Survival of patients living with HIV and cancer in Cali, Colombia

Background: People living with HIV have an increased risk of cancer compared to the general population. However, with the increase in life expectancy and advances in antiretroviral therapy, the survival of patients with cancer and HIV has changed. Objective: To determine the survival of patients living with HIV and cancer in Cali, Colombia Methods: A retrospective cohort study was conducted at the Fundación Valle del Lili, Cali, Colombia. Data from the HIV database was crossed with data from the hospital and population-based cancer registries between 2011-2019. Patients <18 years, limited available clinical information on the diagnosis and treatment of HIV and cancer, and non-oncological tumor diagnosis were excluded. Results: A total of 173 patients were included. The frequencies of AIDS-defining neoplasms were: Non-Hodgkin lymphoma (42.8%), Kaposi sarcoma (27.8%), and cervical cancer (4.6%). Overall survival was 76.4% (95% CI 68.9-82.3) at five years. Poorer survival was found in patients with AIDS-defining infections (56.9% vs. 77.8%, p=0.027) and non-AIDS-defining infections (57.8% vs. 84.2%, p=0.013), while there was better survival in patients who received antiretroviral therapy (65.9% vs. 17.9%, p=0.021) and oncological treatment (66.7% vs. 35.4%, p<0.001). The presence of non-AIDS-defining infections increases the risk of dying (HR = 2.39, 95% CI 1.05-5.46, p=0.038), while oncological treatment decreases it (HR = 0.33, 95% CI 0.14-0.80, p=0.014). Conclusions: In people living with HIV, Non-Hodgkin lymphoma and Kaposi sarcoma are the most common neoplasms. Factors such as AIDS-associated and non-AIDS-associated infections have been identified as determinants of survival. Cancer treatment seems to improve survival.

Antecedentes: Las personas que viven con VIH tienen un riesgo mayor de cáncer en comparación con la población general. Sin embargo, con el aumento de la esperanza de vida y los avances en la terapia antirretroviral, la supervivencia de los pacientes con cáncer y VIH ha cambiado. Objetivo: Determinar la supervivencia de los pacientes que viven con VIH y cáncer en Cali, Colombia. Métodos: Se realizó un estudio de cohorte retrospectivo en la Fundación Valle del Lili, Cali, Colombia. Los datos de la base de datos de VIH se cruzaron con los datos de los registros de cáncer de base hospitalaria y poblacional entre 2011-2019. Se excluyeron los pacientes <18 años, con información clínica limitada disponible sobre el diagnóstico y tratamiento del VIH y el cáncer y los casos con diagnóstico de tumor no oncológico. Resultados: Se incluyeron un total de 173 pacientes. Las frecuencias de neoplasias definitorias de SIDA fueron: linfoma no Hodgkin (42.8%), sarcoma de Kaposi (27.8%) y cáncer cervical (4.6%). La supervivencia global fue del 76.4% (IC 95% 68.9-82.3) a los cinco años. Se encontró una peor supervivencia en pacientes con infecciones definitorias de SIDA (56.9% vs. 77.8%, p=0.027) e infecciones no definitorias de SIDA (57.8% vs. 84.2%, p=0.013), mientras que hubo una mejor supervivencia en pacientes que recibieron terapia antirretroviral (65.9% vs. 17.9%, p=0.021) y tratamiento oncológico (66.7% vs. 35.4%, p<0.001). La presencia de infecciones no definitorias de SIDA aumentó el riesgo de morir (HR = 2.39, IC 95% 1.05-5.46, p=0.038), mientras que el tratamiento oncológico lo disminuyó (HR = 0.33, IC 95% 0.14-0.80, p=0.014). Conclusiones: En las personas que viven con VIH, el linfoma no Hodgkin y el sarcoma de Kaposi son las neoplasias más comunes. Se han identificado factores como las infecciones asociadas al SIDA y las infecciones no asociadas al SIDA como determinantes de la supervivencia. El tratamiento del cáncer parece mejorar la supervivencia.

Diagnostic and Therapeutic Strategy Updates of Rare Oncogenic Mutations in Chinese Society of Clinical Oncology Guidelines on Diagnosis and Treatment of Non-small Cell Lung Cancer (2023 Edition) / 肿瘤防治研究

The Chinese Society of Clinical Oncology (CSCO) issued the new version of the guidelines on diagnosis and treatment of NSCLC in April 2023.The new version updated the diagnostic and therapeutic strategy of rare oncogenic mutations, including ROS1 fusion, BRAF V600E mutation, NTRK fusion, MET exon 14 skipping mutation, RET fusion, and EGFR exon 20 insertion mutation, in NSCLC.This review will interpret the most important updates in the guidelines 2023 regarding the diagnosis as well as first-line and post-line therapies of these rare oncogenic mutations.

