[Translated article] Changes in the Location of Cutaneous Melanoma Over the Past 30 Years. A Retrospective Observational Study.

BACKGROUND: The location of cutaneous melanoma is associated with photoexposure. OBJECTIVES: To retrospectively analyze changes in the location of cutaneous melanoma over the past 30 years. PATIENTS AND METHODS: All patients treated at our hospital for cutaneous melanoma from 1988 through 2017 were prospectively collected. Data obtained in cases diagnosed from 1988 through June 2006 were compared to those diagnosed from July 2006 through 2017. RESULTS: A total of 1,937 patients (876 men and 1061 women; median age, 57 years; interquartile range 27) were diagnosed with primary cutaneous melanoma. The location of melanoma was head and neck (470 cases), trunk (745 cases), upper limbs (239 cases), and lower limbs (483 cases). From July 2006 through 2017 we detected an increase in the incidence of head and neck melanomas (19.9% vs 28.6%, p <0.001). A drop in the incidence of melanomas located in the lower extremities was also seen in women (39.8% vs 30.4%, p <0.001), and in the trunk men (57.5% vs 47.3%, p=0.003). In the multivariate analyses, only the decrease in melanomas located in lower extremities in women remained significant. CONCLUSION: The increased incidence of head and neck melanomas in both sexes and the decrease in trunk melanomas in men can be attributed to the aging of our population. The reduction in the incidence of melanomas in the lower extremities in women could be associated with changes in photoexposure patterns. Analyzing the factors possibly associated with these changes would contribute to better understanding the pathogenesis of cutaneous melanoma for prevention purposes.

Changes in the Location of Cutaneous Melanoma Over the Past 30 Years. A Retrospective Observational Study. / Cambios en la localización del melanoma cutáneo en los últimos 30 años. Estudio observacional retrospectivo.

BACKGROUND: The location of cutaneous melanoma is associated with photoexposure. OBJECTIVES: To retrospectively analyze changes in the location of cutaneous melanoma over the past 30 years. PATIENTS AND METHODS: All patients treated at our hospital for cutaneous melanoma from 1988 through 2017 were prospectively collected. Data obtained in cases diagnosed from 1988 through June 2006 were compared to those diagnosed from July 2006 through 2017. RESULTS: A total of 1,937 patients (876 men and 1061 women; median age, 57 years; interquartile range 27) were diagnosed with primary cutaneous melanoma. The location of melanoma was head and neck (470 cases), trunk (745 cases), upper limbs (239 cases), and lower limbs (483 cases). From July 2006 through 2017 we detected an increase in the incidence of head and neck melanomas (19.9% vs 28.6%, p <0.001). A drop in the incidence of melanomas located in the lower extremities was also seen in women (39.8% vs 30.4%, p <0.001), and in the trunk men (57.5% vs 47.3%, p=0.003). In the multivariate analyses, only the decrease in melanomas located in lower extremities in women remained significant. CONCLUSION: The increased incidence of head and neck melanomas in both sexes and the decrease in trunk melanomas in men can be attributed to the aging of our population. The reduction in the incidence of melanomas in the lower extremities in women could be associated with changes in photoexposure patterns. Analyzing the factors possibly associated with these changes would contribute to better understanding the pathogenesis of cutaneous melanoma for prevention purposes.

Third molar surgical difficulty scales: systematic review and preoperative assessment form.

BACKGROUND: The main objective of this systematic review was to collect the pre-existing scales for assessing the difficulty of third molar extraction. The secondary objective was to design a proposal for a preoperative evaluation protocol for the difficulty of third molar extraction. MATERIAL AND METHODS: Two independent researchers conducted an electronic search in Pubmed (MEDLINE), Cochrane, and Scopus databases during March 2021. Included studies evaluated the prediction of the difficulty of surgical removal of impacted upper or lower third molars using new indices/scales or pre-existing scales with or without modifications. Articles referring to coronectomies or assessing pre-surgical difficulty using other tools were excluded. Neither language nor publication date restrictions were applied. RESULTS: Out of 242 articles, 13 prospective cohort studies were finally selected. Seven developed new indices/scales, and 6 assessed the predictive ability of some pre-existing scales. Most of the indices/scales contained radiological variables and few added any patient-related variables. We proposed a preoperative assessment protocol of the difficulty of third molar extraction to facilitate treatment planning and/or considerate referral in cases of high difficulty. This proposal used patient-related, radiological and surgical variables. CONCLUSIONS: Using a preoperative protocol to evaluate the surgical difficulty, including different patient-specific, radiological and surgical variables, could facilitate treatment planning, help clinicians prevent complications and assess the possibility of referral.

