Humoral Response to SARS-COV-2 Vaccination in Patients with Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder: A Real-World Study.

INTRODUCTION: The risk of SARS-CoV-2 infection or severe coronavirus disease 2019 (COVID-19) has been shown to increase in patients with multiple sclerosis (MS). Vaccination is recommended in this patient population, and the effect of disease-modifying treatments (DMTs) on response to vaccination should be considered. METHODS: This prospective, observational, cross-sectional study investigated humoral response after COVID-19 vaccination as well as possible predictors for response in patients with MS and other neuroinflammatory diseases who received DMTs in routine clinical practice in Spain. Responses were compared versus those seen in healthy controls. RESULTS: After vaccination against COVID-19, most patients with MS developed an immune response comparable to that of healthy individuals. However, approximately half of patients receiving a sphingosine-1-phosphate modulator (SP1-M, fingolimod or siponimod) or a B-cell-depleting agent (aCD20, ocrelizumab or rituximab) did not develop protective antibodies, although patients receiving other DMTs had humoral immune responses comparable to healthy controls. Lymphocyte count was not associated with reduced humoral response in patients receiving an SP1-M or aCD20, whereas, in patients receiving an aCD20 or SP1-M, older age was associated with lower anti-SARS-CoV-2 spike protein immunoglobulin G antibody levels. CONCLUSIONS: Treatment with aCD20 or SP1-M therapies appears to be associated with a lower humoral response to vaccines against SARS-CoV-2. Vaccination prior to initiation of these DMTs should be recommended whenever possible.

IMP3 immunohistochemical expression is related with progression and metastases in xenografted and cutaneous melanomas.

INTRODUCTION: Insulin-like growth factor-II messenger RNA (mRNA)-binding protein-3 (IMP3) over-expression is a predictor of tumor recurrence and metastases in some types of human melanoma. Our objective is to evaluate the immunohistochemical expression of IMP3 and other molecules related to tumor prognosis in melanoma-xeno-tumors undergoing treatment. MATERIAL AND METHODS: We inoculated A375 and G361 human melanoma cell lines into NOD/SCID gamma mice. We assessed the immunohistochemical expression of IMP3, E-cadherin, N-cadherin, PARP1, HIF-1α, and the proliferation marker Ki-67. Additionally, we performed a retrospective study including 114 histological samples of patients diagnosed with malignant cutaneous Superficial Spreading Melanoma, and Nodular Melanoma with at least five years of follow-up. RESULTS: Most morphological and immunohistochemical features show statistically significant differences between the two cell lines. All three treatments reduced the cell proliferation evaluated by the Ki-67 nuclear antigen (P=0.000) and reduced the number of metastases (P=0.004). In addition, the tumor volumes reduced in comparison with the control groups, 31.74% for RT+MSCs in the A357 tumor cell line, and 89.84% RT+MSCs in the G361 tumor cell line. We also found that IMP3 expression is associated with greater tumor aggressiveness and was significantly correlated with cell proliferation, the number of metastases, and reduced expression of adhesion molecules. DISCUSSION/CONCLUSIONS: The combined treatment of RT+MSCs on xenografted melanomas reduces tumor size, metastases frequency and the EMT/PARP1 metastatic phenotype. This treatment also reduces the expression of molecules related to cellular proliferation (Ki-67), molecules that facilitate the metastatic process (E-cadherin) and molecules related with prognosis (IMP3).

Rationale for the Use of Radiation-Activated Mesenchymal Stromal/Stem Cells in Acute Respiratory Distress Syndrome.

We have previously shown that the combination of radiotherapy with human umbilical-cord-derived mesenchymal stromal/stem cells (MSCs) cell therapy significantly reduces the size of the xenotumors in mice, both in the directly irradiated tumor and in the distant nonirradiated tumor or its metastasis. We have also shown that exosomes secreted from MSCs preirradiated with 2 Gy are quantitatively, functionally and qualitatively different from the exosomes secreted from nonirradiated mesenchymal cells, and also that proteins, exosomes and microvesicles secreted by MSCs suffer a significant change when the cells are activated or nonactivated, with the amount of protein present in the exosomes of the preirradiated cells being 1.5 times greater compared to those from nonirradiated cells. This finding correlates with a dramatic increase in the antitumor activity of the radiotherapy when is combined with MSCs or with preirradiated mesenchymal stromal/stem cells (MSCs*). After the proteomic analysis of the load of the exosomes released from both irradiated and nonirradiated cells, we conclude that annexin A1 is the most important and significant difference between the exosomes released by the cells in either status. Knowing the role of annexin A1 in the control of hypoxia and inflammation that is characteristic of acute respiratory-distress syndrome (ARDS), we designed a hypothetical therapeutic strategy, based on the transplantation of mesenchymal stromal/stem cells stimulated with radiation, to alleviate the symptoms of patients who, due to pneumonia caused by SARS-CoV-2, require to be admitted to an intensive care unit for patients with life-threatening conditions. With this hypothesis, we seek to improve the patients' respiratory capacity and increase the expectations of their cure.