Distribución de virus de papiloma humano de alto riesgo oncogénico y otras infecciones de transmisión sexual en mujeres paraguayas con y sin virus de la inmunodeficiencia humana

El virus de papiloma humano de alto riesgo oncogénico (VPH-AR) es causa necesaria pero no suficiente para la ocurrencia de cáncer de cuello uterino (CCU). Mujeres portadoras del virus de inmunodeficiencia humana (VIH) presentan mayor riesgo de desarrollar lesiones precursoras del cáncer de cuello de útero, por ello, el objetivo del presente trabajo prospectivo de corte transversal fue determinar la frecuencia de VPH-AR y otras infecciones de transmisión sexual-ITS (condilomas, sífilis, virus del herpes simple, gonorrea, citomegalovirus, hepatitis B) en 218 mujeres con y sin VIH que acudieron al Programa Nacional de Lucha contra el SIDA (PRONASIDA) desde julio 2017 hasta marzo 2021. Se encontró que 16/54 (29,6%) mujeres VIH-positivas presentaron infección por VPH-AR en comparación a 41/164 (25%) mujeres VIH-negativas (p>0,05). En relación a la edad, mujeres VIH positivas presentaron una frecuencia comparable de infección por VPH-AR (30 años 30,2%), a diferencia de mujeres VIH negativas donde hubo una disminución significativa de la infección por VPH-AR luego de los 30 años (30 años 18,8%, p= 0,028). Esto podría explicarse por la inmunosupresión observada en mujeres VIH positivas que podría favorecer infecciones persistentes, sugiriendo que deben ser controladas más cercanamente. Además, se observó mayor frecuencia de otras ITS en mujeres VIH positivas (29,6% vs 15,8%, p=0,026), lo cual sugiere que aparte del monitoreo más cercano, es fundamental fortalecer la educación sobre factores de riesgo para la ITS sobre todo VPH y VIH, así como la realización de prevención primaria por vacunación contra el VPH.

High-risk human papillomavirus (HPV-HR) is a necessary but not sufficient cause for cervical cancer (CC). Women carriers of human immunodeficiency virus (HIV) present an increased risk for the development of cervical cancer precursor lesions, therefore, the objective of the present prospective cross-sectional study was to determine the frequency of HPV-HR and other sexually transmitted infections-STIs (condylomas, syphilis, herpes simplex virus, gonorrhoea, cytomegalovirus, hepatitis B) in 218 women with and without HIV who attended the Ministry of Health from July 2017 to March 2021. It was found that 16/54 (29.6%) HIV-positive women had HPV infection compared to 41/164 (25%) HIV-negative women (p>0.05). In relation to age, HIV-positive women had a comparable frequency of HPV infection (30 years 30.2%), unlike HIV-negative women whom above 30 years of age presented a significant decrease in HPV-AR infection (30 years 18.8%, p:0.028). This could be explained by the immunosuppression observed in HIV-positive women which could favour persistent infections, suggesting that they should be controlled more closely. In addition, other STIs were observed to be more frequent in HIV-positive women (29.6% vs 15.8%, p:0.026), which suggests that apart from closer monitoring, it is essential to strengthen education on risk factors for STIs, especially HPV and HIV, as well as the implementation of primary prevention by vaccination against HPV.

Infecciones múltiples por Alphapapillomavirus, especie 9, en mujeres ecuatorianas con lesiones intraepiteliales y cáncer cervicouterino / Multiple infections by Alphapapillomavirus, specie 9, in Ecuadorian women with intraepithelial lesions and cervical cancer

Introducción: El significado biológico de las infecciones múltiples con virus del papiloma humano de alto riesgo oncogénico (VPH-AR), pertenecientes a la familia Alphapapillomavirus, en la carcinogénesis cervical aún es controversial. Objetivo: Proporcionar información sobre la circulación del VPH-AR del género Alphapapillomavirus-especie 9, e infecciones múltiples en mujeres ecuatorianas con lesiones intraepiteliales y cáncer cervicouterino (CaCU). Métodos: Se estudiaron 300 mujeres, residentes en la región Litoral del Ecuador. Se detectó la infección viral en muestras cervicales, mediante PCR anidada con cebadores genéricos MY09/11 y GP5/GP6. Los genotipos virales fueron identificados con el sistema comercial ANYPLEX II VPH28. La razón de prevalencia (RP) fue utilizada como medida de asociación entre las lesiones citológicas y las infecciones simples, múltiples o combinaciones de genotipos. Resultados: Se detectó VPH en el 92,00 % (276/300) de las mujeres, con frecuencias altas de infección por genotipos individuales, principalmente de alto riesgo oncogénico. Los VPH-AR más frecuentes fueron VPH58 (18,17 por ciento), 70 (8,64 por ciento), 53 (8,34 por ciento), 35 (7,45 por ciento), 16 (7,37 por ciento), 33 (6,55 por ciento), 31 (5,58 por ciento) y 18 (4,24 por ciento). En el 91,66 por ciento (253/276) de las muestras se detectaron infecciones múltiples, hasta con 13 tipos en una misma paciente, incluyendo varias especies del género Alphapapillomavirus. La combinación VPH16/VPH58 fue la más frecuente en lesiones de alto grado (RP = 2,9; p = 0,000), y la coinfección triple VPH16/VPH58/VPH70 predominó en las mujeres con CaCU (RP = 3,5; p = 0,007). Conclusión: Los resultados demuestran que la combinación VPH16/VPH58 del género Alphapapillomavirus, especie 9, podría ser un factor clave en la aparición de lesiones premalignas y su progresión hacia el CaCU(AU)