Bifid mandibular condyles: A systematic review.

BACKGROUND: Bifid mandibular condyle (BMC) constitutes an extremely rare disorder characterized by a duplication of the head of the mandibular condyle. Its prevalence ranges from 0.31% to 1.82% in the published literature. OBJECTIVES: The primary objective was to describe the main etiological, clinical and radiological characteristics of patients with BMCs and the existent treatment options. The secondary objective was to simultaneously include the characteristics of two new cases of BMC. MATERIAL AND METHODS: An electronic search in Pubmed (MEDLINE), Scopus and The Cochrane Library was carried out by two independent reviewers until April 2018. Prospective or retrospective cohort studies, case series and case reports describing clinical and/or radiological characteristics of patients with BMC were included. Registered variables were demographic, etiological factors, diagnostic exam, clinical characteristics and treatment options. The results from the articles selected were organized in a Table along with the characteristics of two new cases of BMC provided by the authors. RESULTS: From a total of 431 articles found in the initial search, 68 articles were finally included. This systematic review included 216 patients and 270 BMC with an average age of 30.6 (SD=14.7) years and a women:men ratio of 1.4:1. Mediolateral condylar orientation was the most prevalent position (80.1%). Among cases with known etiology, 40.8% of cases had a history of traumatism, while 55.9% did not present any relevant medical background. Half of the symptomatic cases had history of trauma. The most common symptoms were hypomobility (22.7%), arthralgia (18.1%), articular noise (17.2%) and ankylosis (17.6%). Active monitoring and manufacturing an occlusal splint were the most frequent treatment options. CONCLUSIONS: BMC may have congenital or traumatic etiology. Hypomobility and arthralgia are the most frequent symptoms and treatment options are often conservative.

Sustained high serum caspase-3 concentrations and mortality in septic patients.

Caspase-3 is the main executor of the apoptotic process. Higher serum caspase-3 concentrations in non-survivor compared to survivor septic patients have been found. The objectives of this work (with the increase of sample size to 308 patients, and the determination of serum caspase-3 concentrations also on days 4 and 8 of diagnosis of severe sepsis) were to know whether an association between serum caspase-3 concentrationss during the first week, degree of apoptosis, sepsis severity, and sepsis mortality exists. We collected serum samples of 308 patients with severe sepsis from eight intensive care units on days 1, 4 and 8 to measure concentrations of caspase-3 and caspase-cleaved cytokeratin (CCCK)-18 (to assess degree of apoptosis). End point was 30-day mortality. We found higher serum concentrations of caspase-3 and CCCK-18 in non-survivors compared to survivors on days 1 (p < 0.001), 4 (p < 0.001), and 8 (p < 0.001). We found an association between serum caspase-3 concentrations on days 1, 4 and 8 of severe sepsis diagnosis and serum CCCK-18 concentrations (p < 0.001), SOFA (p < 0.001), serum acid lactic concentrations (p < 0.001), and 30-day sepsis mortality (p < 0.001). The new findings of this work were that an association between serum caspase-3 concentrations during the first week, apoptosis degree, sepsis severity, and sepsis mortality exists.

Ligand-dependent Hedgehog pathway activation in Rhabdomyosarcoma: the oncogenic role of the ligands.

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common type of soft tissue sarcoma in children. The Hedgehog (HH) pathway is known to develop an oncogenic role in RMS. However, the molecular mechanism that drives activation of the pathway in RMS is not well understood. METHODS: The expression of HH ligands was studied by qPCR, western blot and immunohistochemistry. Functional and animal model studies were carried out with cells transduced with shRNAs against HH ligands or treated with HH-specific inhibitors (Vismodegib and MEDI-5304). Finally, the molecular characterisation of an off-target effect of Vismodegib was also made. RESULTS: The results showed a prominent expression of HH ligands supporting an autocrine ligand-dependent activation of the pathway. A comparison of pharmacologic Smoothened inhibition (Vismodegib) and HH ligand blocking (MEDI-5304) is also provided. Interestingly, a first description of pernicious off-target effect of Vismodegib is also reported. CONCLUSIONS: The clarification of the HH pathway activation mechanism in RMS opens a door for targeted therapies against HH ligands as a possible alternative in the future development of better treatment protocols. Moreover, the description of a pernicious off-target effect of Vismodegib, via unfolded protein response activation, may mechanistically explain its previously reported inefficiency in several ligand-dependent cancers.