The efficacy of three-dimensional conformal radiation therapy on pain and quality of life in patients with painful bone metastases: a prospective study.

AIM: To evaluate the efficacy of radiation therapy in alleviating pain and improving the quality of life (QoL) with validated questionnaires in patients with painful bone metastases (BoM). METHODS: This prospective, observational study recruited 167 patients with painful BoM who were treated with palliative radiotherapy (PRT) from February 2015 to February 2018. After the first clinical assessment, the patients filled out specific questionnaires and underwent a fast radiotherapy treatment within 48 hours. The patients were followed up for eight weeks. RESULTS: The median age was 66.30 years. The most common primary cancer was lung cancer (31.1%). The most often prescribed scheme was 8 Gy in one fraction (70%). The patients experienced significant pain response and improved QoL compared with baseline, especially in the first two weeks after radiation. Overall, reduced pain and drug score were reported at two weeks of PRT in 68 (51.5%) and 37 (28%) of patients, respectively. CONCLUSIONS: PRT is an effective treatment option for patients with painful BoM.

Enhancing the Bystander and Abscopal Effects to Improve Radiotherapy Outcomes.

In this paper, we summarize published articles and experiences related to the attempt to improve radiotherapy outcomes and, thus, to personalize the radiation treatment according to the individual characteristics of each patient. The evolution of ideas and the study of successively published data have led us to envisage new biophysical models for the interpretation of tumor and healthy normal tissue response to radiation. In the development of the model, we have shown that when mesenchymal stem cells (MSCs) and radiotherapy are administered simultaneously in experimental radiotherapy on xenotumors implanted in a murine model, the results of the treatment show the existence of a synergic mechanism that is able to enhance the local and systemic actions of the radiation both on the treated tumor and on its possible metastasis. We are convinced that, due to the physical hallmarks that characterize the neoplastic tissues, the physical-chemical tropism of MSCs, and the widespread functions of macromolecules, proteins, and exosomes released from activated MSCs, the combination of radiotherapy plus MSCs used intratumorally has the effect of counteracting the pro-tumorigenic and pro-metastatic signals that contribute to the growth, spread, and resistance of the tumor cells. Therefore, we have concluded that MSCs are appropriate for therapeutic use in a clinical trial for rectal cancer combined with radiotherapy, which we are going to start in the near future.

Exosomes derived from mesenchymal stem cells enhance radiotherapy-induced cell death in tumor and metastatic tumor foci.

BACKGROUND: We have recently shown that radiotherapy may not only be a successful local and regional treatment but, when combined with MSCs, may also be a novel systemic cancer therapy. This study aimed to investigate the role of exosomes derived from irradiated MSCs in the delay of tumor growth and metastasis after treatment with MSC + radiotherapy (RT). METHODS: We have measured tumor growth and metastasis formation, of subcutaneous human melanoma A375 xenografts on NOD/SCID-gamma mice, and the response of tumors to treatment with radiotherapy (2 Gy), mesenchymal cells (MSC), mesenchymal cells plus radiotherapy, and without any treatment. Using proteomic analysis, we studied the cargo of the exosomes released by the MSC treated with 2 Gy, compared with the cargo of exosomes released by MSC without treatment. RESULTS: The tumor cell loss rates found after treatment with the combination of MSC and RT and for exclusive RT, were: 44.4% % and 12,1%, respectively. Concomitant and adjuvant use of RT and MSC, increased the mice surviving time 22,5% in this group, with regard to the group of mice treated with exclusive RT and in a 45,3% respect control group. Moreover, the number of metastatic foci found in the internal organs of the mice treated with MSC + RT was 60% less than the mice group treated with RT alone. We reasoned that the exosome secreted by the MSC, could be implicated in tumor growth delay and metastasis control after treatment. CONCLUSIONS: Our results show that exosomes derived form MSCs, combined with radiotherapy, are determinant in the enhancement of radiation effects observed in the control of metastatic spread of melanoma cells and suggest that exosome-derived factors could be involved in the bystander, and abscopal effects found after treatment of the tumors with RT plus MSC. Radiotherapy itself may not be systemic, although it might contribute to a systemic effect when used in combination with mesenchymal stem cells owing the ability of irradiated MSCs-derived exosomes to increase the control of tumor growth and metastasis.

