizó una evaluación inicial, durante y 16 semanas después del tratamiento; se les inyectó 10.5 UI de HeberFERON 3 veces por semana perilesional e intradérmico hasta completar 9 dosis. Las variables fueron la respuesta al tratamiento y presencia o no de eventos adversos. Resultados: Predominó el sexo masculino, la localización en la concha de la oreja, subtipo clínico nódulo ulcerativo y el histológico sólido, con respuesta completa en la mayoría de los pacientes. Como eventos adversos más comunes se presentaron dolor en el sitio de inyección, fiebre, edema y eritema perilesional. Conclusiones: La respuesta al tratamiento fue favorable en la mayoría de los pacientes y los eventos adversos que se observaron fueron los descritos en la literatura sin cambio en la actitud farmacológica.

Background: Basal cell carcinoma of the auricular region is one of the most aggressive cancers and with the worst prognosis, is usually destructive and mutilating, therefore conservative treatment, such as the use of interferons, is important in routine medical practice. Objective: To evaluate the results of HeberFERON application in a series of patients with basal cell carcinoma in the auricular region. Methodology: An observational, descriptive and longitudinal study was conducted on a series of cases with clinical, dermoscopic and histopathologic diagnosis of basal cell carcinoma of the ear treated with HeberFERON at the Center Polyclinic in Sancti Spíritus city, during the period from February 20, 2017 through December 20, 2022. A total of 29 patients were included in the study. An evaluation was conducted at the start of treatment, during treatment, and 16 weeks after treatment; the patients were treated with 10.5 IU of HeberFERON by perilesional and intradermal injections three times a week until completing nine doses. The variables were the response to the treatment and the presence or absence of any adverse events. Results: The male sex predominated, location in the ear turbinate, clinical subtype ulcerative nodule and solid histologic subtype, with a complete response in the majority of patients. The most common adverse events were injection site pain, fever, edema, and perilesional erythema. Conclusions: The response to treatment was favorable in most patients, and the adverse events observed were those described in the literature, with no change in pharmacologic attitude.

Tratamiento con HeberFERON( en el carcinoma basal palpebral

El carcinoma basal palpebral representa un 90 % de los tumores malignos oculares con una alta morbilidad. Su incidencia tiene un comportamiento diferente en las distintas partes del mundo y, por lo general, aumenta con la edad. El diagnóstico positivo se realiza por la evaluación histológica de la muestra mediante biopsia escisional. El tratamiento ideal es el quirúrgico, aunque existen otras opciones de tratamiento. El no quirúrgico tiene como objetivo la eliminación del tumor, así como evitar las complicaciones o las secuelas funcionales y estéticas por la cirugía. Se reconocen numerosas opciones dentro de la modalidad terapéutica no quirúrgica; imiquimod, 5-fluorouracilo, inhibidores de la vía de Hedgehog y los interferones. Diversos estudios han demostrado la utilidad de los interferones en monoterapia o como terapia combinada, en pacientes no susceptibles de actuaciones quirúrgicas. Por esta razón, se decidió revisar la literatura científica actual sobre la eficacia y seguridad del HeberFERON® en el tratamiento del carcinoma basal palpebral. Se realizó una búsqueda actualizada teniendo en cuenta los descriptores correspondientes a las palabras clave relacionadas con la temática a investigar, en las bases de datos bibliográficas Medline (buscador PubMed), SciELO, Ebsco, Clinical Key y en Google Académico. Se recuperaron 35 artículos que su contenido respondía al tema de estudio.

Palpebral basal carcinoma represents 90% of ocular malignant tumors with high morbidity. Its incidence has a different behavior in different parts of the world and generally increases with age. Positive diagnosis is made by histological evaluation of the specimen by excisional biopsy. The ideal treatment is surgical, although other treatment options are available. Non-surgical treatment is aimed at eliminating the tumor, as well as avoiding the complications or functional and esthetic sequelae of surgery. Numerous options are recognized within the non-surgical therapeutic modality; imiquimod, 5-fluorouracil, Hedgehog pathway inhibitors and interferons. Several studies have demonstrated the usefulness of interferons in monotherapy or as combination therapy in patients not amenable to surgery. For this reason, it was decided to review the current scientific literature on the efficacy and safety of HeberFERON® in the treatment of palpebral basal cell carcinoma. An updated search was carried out taking into account the descriptors corresponding to the key words related to the subject under investigation, in the bibliographic databases Medline (PubMed search engine), SciELO, Ebsco, Clinical Key and Google Scholar. Thirty-five articles were retrieved whose content corresponded to the subject of the study.