MYCN repression of Lifeguard/FAIM2 enhances neuroblastoma aggressiveness.

Neuroblastoma (NBL) is the most common solid tumor in infants and accounts for 15% of all pediatric cancer deaths. Several risk factors predict NBL outcome: age at the time of diagnosis, stage, chromosome alterations and MYCN (V-Myc Avian Myelocytomatosis Viral Oncogene Neuroblastoma-Derived Homolog) amplification, which characterizes the subset of the most aggressive NBLs with an overall survival below 30%. MYCN-amplified tumors develop exceptional chemoresistance and metastatic capacity. These properties have been linked to defects in the apoptotic machinery, either by silencing components of the extrinsic apoptotic pathway (e.g. caspase-8) or by overexpression of antiapoptotic regulators (e.g. Bcl-2, Mcl-1 or FLIP). Very little is known on the implication of death receptors and their antagonists in NBL. In this work, the expression levels of several death receptor antagonists were analyzed in multiple human NBL data sets. We report that Lifeguard (LFG/FAIM2 (Fas apoptosis inhibitory molecule 2)/NMP35) is downregulated in the most aggressive and undifferentiated tumors. Intringuingly, although LFG has been initially characterized as an antiapoptotic protein, we have found a new association with NBL differentiation. Moreover, LFG repression resulted in reduced cell adhesion, increased sphere growth and enhanced migration, thus conferring a higher metastatic capacity to NBL cells. Furthermore, LFG expression was found to be directly repressed by MYCN at the transcriptional level. Our data, which support a new functional role for a hitherto undiscovered MYCN target, provide a new link between MYCN overexpression and increased NBL metastatic properties.

Patterns of visceral metastasis in cutaneous melanoma: a descriptive study.

BACKGROUND AND OBJECTIVES: Some types of cancer tend to spread to certain organs. In the case of melanoma, uveal melanoma spreads almost exclusively to the liver, while cutaneous melanoma spreads to the liver and other organs. Although important advances have been made in our understanding of the molecular mechanisms underlying melanoma, few recent studies have focused on the patterns of visceral metastasis in cutaneous melanoma. The aim of this study was to retrospectively investigate whether clinicopathologic variants of cutaneous melanoma and primary tumor site might be associated with pattern and time of onset of metastasis to visceral sites, including the central nervous system (CNS). MATERIALS AND METHODS: We included patients diagnosed with cutaneous melanoma between 1988 and 2009 with at least 2 years' follow-up. RESULTS: Of the 1083 patients studied, 92 developed visceral metastasis. The CNS was affected in 21 cases, the lungs in 24, the liver in 17, the digestive tract in 7, and multiple organs simultaneously in 23. Metastasis to the lungs, the liver, and the digestive tract occurred within 5 years in most cases, while metastasis to the CNS and multiple organs occurred later (>5 years in 38% and 43% of cases, respectively). CONCLUSIONS: Unlike uveal melanoma, cutaneous melanoma spreads to different organs without any particular predilection. We observed no significant associations between the site of visceral metastasis and either clinicopathologic variant or location of the primary tumor. Metastasis occurred within 5 years of diagnosis in most cases, but it can occur after 10 years.

Targeting the voltage-dependent K(+) channels Kv1.3 and Kv1.5 as tumor biomarkers for cancer detection and prevention.

Potassium channels (KCh) are a diverse group of membrane proteins that participate in the control of the membrane potential. More than eighty different KCh genes have been identified, which are expressed in virtually all living cells. In addition to nerve and cardiac action potentials, these proteins are involved in a number of physiological processes, including cell volume regulation, apoptosis, immunomodulation and differentiation. Furthermore, many KCh have been reported to play a role in proliferation and cell cycle progression in mammalian cells, and an important number of studies report the involvement of KCh in cancer progression. The voltage dependent potassium (Kv) channels, in turn, form the largest family of human KCh, which comprises about 40 genes. Because Kv1.3 and Kv1.5 channels modulate proliferation of different mammalian cells, these proteins have been analyzed in a number of tumors and cancer cells. In most cancers, the expression patterns of Kv1.3 and Kv1.5 are remodeled, and in some cases, a correlation has been established between protein abundance and grade of tumor malignancy. The list of cancers evaluated is constantly growing, indicating that these proteins may be future targets for treatment. The aim of this review is to provide an updated overview of Kv1.3 and Kv1.5 channels during cancer development. Unlike Kv1.5, Kv1.3 is characterized by a very selective and potent pharmacology, which could lead to specific pharmacological targeting. Because potassium channels may play a pivotal role in tumor cell proliferation, these proteins should be taken into account when designing new cancer treatment strategies.

