Nutritional status associates with immunotherapy clinical outcomes in recurrent or metastatic head and neck squamous cell carcinoma patients.

BACKGROUND: Beyond programmed death-ligand 1 (PD-L1) assessed by the combined positive score (CPS) and tumor mutational burden (TMB), no other biomarkers are approved for immunotherapy interventions. Here, we investigated whether additional clinical and pathological variables may impact on immunotherapy outcomes in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients. METHODS: R/M HNSCC patients treated with immunotherapy were reviewed. Analyzed variables at baseline included: clinicopathological, laboratory, and variables reflecting the host nutritional status such as the prognostic nutritional index (PNI) and albumin. The primary endpoint was progression free survival (PFS). The secondary endpoints were overall survival (OS) and objective response rate (ORR). Univariable and multivariable Cox models were fitted and random forest algorithm was used to estimate the importance of each prognostic variable. RESULTS: A total of 100 patients were treated with immunotherapy; 50% with single agent and 50% with experimental immunotherapy combinations. In the multivariable analysis, both ECOG performance status (HR: 1.73; 95%CI 1.07-2.82; p = 0.03) and PNI levels (10-point increments, HR: 0.66; 0.46-0.95; p = 0.03) were significantly associated with PFS. However, the derived neutrophil to lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH) were not significantly associated with PFS (p-values > 0.15). In the OS analysis, albumin and PNI were the only statistically significant factors in the multivariable model (p < 0.001). CONCLUSIONS: In our cohort, PNI and ECOG performance status were most strongly associated with PFS in R/M HNSCC patients treated with immunotherapy. These results suggest that parameters informative of nutritional status should be considered before immunotherapy.

Changes in the microbiological diagnosis and epidemiology of cutaneous leishmaniasis in real-time PCR era: A six-year experience in a referral center in Barcelona.

BACKGROUND: Leishmaniasis is a neglected disease caused by different species of the protozoa Leishmania spp. Cutaneous lesions are the most common clinical manifestation. This disease is prevalent in tropical and subtropical areas, including the Mediterranean basin. In Spain, Leishmania (L.) infantum is the only endemic species, but imported cases are often diagnosed. Different classical parasitological methods can be performed for cutaneous leishmaniasis (CL) diagnosis; but currently molecular techniques serve as a relevant tool for the detection and characterization of Leishmania parasites. We aimed to evaluate clinical and epidemiological characteristics of CL diagnosed patients by real-time PCR in a tertiary hospital over a six-year period. METHODOLOGY/PRINCIPAL FINDINGS: Clinical, epidemiological and microbiological data were retrospectively collected and analyzed. In our study, CL was confirmed in 59 (31.4%) out of 188 patients by real-time PCR, showing an increase over recent years: 11 cases of CL between 2014 and 2016 and 48 between 2017 and 2019. Real-time PCR was performed on skin swabs and/or biopsies samples, with a positivity of 38.5% and 26.5%, respectively. Results were 100% concordant when biopsy and skin swab were performed simultaneously. L. (L.) infantum was the most frequent species detected (50%), followed by L. (L.) major (45%) and Viannia subgenus (5%), which were detected only in imported cases. L. (L.) major was almost entirely detected in travelers/migrants from Morocco. Multiple and atypical skin lesions were more common in imported cases than in autochthonous cases (44.4% vs. 21.8%). CONCLUSIONS/SIGNIFICANCE: An increase in both autochthonous and imported CL cases has been observed in past years in our hospital. Molecular techniques assist in improving CL diagnosis and characterization of the Leishmania species, mainly in imported cases.

Nodal metastatic load in papillary thyroid carcinoma. Morphological and molecular analysis with one-step nucleic acid amplification on more than 550 lymph nodes.

BACKGROUND AND OBJECTIVE: The risk of recurrence in papillary thyroid carcinoma (PTC) is likely related to the amount of tumour in the metastatic lymph node (LN). Therefore, the current TNM classification (N0/N1) make it necessary to find a method to quantify the LN metastasis (LNM). We propose that the quantitative molecular assay One-Step Nucleic-Acid Amplification (OSNA), which measures the number of cytokeratin-19 (CK-19) mRNA copies as a marker of LNM, could play this role. Our objective was to describe the characteristics of the LNs from PTC, and to compare the morphological characteristics that have been claimed as criteria for metastatic burden with OSNA. PATIENTS AND METHOD: Prospective study of LNs from 42 patients. All of the LNs were measured, weighed and analysed by OSNA and also by imprint cytology. RESULTS: A total of 573 LNs were included, 187 (32.6%) of them were OSNA-positives. The global consistency between cytology and OSNA was 87.4%. Significant differences were observed in the CK-19 copy number between the LNMs<0.2cm and those >3cm, as well as between those from 0.2 to 3cm with respect to those >3cm, but not between those <0.2cm and those between 0.2 and 3cm. The total tumour load per neck dissection showed no differences based on whether there were ≤5 or >5 LNMs. CONCLUSIONS: In our series the LNMs >3cm show an increased tumour load, but it is unclear if it is necessary to sub-classify the smaller ones as well as the relevance of the number of metastatic nodes according to the cut-off of 5 nodes. We consider that the OSNA analysis avoids the bias of nodal histology and allows for a greater understanding of its real oncological potential.