Proteomics and Phospho-Proteomics Profiling of the Co-Formulation of Type I and II Interferons, HeberFERON, in the Glioblastoma-Derived Cell Line U-87 MG.

HeberFERON, a co-formulation of Interferon (IFN)-α2b and IFN-γ, has effects on skin cancer and other solid tumors. It has antiproliferative effects over glioblastoma multiform (GBM) clones and cultured cell lines, including U-87 MG. Here, we report the first label-free quantitative proteomic and phospho-proteomic analyses to evaluate changes induced by HeberFERON after 72 h incubation of U-87 MG that can explain the effect on cellular proliferation. LC-MS/MS, functional enrichment and networking analysis were performed. We identified 7627 proteins; 122 and 211 were down- and up-regulated by HeberFERON (fold change > 2; p < 0.05), respectively. We identified 23,549 peptides (5692 proteins) and 8900 phospho-peptides; 523 of these phospho-peptides (359 proteins) were differentially modified. Proteomic enrichment showed IFN signaling and its control, direct and indirect antiviral mechanisms were the main modulated processes. Phospho-proteome enrichment displayed the cell cycle as one of the most commonly targeted events together with cytoskeleton organization; translation/RNA splicing, autophagy and DNA repair, as represented biological processes. There is a high interconnection of phosphoproteins in a molecular network; mTOR occupies a centric hub with interactions with translation machinery, cytoskeleton and autophagy components. Novel phosphosites and others with unknown biological functionality in key players in the aforementioned processes were regulated by HeberFERON and involved CDK and ERK kinases. These findings open new experimental hypotheses regarding HeberFERON action. The results obtained contribute to a better understanding of HeberFERON effector mechanisms in the context of GBM treatment.

Tratamiento del carcinoma basocelular de la nariz con una combinación de interferones Alpha-2b y Gamma / Treatment of basal cell carcinoma of the nose with a combination of Interferon alpha-2b and gamma

Introducción: El carcinoma basocelular es una neoplasia maligna derivada de las células epidérmicas de los folículos pilosos o células no queratinizadas puede ser desfigurante y originar deformidades o pérdida de la función del órgano afectado, es más frecuente en zonas sobresalientes como la nariz. Objetivo: Describir los resultados de la aplicación de la combinación sinérgica de interferones alpha-2b y gamma en una serie de casos con carcinoma basocelular nasal. Material y métodos: Se realizó un estudio de serie de casos clínicos, se incluyeron 28 pacientes con diagnóstico clínico, dermatoscópico e histopatológico de carcinoma basocelular de la nariz que acudieron a consulta de dermatología del Policlínico Centro de Sancti Spíritus en el período de 17 de enero de 2016 a 28 de diciembre de 2021. Se realizó una evaluación inicial y otra final a las 16 semanas después del comienzo del tratamiento. Se administró 10,5 UI de HeberFERON, 3 veces por semana perilesional e intradérmica hasta completar 9 dosis. Las variables principales fueron la respuesta al tratamiento y presencia o no de evento adversos. Resultados: Predominó el sexo masculino, fototipocutáneo II, localización en el dorso y ala nasal, subtipo clínico nódulo ulcerativo y el histológico sólido. En la mayoría de los pacientes desapreció el tumor al culminar el esquema terapéutico. Como eventos adversos más comunes se presentaron dolor en el sitio de inyección, fiebre, edema y eritema perilesional. Conclusiones: La respuesta al tratamiento fue completa en la mayoría de los pacientes y los eventos adversos los descritos en la literatura sin cambios en la actitud farmacológica(AU)