Introduction: It is still controversial the biological connotation of multiple infections with high-risk human papillomaviruses (hrHPV), that belong to the genus Alphapapillomavirus, for the cervical carcinogenesis. Objective: To provide information on the circulation of hrHPV, genus Alphapapillomavirus, specie 9, and the multiple infections in Ecuadorian women with intraepithelial lesions and cervical cancer. Methods: 300 women, from the coastal region of Ecuador, were screened. Viral infection was detected in cervix samples by nested PCR with MY09/11 and GP5/GP6 generic primers. Viral genotypes were identified using the commercial kit ANYPLEX II VPH28. The prevalence ratio (PR) was used to measure the association between cytological lesions and the simple, multiple or combined genotype infections. Results: Ninety-two percent of women (276/300) tested positive for HPV. Frequency of infection for single genotypes was high, mainly those of high oncogenic risk. The most frequent hrHPV genotypes were HPV58 (18.17 percent), 70 (8.64 percent), 53 (8.34 percent), 35 (7.45 percent), 16 (7.37 percent), 33 (6.55 percent), 31 (5.58 percent) and 18 (4.24 percent). In 91.66 percent (253/300) of the samples, multiple infections were detected, with up to 13 types in a single patient, including various species from the genus Alphapapillomavirus. The combination HPV16/HPV58 was the most frequent on high-grade lesions (PR = 2.9; p = 0,000), and HPV16/HPV58/HPV70 triple co-infection prevailed in women with cervical cancer (PR = 3.5; p = 0.007). Conclusions: The results evidence that the combination HPV16/HPV58, genus Alphapapillomavirus, specie 9, could be a key factor in the occurrence of premalignant lesions and their evolution into cervical cancer(AU)

Osteomalacia oncogénica secundaria a tumor mesenquimal fosfatúrico del pie / Oncogenic osteomalacia secondary to phosphaturic mesenchymal tumour of the foot

RESUMEN La osteomalacia oncogénica es un síndrome metabólico paraneoplásico caracterizado por hipofosfatemia debida a la pérdida renal de fosfato, con nivel bajo de vitamina D. Este trastorno está asociado con la liberación de factores fosfatúricos por células tumorales, especialmente el factor de crecimiento fibrolástico 23 (FGF23). Las neoplasias relacionadas con la osteomalacia oncogénica suelen ser tumores pequeños de linaje mesenquimatoso y pueden ser difíciles de localizar en algunos casos debido a su tamaño y ubicación poco accesible al examen físico. Presentamos a un paciente que desarrolló fracturas vertebrales y de cadera debido a osteomalacia oncogénica asociada con un tumor mesenquimatoso fosfatúrico del tejido graso profundo de la planta del pie, que finalmente se diagnosticó después de 3 años del inicio de los síntomas, cuando el tumor pudo ser localizado por el rastreo gammagráfico óseo con pentatreótido marcado con indio-111 y por las imágenes de resonancia magnética nuclear.

ABSTRACT Oncogenic osteomalacia is a paraneoplastic metabolic syndrome characterised by a low phosphates in the blood due to renal phosphate losses with inadequately normal or low vitamin D levels. This disorder is associated with the release of tumour cell-secreted phosphaturic factor, most notably fibroblast growth factor 23 (FGF-23). The neoplasms related to oncogenic osteomalacia are usually small tumours of mesenchymal lineage, and they may be difficult to locate in the physical examination in some cases, due to their size and inaccessible location. The case is presented of a patient who developed vertebral and hip fractures due to oncogenic osteomalacia associated with a phosphaturic mesenchymal tumour of the deep fat tissue in the sole of the foot. This was finally diagnosed after 3 years of the onset of symptoms after being located by bone scintigraphy with Indium-111 labelled pentetreotide and magnetic resonance imaging.

Novel agents targeting leukemia cells and immune microenvironment for prevention and treatment of relapse of acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation

Relapse remains the worst life-threatening complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with acute myeloid leukemia (AML), whose prognosis has been historically dismal. Given the rapid development of genomics and immunotherapies, the interference strategies for AML recurrence have been changing these years. More and more novel targeting agents that have received the U.S. Food and Drug Administration (FDA) approval for

Tumor-Induced Osteomalacia: A Case Study Of A Nasal Tumor

Oncogenous osteomalacia, which is also known as tumor-induced osteomalacia, is a condition where a neoplasm isassociated with systemic bone demineralization and renal phosphaturia. We report a case who presented with a bleedingnasal mass, generalized fatigue, and cramps in her leg. Excision was done, and histopathologically, it was diagnosed tobe a phosphaturic mesenchymal tumor. The cramps disappeared soon after surgery and she is on regular follow-up forthe past 2 years.