[Descriptive analysis of cutaneous recurrence patterns in patients with melanoma]. / Análisis descriptivo de los patrones de recidiva cutánea en los pacientes con melanoma.

BACKGROUND AND OBJECTIVES: Few studies have addressed cutaneous recurrence of melanoma. The aim of this retrospective study was to analyze the characteristics and prognostic significance of the different patterns of cutaneous recurrence. MATERIAL AND METHODS: Patients diagnosed with melanoma between 1988 and 2008 at Hospital de Bellvitge, Barcelona, Spain and for whom data were available for at least 2 years of follow-up were included in the study. Local recurrence was defined as melanoma invasion of the skin adjacent to the scar left by excision of the primary tumor, regional metastasis or recurrence as metastasis restricted to the area drained by a regional lymph node station, and distant cutaneous metastasis as metastasis occurring outside this area. The relationship between cutaneous recurrence pattern and age, sex, primary tumor site, tumor subtype, Breslow depth, and ulceration was assessed. RESULTS: Eighty-five out of 1,080 patients (7.87%) had cutaneous recurrence. In 71 of those patients (83.53%; 27 men and 44 women; mean age, 60.68 years), this was the first indication of melanoma recurrence. Thirty-two patients had local recurrence, 32 regional metastasis, and 7 distant metastasis. Significant differences were observed in survival time from diagnosis of the primary tumor (P=.044) and from diagnosis of cutaneous recurrence (P<.001) according to the type of recurrence. CONCLUSIONS: Our results suggest that the pattern of cutaneous recurrence is prognostically significant and related to the site of the primary tumor given that the majority of local and regional recurrences occurred in primary tumors located on the lower limbs and head.

Voltage-dependent potassium channels Kv1.3 and Kv1.5 in human cancer.

Membrane ion channels participate in cancerous processes such as proliferation, migration and invasion, which contribute to metastasis. Increasing evidence indicates that voltage-dependent K(+) (Kv) channels are involved in the proliferation of many types of cells, including tumor cells. Kv channels have generated immense interest as a promising tool for developing new anti-tumor therapies. Therefore, the identification of potential biomarkers and therapeutic targets in specific cancers is an important prerequisite for the treatment. Since Kv1.3 and Kv1.5 are involved in the proliferation of many mammalian cells, we aimed to study the expression of Kv1.3 and Kv1.5 in a plethora of human cancers. Thus, tissues from breast, stomach, kidney, bladder, lung, skin, colon, ovary, pancreas, brain, lymph node, skeletal muscle and some of their malignant counterparts have been analyzed. Whereas Kv1.3 expression was either decreased or did not change in most tumors, Kv1.5 was overexpressed. However, the presence of Kv1.3 was mostly associated with inflammatory lymphoplasmocytic cells. Independent of the suitability of individual channels as therapeutic targets, the identification of a Kv phenotype from tumor specimens could have a diagnostic value of its own. Our results demonstrate that Kv1.5, and to some extent Kv1.3, are aberrantly expressed in a number of human cancers. These channels could serve both as novel markers of the metastatic phenotype and as potential new therapeutic targets. The concept of Kv channels as therapeutic targets or prognostic biomarkers attracts increasing interest and warrants further investigation.

[Multiple primary melanoma]. / Melanoma primario múltiple.

INTRODUCTION: The risk of multiple melanoma is estimated to be between 1 % and 8 %, with the majority of studies being carried out on North American populations. Our objective was to determine the risk and the clinical-pathological features of multiple primary melanoma in a Spanish Mediterranean population. MATERIAL AND METHODS: We performed a retrospective study of the medical records and the database of the Melanoma Unit of Hospital de Bellvitge, Barcelona, Spain, between 1988 and 2005. RESULTS: We found 25 cases of multiple primary melanoma among 934 patients studied, representing a risk of 2.6 % in our population of melanoma patients. In 50 % of cases, the second melanoma appeared during the first year of follow-up. These subsequent lesions occurred at a different site from the initial lesion in 58 % of cases. In the majority of cases, lesions in a single patient showed similar cytological and architectural features. However, we did observe marked interindividual variability in the histology of multiple primary melanomas. CONCLUSION: Although the risk of a second melanoma in our population appears to be lower than in North American populations, it is not negligible. Melanoma patients must therefore be followed up for life, not only for the risk of metastases but also for the risk of a new primary tumor. Complete examination of the skin must be performed at each visit.