Introduction: Basal cell carcinoma is a malignant neoplasm derived from epidermal cells of hair follicles or non-keratinized cells with a high potential for local destruction, which can be disfiguring and may invade the surrounding tissue, resulting in deformities or loss of function of the affected organ, being more frequent in protruding areas such as the nose. Objective: To describe the results of the application of the synergistic combination of interferon alpha-2b and gamma in a series of cases with nasal basal cell carcinoma. Material and Methods: An observational, descriptive and longitudinal study was carried out in a series of 28 clinical cases with basal cell carcinoma of the nose who attended the dermatology clinic of Policlínico Centro in Sancti Spiritus in the period from january 2016 to december 2021. Cases with a clinical, dermoscopic and histopathological diagnoses were included. An initial and a final evaluation at the end of the 16 weeks of treatment were carried out; also, 10,5 IU of HeberFERON was administered 3 times per week perilesional and intradermally until completing 9 doses. The main variables were response to treatment and presence or absence of adverse events. Results: Male sex, skin phototype II, location on the dorsum and nasal ala, clinical subtype ulcerative nodule, and solid histological subtype predominated. In most of the patients, the tumor disappeared at the end of the therapeutic regime. The most common adverse events were pain at the injection site, fever, edema and perilesional erythema. Conclusions: There was a complete response to treatment in most patients and the adverse events were those described in the literature with no change in the pharmacological attitude(AU)

Carcinoma epidermoide de piel tratado con HeberFERON®

RESUMEN Introducción: en la literatura biomédica son escasos los reportes sobre el uso de los interferones como tratamiento en el carcinoma epidermoide. En una unidad de atención primaria, en Colón, Matanzas, se implementó el HeberFERON® en este tipo de tumor, con experiencias favorables. Objetivo: describir la efectividad del HeberFERON® en el carcinoma epidermoide. Materiales y métodos: se realizó un estudio observacional, descriptivo en 33 lesiones de carcinoma epidermoide en 29 pacientes. La dosis fue de 7,0 y 10,5 MUI de actividad antiviral, infiltrada de forma perilesional tres veces por semana durante tres semanas. Se realizó el seguimiento clínico de los pacientes antes del tratamiento y a las 16 semanas del inicio del mismo. Las variables fueron: edad, sexo, fototipo de piel, procedencia, localización, tipo clínico, estadio y respuesta clínica al tratamiento. Se consideraron cuatro categorías de respuesta: completa, parcial, enfermedad estable y progresiva. Se incluyó la respuesta objetiva (completa más parcial). Se recogieron los datos en una historia clínica. Se utilizaron los programas Microsoft Excel y SPSS para el procesamiento estadístico. Resultados: el 65,5 % de los pacientes correspondió al sexo masculino. Un 58,6 % son fototipo II y de procedencia urbana. Predominaron las edades entre 61 y 80 años (55,2 %). Hubo respuesta objetiva en 57,6 % (cinco completas y 14 parciales). Las mejores respuestas la mostraron el carcinoma epidermoide queratósico superficial y el noduloulceroso. Conclusiones: la mezcla de interferones fue efectiva en el carcinoma epidermoide en todos los subtipos clínicos, aunque los autores sugieren un segundo ciclo de HeberFERON® o asociarlo con quimioterapia cuando la respuesta no sea completa.

ABSTRACT Introduction: there are few reports in the literature on the use of interferon in the treatment of the squamous cell carcinoma. In a primary care unit in Colon, Matanzas, HeberFERON® was implemented in this type of tumor with favorable experiences. Objective: to describe the effectiveness of HeberFERON® in epidermoid carcinoma. Materials and methods: an observational, descriptive study was conducted in 33 epidermoid carcinoma lesions in 29 patients. The doses were 7.0 and 10.5 MUI of antiviral activity, perilesionally infiltrated three times a week for three weeks. Clinical follow-up of patients was performed before the treatment and at 16 weeks from the beginning of the treatment. The variables were: age, sex, skin phototype, origin; location, clinical type, stage and clinical response to treatment. Four categories of response were considered: complete, partial, stable and progressive disease. The objective response (complete plus partial) was included. Data were collected in a clinical record. The Microsoft Excel and SPSS programs were used for statistical processing. Results: 65.5 % of patients were male. 58.6 % are phototype II and of urban origin. Ages ranging from 61 to 80 years (55.2 %) predominated. There was objective response in 57.6 % (five complete and 14 partials). The superficial keratotic squamous cell carcinoma and the nodular ulcerative one showed the best responses. Conclusions: interferon mixing was effective in all clinical subtypes of epidermoid carcinoma, although the authors suggest a second cycle of HeberFERON® or to associate it with chemotherapy when the response is not complete.