Melanoma transplants in "green" mice: Fluorescent cells in tumors are not equivalent to host-derived cells

Background: To examine the usefulness of green fluorescent protein (GFP) mice for studying the interactions between normal cells and tumor cells in a host, we used a melanoma model in such "green" mice [C57BL/6-Tg (CAG-EGFP)1Osb mice]. Mice were given a subcutaneous injection of B16-F10 cells, and the resultant primary tumors were removed. Then cells from individual tumors were cultured. Results: The proportion of EFGP+ cells was determined by fluorescence-activated cell sorting (FACS) and was 6.8% ± 3.2% (mean ± s.d.) on day 1 of culture, 0.6% ± 0.3% on day 2, and 0.02% ± 0.01% at day 7. In all cases, isolated cells grew at a constant rate, but fluorescence decreased over time and became undetectable on day 14. Cells were tested using PCR for the presence of an EGFP-specific sequence, and results were negative in all cases, thus indicating that the cells did not harbor the host's reporter gene. Cells were also tested for the presence of EGFP mRNA, which was consistently detected for 22 days after the start of culture. The tumorogenicity of the cultured cells was confirmed in GFP mice injected with cells from a selection of cultures. Conclusions: In a melanoma model in GFP mice, the detection of "green" cells in tumors was not equivalent to the detection of host-derived cells. Such "masking" was caused by a transient, but lasting, transfer of EGFP mRNA from the host's normal cells to tumor cells. Thus, an analysis of tumors postmortem by techniques that yield only a single snapshot can lead to incorrect interpretations and erroneous conclusions.

Relación entre el proceso evolutivo del ser humano y su predisposición al cáncer / Relationship between the human being evolutionary process and cancer predisposition

El cáncer se ha convertido en la primera causa de morbimortalidad en numerosos países. En las últimas décadas se ha asistido a un cambio en el paradigma conceptual de las enfermedades neoplásicas, que ahora se enfoca hacia la perspectiva ecológica-evolutiva de estas. Con el objetivo de analizar, con elementos actualizados, la relación entre el proceso evolutivo del ser humano y su predisposición al cáncer, se realizó una revisión sistemática de la literatura, a partir de tres bases de datos, Medline, Scopus, y SciELO. Se tuvieron en cuenta atributos de consistencia de los artículos revisados, se excluyeron los estudios con niveles IV y V de evidencia y los de calidad insuficiente. Las búsquedas acumuladas actuales sugieren la necesidad de ver a las diversas neoplasias desde la perspectiva de la dinámica de sistemas complejos y sus implicaciones evolutivas. El proceso evolutivo humano posee particularidades biosociales que le predisponen a sufrir tumores malignos. La postura bípeda incrementó vulnerabilidad al efecto oncogénico de las radiaciones ultravioletas. La conducta sexual incrementó el riesgo de contraer infecciones por virus oncogénicos. El paso a una predominantemente cárnica y la introducción de la cocción, se tradujo en la incorporación de agentes xenobióticos cuyo metabolismo deriva agentes carcinógenos. La postergación del envejecimiento humano devino en un mayor tiempo para el acúmulo de mutaciones. Las modificaciones en el patrón sexual y reproductivo en la mujer han influido en su predisposición al cáncer de mama. En la génesis poblacional del cáncer subyacen fundamentos biosociales vinculados al proceso evolutivo de la especie(AU)

Cancer has become the leading cause of morbidity and mortality in many countries. In recent decades there has been a change in the conceptual paradigm of neoplastic diseases, which now focuses on the ecological-evolutionary perspective of these. With the aim of analyzing, with updated elements, the relationship between the evolutionary process of the human being and his predisposition to cancer, a systematic review of the literature was made, based on three databases, Medline, Scopus, and SciELO. Consistency attributes of the reviewed articles were taken into account, studies with levels IV and V of evidence and those of insufficient quality were excluded. The current accumulated searches suggest the need to see the various neoplasms from the perspective of the dynamics of complex systems and their evolutionary implications. The human evolutionary process has biosocial peculiarities that predispose it to suffer malignant tumors. Bipedal posture increased vulnerability to the oncogenic effect of ultraviolet radiation. Sexual behavior increased the risk of contracting oncogenic virus infections. The transition to a predominantly meat and the introduction of cooking, resulted in the incorporation of xenobiotic agents whose metabolism derives carcinogens. The postponement of human aging became in a longer time for the accumulation of mutations. Modifications in the sexual and reproductive pattern in women have influenced their predisposition to breast cancer. In the population genesis of cancer underlying biosocial foundations linked to the evolutionary process of the species(AU)

Oncogene-Driven Metabolic Alterations in Cancer

Cancer is the leading cause of human deaths worldwide. Understanding the biology underlying the evolution of cancer is important for reducing the economic and social burden of cancer. In addition to genetic aberrations, recent studies demonstrate metabolic rewiring, such as aerobic glycolysis, glutamine dependency, accumulation of intermediates of glycolysis, and upregulation of lipid and amino acid synthesis, in several types of cancer to support their high demands on nutrients for building blocks and energy production. Moreover, oncogenic mutations are known to be associated with metabolic reprogramming in cancer, and these overall changes collectively influence tumor-microenvironment interactions and cancer progression. Accordingly, several agents targeting metabolic alterations in cancer have been extensively evaluated in preclinical and clinical settings. Additionally, metabolic reprogramming is considered a novel target to control cancers harboring un-targetable oncogenic alterations such as KRAS. Focusing on lung cancer, here, we highlight recent findings regarding metabolic rewiring in cancer, its association with oncogenic alterations, and therapeutic strategies to control deregulated metabolism in cancer.