Naloxegol to Treat Constipation in a Patient Taking Opioids for Cancer Pain: A Case Report.

Opioid-induced constipation (OIC) is a common gastrointestinal adverse effect of opioids, which can severely affect compliance and adherence to pain medication regimens and quality of life. Naloxegol has demonstrated efficacy against OIC in several studies involving patients with nonmalignant chronic pain. Here we report efficacy and tolerability of naloxegol in a 68-year-old patient with metastatic lung cancer and severe pain, treated with opioids, who presented with OIC resistant to traditional measures. Addition of naloxegol produced rapid improvement in his OIC symptoms and no apparent adverse effects while taking extended-release morphine 130 mg orally every 12 hours.

Pattern of use of radiotherapy for lung cancer: a descriptive study.

BACKGROUND: Lung cancer remains one of the most prevalent forms of cancer. Radiotherapy, with or without other therapeutic modalities, is an effective treatment. Our objective was to report on the use of radiotherapy for lung cancer, its variability in our region, and to compare our results with the previous study done in 2004 (VARA-I) in our region and with other published data. METHODS: We reviewed the clinical records and radiotherapy treatment sheets of all patients undergoing radiotherapy for lung cancer during 2007 in the 12 public hospitals in Andalusia, an autonomous region of Spain. Data were gathered on hospital, patient type and histological type, radiotherapy treatment characteristics, and tumor stage. RESULTS: 610 patients underwent initial radiotherapy. 37% of cases had stage III squamous cell lung cancer and were treated with radical therapy. 81% of patients with non-small and small cell lung cancer were treated with concomitant chemo-radiotherapy and the administered total dose was ≥60 Gy and ≥45 Gy respectively. The most common regimen for patients treated with palliative intent (44.6%) was 30 Gy. The total irradiation rate was 19.6% with significant differences among provinces (range, 8.5-25.6%; p<0.001). These differences were significantly correlated with the geographical distribution of radiation oncologists (r=0.78; p=0.02). Our results were similar to other published data and previous study VARA-I. CONCLUSIONS: Our results shows no differences according to the other published data and data gathered in the study VARA-I. There is still wide variability in the application of radiotherapy for lung cancer in our setting that significantly correlates with the geographical distribution of radiation oncologists.

Underuse of radiotherapy in lung cancer has negative consequences for patients.

INTRODUCTION: Radiotherapy has proven to be an effective treatment when used alone or with other therapies. However, underuse of radiotherapy has been observed in various studies. The objective of this investigation was to assess the use of radiotherapy as initial treatment for lung cancer in a southern region of Europe. METHODS: A systematic review of lung cancer treatment guidelines and observational studies was performed to estimate expected radiation rates and the associated survival outcomes. We then reviewed the clinical and treatment records of all patients undergoing radiotherapy for lung cancer during 2007 in all the 12 public hospitals in Andalusia with radiotherapy facilities. Data were grouped according to type of hospital, patient, treatment characteristics, histological type, and tumor stage. RESULTS: In 2007, of the 3051 patients estimated to be diagnosed with lung cancer, 610 were treated with initial radiotherapy with an overall radiation rate of 20%, which significantly differed among provinces (range, 8.5%-25.6%, p < 0.001). Given the expected radiation rate of 1383 patients, 773 more patients of lung cancer (25%) should have been treated. According to the literature, the maximum increased survival attributable to the use of radiotherapy in patients diagnosed with non-small-cell lung cancer ranges from 1.8 to 14.1 months. The underuse estimated in the region would correspond to a loss of more than 3000 months in survival time. CONCLUSIONS: The observed underuse of radiotherapy in lung cancer in our region should be a matter of concern, given its negative and measurable impact on the survival of the patients.