HeberFERON en el carcinoma basocelular periocular. Serie de casos / HeberFERON in periocular basal cell carcinoma. Case series

RESUMEN Fundamento: El carcinoma basocelular periocular es una lesión tumoral que surge de las células basales de la epidermis y los folículos pilosos, con un alto potencial de destrucción local, pueden ser desfigurantes e invaden el tejido que los rodea dando lugar a deformidades o pérdida de la función del órgano afectado. En orden de aparición es más común en el párpado inferior, el canto medial, el párpado superior y el canto temporal. Objetivo: Describir los resultados de la aplicación del HeberFERON en una serie de casos con carcinoma basocelular periocular que acudieron a consulta de dermatología del Policlínico Centro, de enero de 2017 a diciembre del 2020. Metodología: Se realizó un estudio de serie de casos clínicos con carcinoma basocelular periocular que acudieron a la consulta de dermatología del Policlínico Centro. Se incluyeron 17 casos con diagnóstico clínico, dermatoscópico e histopatológico. Se realizó una evaluación inicial, durante y 16 semanas después del tratamiento; se administró 10.5 UI de HeberFERON 3 veces por semana perilesional e intradérmica hasta completar 9 dosis. Las variables principales fueron la respuesta al tratamiento y la presencia o no de eventos adversos. Resultados: Predominó el sexo masculino, el fototipocutáneo II, la localización en párpado inferior, el subtipo clínico nódulo ulcerativo y el histológico sólido, se logró respuesta completa en la mayoría de los pacientes. Como eventos adversos se presentaron dolor en el sitio de inyección, fiebre, mal estar general, edema y eritema perilesional. Conclusiones: La respuesta al tratamiento fue favorable en la mayoría de los pacientes tratados con HeberFERON.

ABSTRACT Background: Periocular basal cell carcinoma is a tumor lesion arising from the epidermis and hair follicles basal cells, with a high potential local destruction, can be disfiguring and invade the surrounding tissue leading to deformities or loss of function of the affected organ. In order of appearance it is most common in the lower eyelid, medial edge, upper eyelid and temporal edge. Objective: To describe the results of the application of HeberFERON in a case series with periocular basal cell carcinoma who attended dermatology appointment at the Policlínico Centro, from January 2017 to December 2020. Methodology: A series study of clinical cases with periocular basal cell carcinoma who attended the dermatology appointment at the Policlínico Centro was conducted. 17 cases with clinical, dermatoscopic and histopathological diagnosis were included. A baseline evaluation was conducted, during and 16 weeks after treatment; 10.5 IU of HeberFERON was administered 3 times a week perilesional and intradermally until completing 9 doses. The main variables were the treatment response and the presence or absence of adverse events. Results: Male sex, phototypocutaneous II, lower eyelid location, clinical subtype ulcerative nodule and solid histological subtype predominated, complete response was achieved in most patients. Adverse events were pain at the injection site, fever, general malaise, edema and perilesional erythema. Conclusions: Treatment response was favorable in most patients treated with HeberFERON.

The time to offer treatments for COVID-19.

Background: COVID-19 has several overlapping phases. Treatments to date have focused on the late stage of disease in hospital. Yet, the pandemic is by propagated by the viral phase in out-patients. The current public health strategy relies solely on vaccines to prevent disease.Methods: We searched the major national registries, pubmed.org, and the preprint servers for all ongoing, completed and published trial results.Results: As of 2/15/2021, we found 111 publications reporting findings on 14 classes of agents, and 9 vaccines. There were 62 randomized controlled studies, the rest retrospective observational analyses. Only 21 publications dealt with outpatient care. Remdesivir and high titer convalescent plasma have emergency use authorization for hospitalized patients in the U.S.A. There is also support for glucocorticoid treatment of the COVID-19 respiratory distress syndrome. Monoclonal antibodies are authorized for outpatients, but supply is inadequate to treat all at time of diagnosis. Favipiravir, ivermectin, and interferons are approved in certain countries.Expert Opinion: Vaccines and antibodies are highly antigen specific, and new SARS-Cov-2 variants are appearing. We call on public health authorities to authorize treatments with known low-risk and possible benefit for outpatients in parallel with universal vaccination.