Successful Localization Using ⁶⁸Ga-DOTATOC PET/CT of a Phosphaturic Mesenchymal Tumor Causing Osteomalacia in a Patient with Concurrent Follicular Lymphoma / 대한핵의학회잡지

Diagnosing tumor-induced osteomalacia is often challenging because conventional imaging modalities may fail to locate the responsible tumor. This report describes the ability of ⁶⁸Ga-DOTATOC PET/CT to successfully distinguish between the responsible phosphaturic mesenchymal tumor and concurrent lymphoma lesions. A 52-year-old man with bone pain for several years was diagnosed with a vitamin D-resistant hypophosphatemic osteomalacia. Whole body ¹⁸F-FDG PET/CT revealed multiple enlarged hypermetabolic lymph nodes in his bilateral cervical, axillary, mediastinal, abdominal, pelvic, and inguinal regions. Core needle biopsy of the right cervical lymph node confirmed the diagnosis of follicular lymphoma. However, lymphoma was not considered the cause of osteomalacia. ⁶⁸Ga-DOTATOC PET/CT before chemotherapy showed a small nodule with intensely increased uptake in the right inguinal region, which was distinguished from the other enlarged lymph nodes. The nodule was surgically removed and histopathologically consistent with phosphaturic mesenchymal tumor. After surgery, the patient's serum phosphorus and alkaline phosphatase levels normalized without nutritional supplement.

Current opinions on the viral etiology of leukemia / 中国肿瘤临床

Half a century ago,it was confirmed that leukemia could be induced by retroviruses in some animals.There are numerous en-dogenous retroviruses in the human genome.However,retrovirus-related human adult T-cell leukemia is only endemic in some local areas. Recently,an extensive study on apolipoprotein B mRNA editing enzyme catalytic polypeptide 3(APOBEC3)family members has revealed the resistance mechanism in human to retrovirus-induced leukemia.The Epstein-Barr virus is widely spread in the human population and exists as a latent infection in the human body for a long time.It is closely associated with the occurrence and development of some lymphomas and solid tumors,indicating its tumorigenicity.The relationship between other viral infections and leukemia/lymphoma remains unclear. The interaction may be mediated by complex,multistep,and indirect networks,which need to be further illuminated.

Clinical characteristics and treatment strategy of five phosphaturic mesenchymal tumors in hips / 中华骨科杂志

Objective To analyze the clinical characteristics and treatment strategy of phosphaturic mesenchymal tumors in hips.Methods From May 2017 to November 2017,five patients with phosphaturic mesenchymal tumors in hips,who treated in our hospital were retrospectively reviewed.The clinical manifestations,laboratory inspection,radiological examination,pathological examination and treatment were analyzed.Results Two male cases (40％) and 3 female (60％) were included.The overall age was 49～63 years old (average 54.40±5.37 years old).The course was 19～101 months (average 51.20±32.41months).Four cases of tumor were located in femoral head and 1 case was in femur intertrochanteric region.The maximum tumor diameter was 0.76～1.83 cm (average 1.28±0.39 cm).The early clinical manifestations of the patients were mainly non-specific bone pain or fatigue.The symptoms of the hip were not obvious.All patients had been misdiagnosed.After pathological frac-ture of the hip,the patient suffered from hip pain,thigh pain,fatigue,etc.,or limited hip function.The severe patients had a systemic multiple pathologic fractures.The serum phosphorus was lower than normal in preoperative period and recovered to normal level in 3-8 days after surgery.The postoperative ALP decreased significantly than preoperative in 4 patients and 1 case was slightly higher than preoperative.Preoperative 1,25-(OH)2-D3 and PTH were in normal range.99Tcm-octreotide (OCT) scan or 68Ga DOTA-TATE PET/CT can detect the disease.X-ray,CT and MRI can identify the lesions.The lesions of femoral head were basically under the joint surface,with a nodular change.Part of the tumor was infiltrating and close to the cortex.The pathology was mainly manifested as a large number of thin-walled vessels in the bone trabeculae.There were dense spindle cells or astrocytes between the blood vessels and the atypia is not obvious.Three patients were treated with total hip arthroplasty and two with segmental resection and bone graft.After surgical removal of the tumor,the patient's systemic pain or anemic symptoms were gradually relieved and the joint function was restored.Meanwhile,the bone density was increased.Conclusion The clinical features of the phosphaturic mesenchymal tumors in hips were not obvious.Comprehensive diagnosis should be carried out in combination with the clinical manifestations,laboratory examination,radiological examination and pathological examination.Total hip arthroplasty or segmental resection with bone graft can effectively remove the tumor and achieve good prognosis.