Hip fractures in Spain: are we on the right track? Statistically significant differences in hip fracture management between Autonomous Communities in Spain.

Although medicine is currently protocol-based, there are still differences in the management of the hip fracture in Spain, especially regarding surgical delay, type of anesthesia, early mobilization, and discharge destinations. This data will be of great value to assist stakeholders in formulating health policies. PURPOSE: Analysis of demographic, clinical, surgical, and functional data of the Spanish National Hip Fracture National Registry (RNFC), during admission and at 1-month follow-up, by Autonomous Communities (ACs). METHODS: Cross-sectional analysis in the framework of a RNFC cohort, from January 2017 to May 2018, including 15 ACs from Spain, with 1 month of follow-up. Sociodemographic, clinical, surgical, and outcome variables were analyzed. RESULTS: In total, 13,839 patients were analyzed. There were significant differences (p <0.001) in median surgical delay and percentage of patients operated in less than 48 h. Mean surgical delay was 70.75 h, with a 12-h difference between the Communities of Madrid (71.22) and Catalonia (59.65). Only 43% of patients had less than 48-h delay. Overall, most patients received regional anesthesia (91.9%); however, there was a significant difference between ACs (p = 0.0001). There were also differences in inpatient stay, early mobilization, discharge destination, and mortality (p <0.001). Mortality 30 days after surgery was 7.8%, and highest in the Basque Country (12.5%). CONCLUSIONS: The registry showed homogeneity among ACs regarding sociodemographic variables, fracture type, surgical treatment, ASA risk, and co-management with a geriatrician or an integrated internist. There were significant differences in hip fracture management between ACs in Spain, especially regarding surgical delay, type of anesthesia, early mobilization, and discharge destinations.

Nodal metastatic load in papillary thyroid carcinoma. Morphological and molecular analysis with one-step nucleic acid amplification on more than 550 lymph nodes.

BACKGROUND AND OBJECTIVE: The risk of recurrence in papillary thyroid carcinoma (PTC) is likely related to the amount of tumour in the metastatic lymph node (LN). Therefore, the current TNM classification (N0/N1) make it necessary to find a method to quantify the LN metastasis (LNM). We propose that the quantitative molecular assay One-Step Nucleic-Acid Amplification (OSNA), which measures the number of cytokeratin-19 (CK-19) mRNA copies as a marker of LNM, could play this role. Our objective was to describe the characteristics of the LNs from PTC, and to compare the morphological characteristics that have been claimed as criteria for metastatic burden with OSNA. PATIENTS AND METHOD: Prospective study of LNs from 42 patients. All of the LNs were measured, weighed and analysed by OSNA and also by imprint cytology. RESULTS: A total of 573 LNs were included, 187 (32.6%) of them were OSNA-positives. The global consistency between cytology and OSNA was 87.4%. Significant differences were observed in the CK-19 copy number between the LNMs<0.2cm and those >3cm, as well as between those from 0.2 to 3cm with respect to those >3cm, but not between those <0.2cm and those between 0.2 and 3cm. The total tumour load per neck dissection showed no differences based on whether there were ≤5 or >5 LNMs. CONCLUSIONS: In our series the LNMs >3cm show an increased tumour load, but it is unclear if it is necessary to sub-classify the smaller ones as well as the relevance of the number of metastatic nodes according to the cut-off of 5 nodes. We consider that the OSNA analysis avoids the bias of nodal histology and allows for a greater understanding of its real oncological potential.

TSPAN1: A Novel Protein Involved in Head and Neck Squamous Cell Carcinoma Chemoresistance.