Seguridad del HeberFERON( en pacientes con carcinoma basal palpebral / Safety of HeberFERON in patients with basal cell eyelid carcinoma

Objetivo: Evaluar la seguridad del HeberFERON( en el tratamiento del carcinoma basal palpebral. Métodos: Se realizó un estudio descriptivo en pacientes con carcinoma basal palpebral, a quienes se les aplicó HeberFERON( perilesional, de enero del año 2013 a enero de 2018. La muestra quedó constituida por 20 pacientes que cumplieron los criterios de inclusión. La dosis protocolizada fue de 3,5 x 106 UI, perilesional, dos veces a la semana por 5 semanas consecutivas. Las variables del estudio fueron: edad, sexo, color de la piel, localización del tumor, así como tipo y grado de evento adverso. Para todas las variables del estudio fueron calculadas las frecuencias absolutas y relativas. Resultados: La población estudiada con carcinoma basal palpebral mostró mayor frecuencia entre los 60 y 79 años de edad (80 por ciento) y las lesiones se presentaron fundamentalmente en el párpado inferior (60 (). El eritema palpebral y el dolor en el sitio de la inyección constituyeron los eventos adversos oculares más frecuentes (95,0 y 70,0 por ciento respectivamente) y se presentaron en el 95 por ciento de los pacientes investigados. Los eventos adversos sistémicos (fiebre, artralgia y la cefalea) prevalecieron en el 100 por ciento de los casos, en quienes el grado de severidad fue leve. Conclusiones: El HeberFERON( en el tratamiento del carcinoma basal palpebral es una buena alternativa no quirúrgica; es seguro y bien tolerado(AU)

Objective: Evaluate the safety of HeberFERON in the treatment of basal cell eyelid carcinoma. Methods: A descriptive study was conducted of patients with basal cell eyelid carcinoma undergoing perilesional HeberFERON therapy from January 2013 to January 2018. The sample was composed of 20 patients meeting the inclusion criteria. The protocol dose was 3.5 x 106 UI perilesional twice a week for five consecutive weeks. The variables analyzed were age, sex, skin color and tumor location, as well as adverse event type and degree. Absolute and relative frequencies were estimated for all the study variables. Results: The prevailing age group in the study basal cell eyelid carcinoma population was 60-79 years (80 percent). The most common lesion site was the lower eyelid (60 percent). Eyelid erythema and injection site pain were the most frequent ocular adverse events (95.0 percent and 70.0 percent, respectively), presenting in 95 percent of the study subjects. Systemic adverse events (fever, arthralgia and headache) prevailed in 100 percent of the cases studied, among whom the degree of severity was mild. Conclusions: HeberFERON is a good non-surgical alternative for basal cell eyelid carcinoma. It is safe and well tolerated(AU)

Respuesta clínica del tratamiento con HerberFERON( en pacientes con carcinoma basal palpebral / Clinical response to treatment with HerberFERON® in patients with basal palpebral carcinoma

Objetivo: Determinar la respuesta clínica en pacientes con carcinoma basal palpebral tratados con HeberFERON. Métodos: Se realizó un estudio descriptivo en pacientes con carcinoma basal palpebral, a quienes se les aplicó HeberFERON( perilesional en el Instituto Cubano de Oftalmología "Ramón Pando Ferer", de enero del año 2013 a enero de 2015. La muestra quedó constituida por 10 pacientes que cumplieron con los criterios de inclusión. Las variables del estudio fueron: edad, sexo, color de la piel, forma clínica, diámetro tumoral, subtipo histológico del tumor, así como la respuesta clínica después del tratamiento de los casos estudiados. Para todas las variables del estudio fueron calculadas las frecuencias absolutas y relativas. Resultados: Predominaron el género masculino y los sujetos de piel blanca. En los pacientes estudiados se presentaron la forma clínica nódulo ulcerativo, el subtipo histológico tumoral poco diferenciado y la respuesta clínica objetiva. Conclusiones: En la mayoría de los pacientes se logró una buena respuesta clínica al tratamiento con HeberFERON(, por lo que este tratamiento se convierte una nueva alternativa no quirúrgica(AU)