Tumor-induced osteomalacia

Tumor-induced osteomalacia (TIO), also known as oncogenic osteomalacia, is a rare paraneoplastic syndrome characterized by hypophosphatemia resulting from decreased tubular phosphate reabsorption, with a low or inappropriately normal level of active vitamin D. The culprit tumors of TIO could produce fibroblast growth factor 23 which plays a role in regulating renal Pi handling and 25-hydroxyvitamin D 1α-hydroxylase activity. Chronic hypophosphatemia could eventually lead to inadequate bone mineralization, presenting as osteomalacia. The diagnosis should be considered when patients manifest as hypophosphatemia and osteomalacia, or rickets and needs to be differentiated from other disorders of phosphate metabolism, such as the inhereditary diseases like X-linked hypophosphataemic rickets, autosomal dominant hypophosphataemic rickets, autosomal recessive hypophosphataemic rickets and acquired diseases like vitamin D deficiency. Localization of responsible tumors could be rather difficult since the vast majority are very small and could be everywhere in the body. A combination of thorough physical examination, laboratory tests and imaging techniques should be applied and sometimes a venous sampling may come into handy. The technology of somatostatin-receptor functional scintigraphy markedly facilitates the localization of TIO tumor. Patients undergoing complete removal of the causative neoplasm generally have favorable prognoses while a few have been reported to suffer from recurrence and metastasis. For those undetectable or unresectable cases, phosphate supplements and active vitamin D should be administrated and curative intended radiotherapy or ablation is optional.

Phosphaturic mesenchymal tumor (PMT): exceptionally rare disease, yet crucial not to miss

Phosphaturic mesenchymal tumors (PMTs) are very rare tumors which are frequently associated with Tumor Induced Osteomalacia (TIO), a paraneoplastic syndrome that manifests as renal phosphate wasting. The tumor cells produce a peptide hormone-like substance known as fibroblast growth factor 23 (FGF23), a physiologic regulator of phosphate levels. FGF23 decreases proximal tubule reabsorption of phosphates and inhibits 1-α-hydroxylase, which reduces levels of 1-α, 25-dihydroxyvitamine D3. Thus, overexpression of FGF23 by the tumor cells leads to increased excretion of phosphate in the urine, mobilization of calcium and phosphate from bones, and the reduction of osteoblastic activity, ultimately resulting in widespread osteomalacia. Patients typically present with gradual muscular weakness and diffuse bone pain from pathologic fractures. The diagnosis is often delayed due to the non-specific nature of the symptoms and lack of clinical suspicion. While serum phosphorus and FGF23 testing can assist in making a clinical diagnosis of PMT, the responsible tumor is often difficult to locate. The pathologic diagnosis is often missed due to the rarity of PMTs and histologic overlap with other mesenchymal neoplasms. While patients can experience severe disabilities without treatment, excision is typically curative and results in a dramatic reversal of symptoms. Histologically, PMT has a variable appearance and can resemble other low grade mesenchymal tumors. Even though very few cases of PMT have been reported in the world literature, it is very important to consider this diagnosis in all patients with hypophosphatemic osteomalacia. Here we present a patient who suffered for almost 5 years without a diagnosis. Ultimately, the PMT was located on a 68Ga-DOTA TATE PET/CT scan and subsequently confirmed by histologic and immunohistologic study. Interestingly, strong positivity for FGFR1 by IHC might be related to the recently described FN1-FGFR1 fusion. Upon surgical removal, the patient's phosphate and FGF23 levels returned to normal and the patient's symptoms resolved.

Oncogenic Osteomalacia with Multiple Insufficiency Fractures: A Case Report

Oncogenic osteomalacia is a rare paraneoplastic syndrome, characterized by hypophosphatemia, renal phosphate wasting, osteomalacia, and multiple insufficiency fractures, as a result of the tumor. A wide excision of the causative tumor is considered as the treatment of choice, following which, a dramatic recovery is expected. Authors report a case in which the symptoms and bone mineral density were dramatically recovered after an excision of the causative tumor around the tibialis posterior muscle in oncogenic osteomalacia.