Sensitization of resistant cells and cancer stem cells (CSCs) represents a major challenge in cancer therapy. A proteomic study revealed tetraspanin-1 (TSPAN1) as a protein involved in acquisition of cisplatin (CDDP) resistance (Data are available via ProteomeXchange with identifier PXD020159). TSPAN1 was found to increase in CDDP-resistant cells, CSCs and biopsies from head and neck squamous cell carcinoma (HNSCC) patients. TSPAN1 depletion in parental and CDDP-resistant HNSCC cells reduced cell proliferation, induced apoptosis, decreased autophagy, sensitized to chemotherapeutic agents and inhibited several signaling cascades, with phospho-SRC inhibition being a major common target. Moreover, TSPAN1 depletion in vivo decreased the size and proliferation of parental and CDDP-resistant tumors and reduced metastatic spreading. Notably, CDDP-resistant tumors showed epithelial-mesenchymal transition (EMT) features that disappeared upon TSPAN1 inhibition, suggesting a link of TSPAN1 with EMT and metastasis. Immunohistochemical analysis of HNSCC specimens further revealed that TSPAN1 expression was correlated with phospho-SRC (pSRC), and inversely with E-cadherin, thus reinforcing TSPAN1 association with EMT. Overall, TSPAN1 emerges as a novel oncogenic protein and a promising target for HNSCC therapy.

Newcastle approach for the treatment of supra-intercondylar fractures in children.

PURPOSE: The aim of this study is to evaluate the functional results of open reduction using the Newcastle approach and internal fixation for complex intra-articular distal humeral fractures in children through the report of cases. MATERIAL AND METHODS: A retrospective case series of patients who underwent open reduction and internal fixation surgery because of a complex intra-articular distal humeral fracture using the Newcastle approach were reviewed. Minimum follow-up was 2 years. Demographic, clinical, and radiological data were analyzed. Also, Mayo Elbow Performance Score and four-point Likert scale were evaluated. RESULTS: 2 children were included in the final analysis. In both fractures, the approach was sufficient for accurate reduction and the functional outcome on both elbows was satisfactory. The Mayo elbow score was 95 points (excellent results) and the five-point Likert scale, both patients were very satisfied with the outcomes. In the radiographic study, no necrosis or secondary deformities were observed. CONCLUSIONS: Our study provides evidence that the Newcastle approach is an alternative to perform open reduction in those children supra-intercondylar fractures that cannot be reduced using a close reduction. To our knowledge, there is not previous paper that has reported the used of this approach in the treatment in this kind of fractures.

Clinical management of early-stage cervical cancer: The role of sentinel lymph node biopsy in tumors ≤2 cm.

OBJECTIVE: To evaluate the experience with sentinel lymph node (SLN) biopsy in patients with early-stage cervical cancer at our hospital, and to analyze factors influencing the rate of false negatives. STUDY DESIGN: This study was carried out at the Vall d'Hebron Hospital (Barcelona, Spain) between September 2000 and October 2016. All patients underwent SLN biopsy and systematic and bilateral pelvic lymphadenectomy, followed by radical hysterectomy. SLNs were analyzed by the pathologist by staining with hematoxylin-eosin and immunohistochemistry. RESULTS: Patients (N = 128) had been diagnosed with early-stage cervical cancer (FIGO-2009 stages 1A2, IB1, and IIA1). The combined SLN detection rate (99-technecium and a blue dye) was 98.4%, bilateral in 76% of the patients. Positive SLNs were found in 19 patients (14.8%). Sensitivity of detection was 79.2% (CI95, 57.9-92.9), false negative rate 20.8% (CI95, 7.1-42.2), and negative predictive value 95.4% (CI95, 89.6-98.5). False negative cases were observed in 5 patients with tumors >2 cm and presenting lymphovascular space invasion. Micrometastases were detected during SLN ultrastaging in 3 patients (2.3%). The median follow-up was 8.24 years and the 5-year overall survival (OS) was 88.4% (CI95, 80.9-93.1). CONCLUSION: SLN mapping and biopsy in early-stage cervical cancer is feasible and has high sensitivity to detect patients with initial metastases. The risk of false negatives could be lower in certain groups of patients, such as those with tumors ≤2 cm and no lymphovascular space invasion, but future studies will be required to test this hypothesis.

Insight into the Role and Regulation of Gap Junction Genes in Lung Cancer and Identification of Nuclear Cx43 as a Putative Biomarker of Poor Prognosis.