Objective: To determine the clinical response in patients with basal palpebral carcinoma treated with HeberFERON(. Methods: A descriptive study was carried out in patients with eyelid cell basal carcinoma tried with HeberFERON in the Cuban Institute of Ophthalmology "Ramón Pando Ferrer" from January 2013 to January 2015. The sample consisted of 10 patients who fulfilled the inclusion criteria. The study variables were: age, sex, skin color, clinical form, tumor diameter, histological subtype of the tumor, as well as the clinical response after treatment of the cases studied. In all the variables, absolute and relative frequencies were calculated. Results: Male gender and white-skinned subjects predominated. The clinical form ulcerative nodule, poorly differentiated histological tumor subtype, and objective clinical response were present in the patients studied. Conclusions: In most of the patients a good clinical answer was achieved to the treatment with HeberFERON, which becomes a new non surgical alternative(AU)

Carcinoma basocelular tratado con HeberFERON, seguimiento clínico, histológico y ecográfico. Reporte de caso / Basal cell carcinoma treated with HeberFERON, clinical, histological and ultrasound follow-up. Case report

RESUMEN Fundamento: El carcinoma basocelular es el cáncer de piel no melanoma más frecuente, es un tumor de invasión local y crecimiento lento, su incidencia está incrementándose y esto requiere métodos diagnósticos y terapéuticos eficaces, accesibles y rápidos. La ecografía cutánea es una técnica diagnóstica no invasiva que utiliza las propiedades físicas del ultrasonido para el estudio de la piel. Objetivo: Describir el caso de una paciente con carcinoma basocelular en borde del pabellón auricular derecho tratado con HeberFERON y seguimiento con ecografía cutánea. Presentación de caso: Paciente femenina de 60 años con carcinoma basocelular en borde del pabellón auricular derecho, al cual se le aplicó tratamiento con HeberFERON con respuesta completa al eliminar el tumor, lo que se comprobó con la clínica, la histopatología y la ecografía cutánea. Conclusiones: La ecografía cutánea permitió visualizar en tiempo real el tamaño y profundidad del tumor en la piel, asimismo fue útil para confirmar la desaparición de la lesión luego del tratamiento con el HeberFERON.

ABSTRACT Background: Basal cell carcinoma is the most frequent non-melanoma skin cancer, it is a locally invasive and slow growing tumor, its incidence is increasing, so requires efficient, accessible and rapid diagnostic and therapeutic methods. Skin ultrasound is a non-invasive diagnostic technique that uses the physical properties of ultrasound to study the skin. Objective: To describe a patient´s case with basal cell carcinoma on the border of the right auricular pavilion treated with HeberFERON and follow-up with skin ultrasound. Case presentation: 60-year-old female patient with basal cell carcinoma on the edge of the right auricular pavilion, treated with HeberFERON with a complete response after eliminating the tumor, it was verified with the clinic, histopathology and skin ultrasound. Conclusions: The skin ultrasound allowed to visualize in real time the size and depth of the skin tumor, it was also useful to confirm the disappearance of the lesion after the treatment with HeberFERON.

Effect and safety of combination of interferon alpha-2b and gamma or interferon alpha-2b for negativization of SARS-CoV-2 viral RNA. Preliminary results of a randomized controlled clinical trial.