O papel da autofagia no estresse oncogênico promovido por HRASG12V em queratinócitos humanos imortalizados por E6E7 / The role of autophagy in the face of the oncogenic stress triggered by HRASG12V in human keratinocytes immortalized by E6E7

RAS é a oncoproteína mutada mais encontrada em tumores sólidos, o que mostra seu grande potencial transformador. Não obstante, células que carregam essa mutação apresentam estresse oncogênico gerado por excessiva sinalização mitogênica, o que direciona preferencialmente as células portadoras para a morte em detrimento da transformação maligna. Basicamente a transformação direcionadapela proteína RAS mutada age sinergicamente com deficiência em supressores de tumor para evitar o destino celular preferencial frente ao estresse oncogênico. Este é o caso da interação observada entre HRASG12V e E6E7 de HPV, sendo que a infecção pelo vírus aparentemente é condição necessária em cânceres cervicais e muito presente em cânceres de cabeça e pescoço. A sinergia entre HRASG12V e queratinócitos imortalizados por E6E7 desequilibra o balanço homeostático entre subsistemas pró-morte, devido ao estresse oncogênico, ou pró-sobrevivência, que garante viabilidade por meio de novos padrões de robustez celular. Em ambos os casos, o processo que gera uma célula transformada, ou as elimina pelo caminho, apresenta pistas de vulnerabilidades às quais os queratinócitos são expostos uma vez que carreguem tal combinação de fatores. Apresentamos nesse trabalho os principais atores que compõem o estresse oncogênico deletério desencadeado pela atividade de HRASG12V: estresse mitogênico, replicativo e oxidativo; todos eles são responsáveis por provocar dano no DNA, que por sua vez promove parada no ciclo celular até que as células não possam mais suportar tamanha injúria, o que acaba levando-as maciçamente a morte. Mostramos que a alta intensidade mitogênica gerada pela atividade de HRASG12V provoca um desequilíbrio metabólico que leva ao aumento de espécies oxidantes e ao estresse replicativo. Todavia, um tratamento exógeno com o antioxidante NAC restaurou parcialmente a proliferação celular assim como a sobrevivência, agindo como um amenizador do dano no DNA gerado pelas espécies oxidantes. Já uma suplementação com nucleosídeos exógenos restaurou fortemente a sobrevivência celular, sugerindo que o desequilíbrio metabólico pode estar agindo no pool de nucleotídeos, o que poderia ser uma das causas do estresse replicativo. Como mecanismo intrínseco de sobrevivência, a autofagia se intensifica em resposta ao desequilíbrio sistêmico desencadeado pela atividade de HRASG12V. Por meio de sublinhagens defectivas para autofagia, mostramos que o processo retarda o aparecimento de espécies oxidantes, além de evitar sua elevação a níveis ainda mais drásticos, o que consequentemente ameniza o dano no DNA observado. Além disso, hipotetizamos que o processo poderia também estar contribuindo fortemente para a reciclagem de substratos básicos tais como nucleotídeos, assim acarretando em menor estresse replicativo. Na literatura atual, debate-se a noção de que, dependendo do contexto celular, a autofagia poderia promover tanto morte celular como transformação maligna. Entretanto, nesta tese mostramos que, na interação entre queratinócitos, E6E7 e HRASG12V, a autofagia é um mecanismo pró-sobrevivência: se por um lado a demanda autofágica é recrutada além de sua capacidade de processamento, fazendo com que seu fluxo seja bloqueado, por outro a eliminação do sistema se torna demasiadamente deletério, direcionando as células expostas ao estresse oncogênico causado pela atividade de HRASG12V necessariamente à morte.

Mutated RAS is the oncoprotein most found in solid tumors, which shows its huge tumorogenic potential. Despite of that, mutated RAS triggers a strong oncogenic stress, which very often drives cells to death instead of malignant transformation. Basically, the success of the Ras malignant transformation driving activity depends on a synergy between that mutated protein and inhibition of tumor suppression genes. This is the case of the interaction between HRASG12V and E6E7 proteins of HPV: It seems that HPV infection is an initial necessary condition for cervical cancer development and is also very frequent in head and neck carcinomas. The synergy between HRASG12V and E6E7, in pre-malignant keratinocytes, imbalances the homeostasis between pro-death subsystems, due oncogenic stress, and pro-survival subsystems that ensure new patterns of cellular robustness. In both cases, the process responsible for generating a malignant transformed cell or, more frequently, eliminating those cells carrying the combined characteristics, exposes the keratinocytes vulnerabilities. We showed in this work that the main actors of deleterious oncogenic stress triggered by HRASG12V activity are: Mitogenic, replicative and oxidative stresses; all of them induce DNA damage, hence cell cycle arrests until the cell cannot resist such injury any further, which leads to massive cell death. The intense mitogenic activity triggered by HRASG12Vcauses metabolic imbalance, which is responsible for an increase of oxidative species and replicative stress levels; the exogenous treatment with antioxidant NAC partially restored cell growth and cell survival, acting as a softener of the DNA damage caused by oxidative species. On the other hand, nucleoside supplementation strongly restored cell survival, suggesting that the aforementioned metabolic imbalance might be acting in the pool of nucleotides, hence it might be a possible cause of replicative stress. As an intrinsic survival mechanism, the autophagy is intensified in response to systemic imbalance triggered by HRASG12V activity. Through the autophagy defective subline, we showed that that mechanism both delays the increase of oxidative species and avoids their elevation to catastrophic highlevels. Furthermore, autophagy could strongly contribute to the recycling of basic substrates such as nucleotides, which might be mitigating the replicative stress. Nowadays, there is a debate on the role of autophagy promoting either malignant transformation or cell death depending on metabolic context. In this work, we showed an instance of the interaction between E6E7 and HRASG12V triggering autophagy pro-survival mechanisms and hence increasing general cell viability