Sarcoma de Ewing costal / Costal Ewing Sarcoma

The Sarcomas Ewing/PNET is highly aggressive and both tumors present/display he himself phantom of genetic anomalies reason for which the term of “Tumors of the family of sarcoma of Ewing is used (TFSE)” that includes to a group of tumors with a phantom of neuroectodermic differentiation. Case of feminine adolescent of eleven years, that referred sharp pain, in hemitorax appears left, in Rx of the thorax heterogenous dense image of diffuse edges projected on third basal means in left pulmonary field received antibiotics, remained asymptomatic up to eight months later when chest pain reappeared, made Rx of the thorax where demonstrate at level of the eighth costal arc bony erosion, in addition to the image previously described to greater size. Normal physical examinations. normal examinations of laboratory, computerized axial Tomography of the chest demonstrate bony erosion, and commitment of the local pleura biopsy of the injury reported: “Malignant Tumor of round cells, extensive necrosis”. Bony scintygraphy indicated osteoblastic activity altered in D8, suggestive of secondary bony infiltration. Made resection of tumor like injury in chest wall with reconstruction, positioning of prosthesis and central catheter biopsy of bony Marrow: refusal. The morphologic and inmunohistochemical findings with positivity for compatible FLy and CD99 with tumor of the family of sarcoma of Ewing/primtive neuroectodermic tumor. At the moment in treatment programmed with standard chemotherapy every 21 days X-ray in week 12.

Los Sarcomas Ewing/PNET son altamente agresivos y ambos tumores presentan el mismo espectro de anomalías genéticas razón por la que se usa el término de “Tumores de la familia del sarcoma de Ewing (TFSE)” que abarca a un grupo de tumores con un espectro de diferenciación neuroectodérmica. Se presenta caso de adolescente femenina de once años, quien refirió dolor punzante, en hemitorax izquierdo, en Rx del tórax imagen densa heterogénea de bordes difusos proyectada sobre tercio medio basal en campo pulmonar izquierdo. Recibió antibióticos, permaneció asintomática hasta ocho meses después cuando reapareció dolor torácico, y en Rx del tórax se evidencio a nivel del octavo arco costal erosión ósea, además de la imagen anteriormente descrita de mayor tamaño. Examen físico y de laboratorios fueron normales, en Tomografía axial computarizada del tórax se evidencio erosión ósea, y compromiso de la pleura local. Biopsia de la lesión reportó: “Tumor maligno de células redondas, extensa necrosis”. Gammagrama Óseo señaló actividad osteoblástica alterada en D8 sugestivo de infiltración ósea secundaria. Se realizó resección de lesión tumoral, reconstrucción, colocación de prótesis, catéter central biopsia de Médula ósea: negativa. Los hallazgos morfológicos e inmunohistoquímicos con positividad para FLy y CD99 compatible con tumor de la familia del sarcoma de Ewing/tumor neuroectodérmico primitivo. Actualmente en tratamiento programado con quimioterapia estándar cada 21 días Radioterapia en la semana 12.

Use of palliative radiotherapy in brain and bone metastases (VARA II study).

INTRODUCTION: Metastases are detected in 20% of patients with solid tumours at diagnosis and a further 30% after diagnosis. Radiation therapy (RT) has proven effective in bone (BM) and brain (BrM) metastases. The objective of this study was to analyze the variability of RT utilization rates in clinical practice and the accessibility to medical technology in our region. PATIENTS AND METHODS: We reviewed the clinical records and RT treatment sheets of all patients undergoing RT for BM and/or BrM during 2007 in the 12 public hospitals in an autonomous region of Spain. Data were gathered on hospital type, patient type and RT treatment characteristics. Calculation of the rate of RT use was based on the cancer incidence and the number of RT treatments for BM, BrM and all cancer sites. RESULTS: Out of the 9319 patients undergoing RT during 2007 for cancer at any site, 1242 (13.3%; inter-hospital range, 26.3%) received RT for BM (n = 744) or BrM (n = 498). These 1242 patients represented 79% of all RT treatments with palliative intent, and the most frequent primary tumours were in lung, breast, prostate or digestive system. No significant difference between BM and BrM groups were observed in: mean age (62 vs. 59 yrs, respectively); gender (approximately 64% male and 36% female in both); performance status (ECOG 0-1 in 70 vs. 71%); or mean distance from hospital (36 vs. 28.6 km) or time from consultation to RT treatment (13 vs. 14.3 days). RT regimens differed among hospitals and between patient groups: 10 × 300 cGy, 5 × 400 cGy and 1x800cGy were applied in 32, 27 and 25%, respectively, of BM patients, whereas 10 × 300cGy was used in 49% of BrM patients. CONCLUSIONS: Palliative RT use in BM and BrM is high and close to the expected rate, unlike the global rate of RT application for all cancers in our setting. Differences in RT schedules among hospitals may reflect variability in clinical practice among the medical teams.