ObjectivesAn IFN-2b and IFN-{gamma} combination has demonstrated favorable pharmacodynamics for genes underlying antiviral activity which might be involved in the defense of a host from a SARS-CoV-2 infection. Considering this synergy, we conducted a randomized controlled clinical trial for efficacy and safety evaluation of subcutaneous IFN - 2b and IFN-{gamma} administration in patients positive for SARS-CoV-2. MethodsWe enrolled 19-82 years-old inpatients at the Military Central Hospital Luis Diaz Soto, Havana, Cuba. They were hospitalized after confirmed diagnosis for SARS-CoV-2 RNA by real-time reverse transcription polymerase chain reaction. Patients were randomly assigned in a 1:1 ratio to receive either, subcutaneous treatment with a co-lyophilized combination of 3.0 MIU IFN-2b and 0.5 MIU IFN-{gamma} (HeberFERON, CIGB, Havana, Cuba), twice a week for two weeks, or thrice a week intramuscular injection of 3.0 MIU IFN-2b (Heberon(R) Alpha R, CIGB, Havana, Cuba). Additionally, all patients received lopinavir-ritonavir (200/50 mg every 12 h) and chloroquine (250 mg every 12 h, i.e.standard of care). The primary endpoints were, from the start of treatment, the time to elimination of viral RNA and the time to progression to severe COVID-19. The protocol was approved by the Ethics Committee on Clinical Investigation from the Hospital and the Center for the State Control of Medicines, Equipment and Medical Devices in Cuba. Informed consent was obtained from each participant (INSTITUTION PROTOCOL IG/IAG/CV/2001). ResultsA total of 79 patients with laboratory-confirmed SARS-CoV-2 infection, including symptomatic or asymptomatic conditions, fulfilled the inclusion criteria and underwent randomization. Thirty-three subjects were assigned to the HeberFERON group, and 33 to the Heberon Alpha R group. Sixty-three patients were analyzed for viral elimination, of these 78.6% in the HeberFERON group eliminated the virus after 4 days of treatment versus 40.6% of patients in the Heberon Alpha R groups (p=0.004). Time to reach the elimination of SARS-CoV-2, as measured by RT-PCR was 3.0 and 5.0 days for the HeberFERON and Heberon Alpha R groups, respectively. A significant improvement in the reduction of time for virus elimination was attributable to HeberFERON (p=0.0027, Log-rank test) with a Hazard Ratio of 3.2 and 95% CI of 1.529 to 6.948, as compared to the Heberon Alpha R treated group. Worsening of respiratory symptoms was detected in two (6.6%) and one (3.3%) patients in HeberFERON and IFN-2b groups, respectively. However, none of the subjects transited to severe COVID-19 during the study or during the following clinical evaluation (21 more days). RT-PCR on day 14 after the start of the treatment was negative to SARS-CoV-2 in 100% and 91% of patients of the combination of IFNs and IFN-2b, respectively. Elimination in HeberFERON treated patients was related to a significant increase in lymphocytes counts and also a significant reduction in CRP as early as 7 days after commencing the therapeutic schedule. All the patients in both cohorts recovered and had their laboratory parameters return to normal values by day 14 after treatment initiation. Adverse events were identified in 31.5% of patients, 28.5% in the control group, and 34.4% in the HeberFERON group, with the most frequent adverse event being headaches (17.4%). ConclusionsIn a cohort of 63 hospitalized patients between 19 to 82 years-old with positive SARS-CoV-2, HeberFERON significantly eliminated the virus on day 4 of treatment when compared to treatment with IFN-2b alone. However, Heberon Alpha R alone also showed efficacy for the treatment of the viral infection. Both treatments were safe and positively impacted on the resolution of the symptoms. None of the patients developed severe COVID-19.

A co-formulation of interferons type I and II enhances temozolomide response in glioblastoma with unmethylated MGMT promoter status.

Temozolomide (TMZ) is a chemotherapeutic used for the treatment of glioblastoma. The MGMT repair enzyme (O'-(6)-methyl guanine-DNA-methyltransferase) promoter methylation is a predictive biomarker to TMZ response; interferons (IFNs) type I can downregulate MGMT expression improving survival in patients with unmethylated MGMT promoter. HeberFERON is a co-formulation of IFNs type I and II with higher antiproliferative effect over glioblastoma cell lines than individual IFNs. We investigated the proliferative response of patient-derived glioblastoma cultures to HeberFERON and its combination with TMZ in relation to MGMT promoter methylation and the regulation of MGMT transcript after HeberFERON treatment. Eleven glioblastoma-derived cultures, molecularly classified according to TCGA and MGMT promoter methylation, were assayed for proliferation inhibition with HeberFERON at low doses (1-25 IU/mL) [alone or combined with TMZ] or at higher doses (50-200 IU/mL) using CellTiter-Glo Luminescent Cell Viability Assay (Promega). Eight cultures were further treated with 100 IU/mL of HeberFERON for 72 h, total RNA purified (Qiagen) and converted to cDNA (Superscript III kit, Invitrogen) as quantitative PCR templates. Changes of MGMT&P53 transcripts level were monitored. Response of cultures to HeberFERON is variable, dose-dependent and apparently independent from TCGA classification and MGMT methylation status, based on the eight Classical cultures data. When combining HeberFERON with TMZ there was an increase in cell death for cultures, 2/4 with methylated and 5/5 with unmethylated MGMT promoter. In two out five cultures with unmethylated MGMT status, we observed a decrease of MGMT gene levels and an increase in P53 encoding gene levels. HeberFERON and TMZ combination should be further assayed in glioblastoma, mainly for those with unmethylated MGMT promoter.