Direct intercellular communication, mediated by gap junctions formed by the connexin transmembrane protein family, is frequently dysregulated in cancer. Connexins have been described as tumour suppressors, but emerging evidence suggests that they can also act as tumour promoters. This feature is connexin- and tissue-specific and may be mediated by complex signalling pathways through gap junctions or hemichannels or by completely junction-independent events. Lung cancer is the number one cancer in terms of mortality worldwide, and novel biomarkers and therapeutic targets are urgently needed. Our objective was to gain a better understanding of connexins in this setting. We used several in silico tools to analyse TCGA data in order to compare connexin mRNA expression between healthy lung tissue and lung tumours and correlated these results with gene methylation patterns. Using Kaplan-Meier plotter tools, we analysed a microarray dataset and an RNA-seq dataset of non-small cell lung tumours in order to correlate connexin expression with patient prognosis. We found that connexin mRNA expression is frequently either upregulated or downregulated in lung tumours. This correlated with both good and poor prognosis (overall survival) in a clear connexin isoform-dependent manner. These associations were strongly influenced by the histological subtype (adenocarcinoma versus squamous cell carcinoma). We present an overview of all connexins but particularly focus on four isoforms implicated in lung cancer: Cx26, Cx30.3, Cx32 and Cx43. We further analysed the protein expression and localization of Cx43 in a series of 73 human lung tumours. We identified a subset of tumours that exhibited a unique strong nuclear Cx43 expression pattern that predicted worse overall survival (p = 0.014). Upon sub-stratification, the prognostic value remained highly significant in the adenocarcinoma subtype (p = 0.002) but not in the squamous carcinoma subtype (p = 0.578). This finding highlights the importance of analysis of connexin expression at the protein level, particularly the subcellular localization. Elucidation of the underlying pathways regulating Cx43 localization may provide for novel therapeutic opportunities.

One-step nucleic acid amplification for intraoperative analysis of sentinel lymph node in papillary thyroid carcinoma.

Objective Lymphadenectomy in papillary thyroid carcinoma (PTC) is controversial. It is indicated whenever metastases have been proven before or during surgery and as a prophylactic treatment in high-risk patients. However, 30-50% of cN0 patients become pN1 postoperatively. In PTC, selective-sentinel-lymph-node-biopsy (SLNB) with conventional intraoperative analysis is 8% false negative. One-step nucleic acid amplification (OSNA) is a molecular technique which allows real-time detection of mRNA encoding for cytokeratin 19. OSNA has been introduced in intraoperative analysis of several tumors to reduce false-negative rates and distinguish micrometastasis from macrometastasis. Our objective was to evaluate the impact of the introduction of OSNA in the intraoperative evaluation of the sentinel node (SN) in PTC. Design We analyzed a series of 35 patients subjected to SLNB. Methods All the dissected nodes, SN and non-SN, were evaluated with OSNA and cytology. Results We obtained a total of 110 SN. SLNB proved positive in 14 patients (40%) with cytology and in 23 (65.7%) with OSNA (P < 0.001). In the 29 patients with subsequent lymphadenectomy we obtained 360 lymph nodes ((52 positive in cytology (14.4%) and 107 in OSNA (29.7%)). Lymphadenectomy proved positive in 16 patients according to cytology (55%) and in 24 according to OSNA (83%) (P = 0002). The majority of patients with micrometastasis in SN showed only micrometastasis in lymphadenectomy. Conclusions The present study shows selective-sentinel-lymph-node-biopsy with one-step nucleic acid amplification technique to be feasible in papillary thyroid carcinoma. The quantitative nature of one-step nucleic acid amplification paves the way toward a more personalized surgical approach, limiting lymphadenectomy to patients with intraoperative evidence of macrometastasis in the sentinel node.

Human papillomavirus in laryngeal and hypopharyngeal lymphoepithelial carcinoma.

The involvement of human papillomavirus (HPV) in laryngeal and hypopharyngeal lymphoepithelial carcinoma was investigated in a series of ten cases (seven laryngeal and three hypopharyngeal), retrieved from the files of three tertiary hospitals in the 2000-2017 period, through polymerase chain reaction with SPF10 primers and INNO-LiPA HPV Genotyping Extra II (Innogenetics). Epstein-Barr virus (EBV) was tested in all cases with in situ hybridization INFORM EBER Probe (Ventana Medical Systems). p16 and p53 expression were immunohistochemically analyzed. Calculated annual incidence was 0.013/100,000, and prevalence was 0.2% of laryngeal and hypopharyngeal carcinomas. All cases were EBV negative. HPV was detected in five cases, three of which also overexpressed p16. HPV16 was detected in four cases, and HPV58 in one case. Five cases were HPV negative, only one of these five overexpressed p16. No recurrence was observed in nine cases during follow-up. The 5-year disease-specific-survival rate was 100%. Mean overall survival was 87 months. Lymphoepithelial carcinoma of the larynx and hypopharynx are not related to EBV. Simultaneous HPV+/p16+ is consistent with HPV causation in a fraction of laryngeal and hypopharyngeal lymphoepithelial carcinomas.