Cluster K mycobacteriophages: insights into the evolutionary origins of mycobacteriophage TM4.

Five newly isolated mycobacteriophages--Angelica, CrimD, Adephagia, Anaya, and Pixie--have similar genomic architectures to mycobacteriophage TM4, a previously characterized phage that is widely used in mycobacterial genetics. The nucleotide sequence similarities warrant grouping these into Cluster K, with subdivision into three subclusters: K1, K2, and K3. Although the overall genome architectures of these phages are similar, TM4 appears to have lost at least two segments of its genome, a central region containing the integration apparatus, and a segment at the right end. This suggests that TM4 is a recent derivative of a temperate parent, resolving a long-standing conundrum about its biology, in that it was reportedly recovered from a lysogenic strain of Mycobacterium avium, but it is not capable of forming lysogens in any mycobacterial host. Like TM4, all of the Cluster K phages infect both fast- and slow-growing mycobacteria, and all of them--with the exception of TM4--form stable lysogens in both Mycobacterium smegmatis and Mycobacterium tuberculosis; immunity assays show that all five of these phages share the same immune specificity. TM4 infects these lysogens suggesting that it was either derived from a heteroimmune temperate parent or that it has acquired a virulent phenotype. We have also characterized a widely-used conditionally replicating derivative of TM4 and identified mutations conferring the temperature-sensitive phenotype. All of the Cluster K phages contain a series of well conserved 13 bp repeats associated with the translation initiation sites of a subset of the genes; approximately one half of these contain an additional sequence feature composed of imperfectly conserved 17 bp inverted repeats separated by a variable spacer. The K1 phages integrate into the host tmRNA and the Cluster K phages represent potential new tools for the genetics of M. tuberculosis and related species.

Dependencia temporal del valor pronóstico de los receptores esteroides en el cáncer de mama / Temporary dependency of steroid-receptor prognostic value in breast cancer

FUNDAMENTO: La influencia de los factores pronósticos en el cáncer de mama presenta variaciones temporales a lo largo de su seguimiento. Nuestro objetivo fue valorar los cambios acontecidos en el riesgo relativo de recurrencia aportado por los receptores esteroides. PACIENTES Y MÉTODO: Estudiamos a 455 pacientes con cáncer de mama primario operable de las que se determinaron parámetros clínicos, histopatológicos y los receptores de estrógeno (RE) y progesterona (RPg), con un seguimiento medio de 72 meses (intervalo, 42-130 meses), valorando su significación pronóstica en la supervivencia libre de enfermedad (SLE) y supervivencia global (SG) mediante un análisis multivariante proporcional y modelo de regresión no proporcional de Cox (dependiente del tiempo). RESULTADOS: El 66,8 por ciento de las pacientes resultaron RE+ y un 54,7 por ciento RPg+. Encontramos una alta asociación de ambos receptores con el grado histológico, permeación linfática-venosa, estado menopáusico e índice de mitosis. No observamos tal asociación con el tamaño, invasión ganglionar axilar y estadio del tumor. En el análisis univariable, el fenotipo RE-/RPg- frente a RE+/RPg+ presentó un riesgo relativo de 2,15 (IC del 95 por ciento, 1,59-2,99) en SLE (p = 0,001) y 1,95 (IC del 95 por ciento, 1,38-2,59) en SG (p = 0,0043). En el análisis multivariante, el fenotipo RE-/RPg- frente a RE+/RPg+ fue un factor pronóstico independiente junto con el grado de invasión ganglionar axilar y el índice de mitosis, tanto para la SLE como la SG. En el modelo dependiente del tiempo, las pacientes RE-/RPg- presentaron un riesgo relativo de recidiva 5,6 veces superior a las pacientes RE+/RPg+ al iniciar el seguimiento, que decreció durante los 4 primeros años hasta converger. CONCLUSIONES: En pacientes con cáncer de mama el fenotipo del receptor esteroide tiene un valor pronóstico relativo, cuya significación disminuye con el tiempo (AU)