A SYSTEMATIC ANALYSIS OF THE TIME COURSE TO DEVELOP TREATMENTS FOR COVID-19

BACKGROUNDThe spread of COVID-19 from Wuhan China, has been alarmingly rapid. Epidemiologic techniques succeeded in containing the disease in China, but efforts have not been as successful in the rest of the World, with a total of 29,155,581 confirmed cases of COVID-19, including 926,544 deaths worldwide as of September 15, 2020. Projections are for continued new infections and deaths if no effective therapeutic interventions can be initiated over the next several months. We performed a systematic review to determine the potential time course for development of treatments and vaccines, focusing on availability now and continuing in the last half of 2020. METHODS Clinical TrialsWe reviewed up-to-date information from several sources to identify potential treatments for COVID-19: The Reagan-Udall Expanded Access Navigator COVID-19 Treatment Hub was used to track the efforts of companies to develop agents. We focused on trials completed as of September 1, 2020 on identified agents We used several different sources: (A) covid-trials.org, then validated results on (B) clinicaltrials.gov and the (C) World Health Organizations International Clinical Trials Registry Platform (WHO ICTRP). We excluded studies which were clearly observational, with no randomization, control, or comparison group. We further set a cutoff of 100 for numbers of subjects, since smaller trial size could lack statistical power to establish superiority of the intervention over the control. PublicationsWe searched for published trial results on pubmed.gov and on medRxiv, the preprint server, and used a targeted Google search to find announcements of unpublished trial results RESULTS Clinical Trials in RecruitmentAs of our cutoff date of April 1, 2020, we found 409 trials meeting our minimum requirement of 100 subjects. The WHO Solidarity megatrial for hospitalized patients was launched in over 100 countries, actively comparing hydroxychloroquine (HCQ), lopanovir/ritonavir (LPV/r) alone and in combination with interferon beta-1, and remdesivir. The LPV/r alone and HCQ arms have already been discontinued. Of these, only 9 were conducted on outpatients. A few vaccine trials are hoping to complete Phase 3 enrollment by the end of the third quarter 2020, but a prolonged follow-up of patients will likely be required. Clinical trials CompletedAs of September 1, 2020, there were 231 trials reporting completion, Of these, only 59 studies enrolled 100 or more subjects. There were 34 trials in hospitalized patients, 9 directed at outpatients, and 8 prevention studies, Published DataAs of September 1, 2020 we found 70 publications reporting findings in human studies on 13 classes of drugs and on 6 vaccines. There were 33 randomized placebo or active control studies; the rest were retrospective observational. Only seven publications dealt with outpatient care, the rest all in hospitalized patients. Available TreatmentsAt this time, remdesivir and convalescent plasma have been granted emergency use authorization in the U.S.A., solely for hospitalized patients. There is also support for glucocorticoid treatment of the COVID-19 respiratory distress syndrome. No treatments or prophylaxis are offered for outpatients. CONCLUSIONCOVID-19 is propagated primarily by infected ambulatory individuals. There have been no options brought forward for prevention and non-hospital treatment with only a few randomized, controlled outpatient studies expected to yield results in time to impact on the continuing pandemic by the end of 2020. It will be necessary for public health authorities to make hard decisions, with limited data, to prevent the continued spread of the disease. The choices will be hardest when dealing with possible early release of safe and effective vaccines which would, of course, be of greatest benefit to the Worlds population.