Visceral Marek's disease in white-peafowl (Pavo cristatus) / Doença de Marek visceral em pavão-branco (Pavo cristatus)

Marek's disease (MD) is a lymphoproliferative disorder caused by Gallid herpesvirus 2 (MDV) that infects mainly domestic gallinaceous birds although wild birds may occasionally be affected. The current report describes the anatomopathological and molecular findings of a case of MD in a white-peafowl (Pavo cristatus). The signs included apathy, hyporexia, and diarrhea. Grossly, 0.5 to 1.5cm in diameter, yellow, soft nodules were observed in the skeletal muscle, lung, kidney, air sacs, small intestine, heart, ovary, ventriculus, and proventriculus. Microscopically, numerous atypical round neoplastic cells were noted. The molecular detection of MDV DNA was implemented to amplify part of the meq gene and products were sequenced for the phylogenetic analysis. Template DNA was obtained from tissues of the affected bird and from blood of all the gallinaceous birds of the Zoo. The expected amplicon for the partial amplification of MDV meq gene was obtained and the amplicons were sequenced. Sequences obtained enabled grouping the strain (accession no. KT768121) with MDV serotype 1 strains from the GenBank. Based on the anatomopathological and molecular findings, the diagnosis of MD in a white-peafowl was reached, and to the authors' knowledge, no previous report regarding MD was published in Pavo cristatus.(AU)

Doença de Marek (MD) é uma desordem linfoproliferativa causada pelo Gallid herpesvirus 2 (MDV), que infecta principalmente galináceos domésticos, porém aves silvestres podem ser ocasionalmente afetadas. O presente relato descreve os achados anatomopatológicos e moleculares de um caso de MD em um pavão-branco (Pavo cristatus). Os sinais clínicos incluíram apatia, hiporexia e diarreia. Macroscopicamente, foram observados nódulos macios, de 0,5 a 1,5cm de diâmetro, no músculo esquelético, no pulmão, nos rins, nos sacos aéreos, no intestino delgado, no coração, no ovário, no ventrículo e no proventrículo. Microscopicamente, numerosas células redondas neoplásicas atípicas foram notadas. A detecção molecular do DNA do MDV foi implementada para amplificar parte do gene meq, e os produtos foram sequenciados para análise filogenética. DNA foi obtido de tecidos de aves afetadas e do sangue de todos os galináceos do zoológico. A esperada amplificação de parte do gene meq de MDV amplificado foi ampliada e sequenciada. As sequências obtidas permitiram o agrupamento da cepa (acesso KT768121) com cepas do sorotipo 1 de MDV do GenBank.. O diagnóstico de MD em pavão-branco foi obtido com base nos achados anatomopatológicos e moleculares e, pelo conhecimento dos autores, não há relatos anteriores publicados de MD em Pavo cristatus.(AU)

Micro RNAs and Non-Small Cell Lung Cancer

Non-small cell lung cancer is a major leading cause of cancer-related death and its late diagnosis/prognosis, accounting for the high rate of mortality. Presences of circulating microRNAs (miRNAs) in body fluids represent stable and reproducible biomarkers for several solid tumors, including non-small cell lung cancer. Micro RNAs have been categorized as oncogenic microRNAs and “tumor suppressor micro RNAs” and miRNAs activities may provide exciting opportunities for early cancer detection. There is an urgent need to find a less invasive and a more reliable biomarker which can increase the probability of early non-small cell lung cancer detection.

Prevalence of genital human papillomavirus among rural and urban populations in southern Yunnan province, China

This study was designed to investigate and compare the HPV prevalence, genotypes distribution and associated risk factors in rural and urban women living in Xishuang Banna district, in the province of Yunnan. A total of 177 and 190 women from rural and urban areas were engaged, respectively. HPV DNA was amplified using the L1 consensus primers system (MY09/11 and GP5/6) and HPV GenoArray test was conducted for genotyping. Proportions were compared by chi-square test, and logistic regression was used to evaluate risk factors. A total of 54 women were positive for HPV DNA. Among rural women, 23 women were positive for HPV infection, of which 21 showed a single infection and 2 had a multiple infection. HPV-16 (10/23) was the most prevalent genotype followed by HPV-52 (5/23), and HPV-58 (5/23). Urban women had a higher infection rate for overall HPV (31/54) and for multiple genotype infection (8/31). HPV-52 (9/31) was the most prevalent genotype followed by HPV-39 (7/31) and HPV-68 (5/31). The age-specific HPV prevalence was also different between rural and urban women. In urban area, women with age <35 years had the highest HPV prevalence, which declined thereafter as age advanced. However, in rural women the highest HPV prevalence was observed in an older age group (>56 years). Ethnicity, smoking and parity were significantly associated with HPV infection among urban women. Our study demonstrates that HPV prevalence and genotype distribution varies among women from rural and urban areas in the south of Yunnan.