Cerclage wiring and intramedullary nailing, a helpful and safe option specially in proximal fractures. A multicentric study.

PURPOSE: Antegrade intramedullary nailing is an alternative for humeral shaft fracture treatment. This surgical technique can be especially demanding in some fracture patterns, leading to problems like malunion and non-union. The purpose of our study is to demonstrate that the use of a nail with cerclage wires could be a safe procedure that facilitate reduction, specially in fractures with abduction of the proximal fragment. MATERIALS AND METHODS: Fifty-six patients were included, from January 2007 to March 2016. In this cohort forty-two patients were females and eighteen males; mean age was sixty-seven (32-89). The fractures were reduced using a cerclage wire through a small lateral or anterior approach, then, antegrade intramedullary nailing was performed. Fracture healing was established by clinical and radiographic evaluation. Shoulder function was assessed using the Constant Score. RESULTS: Fifty-three patients healed (94.6%) adequately. Two patients developed a non-union (3.5%). One patient developed an infection (1.8%). Transient radial nerve palsy was observed in two patients (3.5%). The mean Constant Score at the end of the study was 70 points (range from 34 to 98 points). CONCLUSIONS: Surgical treatment of humeral shaft fractures with cerclage wire and intramedullary nailing is a safe technique to improve fracture reduction. The use of cerclage wires leads to better bone contact while minimizing malunions. The rate of non-union in our study is lower than the rate reported in the literature for humeral shaft fractures treated by intramedullary nailing alone.

Use of an acellular collagen-elastin matrix to support bladder regeneration in a porcine model of peritoneocystoplasty.

INTRODUCTION: Bladder reconstruction without using the intestine remains a challenge to this day despite the development of new biomaterials and cell cultures. Human bladder engineering is merely anecdotic, and mostly in vitro and animal studies have been conducted. MATERIAL AND METHODS: In our study using a porcine model, we performed a bladder augmentation using an autologous parietal peritoneum graft (peritoneocystoplasty) and determined whether the attachment of an acellular collagen-elastin matrix (Group 1) or lack of (Group 2) had better histologic and functional results. Thus far, peritoneocystoplasty has rarely been performed or combined with a biomaterial. RESULTS: After 6 weeks, we observed different degrees of retraction of the new bladder wall in both groups, although the retraction was lower and the histological analysis showed more signs of regeneration (neoangiogenesis and less fibrosis) in Group 1 than when compared with Group 2. No transitional cells were found in the new bladder wall in any of the groups, and no differences were observed in the functional test results. CONCLUSIONS: Performing a peritoneocystoplasty is an easy and safe procedure. The data supports the benefit of an acellular collagen-elastin matrix to reinforce bladder regeneration. However, in our study we observed too much retraction of the new wall and the histologic results were not acceptable to consider it an appropriate cystoplasty technique.

[Embolizing cardiac hibernoma and acute respiratory failure]. / Hibernoma cardiaco embolizante y fallo respiratorio agudo.

Not only ae cardiac hibernomas rare, ante-mortem diagnosis is poor, due to the clinical and radiological similarity with other intracardiac masses. Furthermore, cardiac hibernomas can be asymptomatic and thus escape detection with imaging studies. We present a case of an 81-year-old woman who died as a result of pulmonary tumor embolism. This unusual case highlights the necessity for clinicians and pathologists to be familiar with intra-cardiac neoplasms. We discuss its diagnostic difficulty and the complication of pulmonary tumor embolism.

Cytogenetic and immunohistochemical study of 42 pigmented microcystic chromophobe renal cell carcinoma (PMChRCC).

Pigmented microcystic chromophobe renal cell carcinoma (PMChRCC) is a recently described morphologic variant of ChRCC. We have identified 42 cases in 40 patients in the last 24 years. We have investigated their clinical, morphologic, immunohistochemical, and cytogenetic features. Chromosomal abnormalities of chromosomes 7 and 17 were evaluated by automated dual-color silver-enhanced in situ hybridization on paraffin-embedded tissue. Chromosomal imbalance was defined on the basis of changes in both chromosomal index and signal distribution. The main age was 60.20 years, being 34 males and 6 women. The mean tumor diameter was 4.84 cm, with 39 intrarenal tumors. Grossly, the tumors were solid with a brown dark colored. Microscopically, tumors consisted of pale and eosinophilic cells arranged in microcysts or microalveolar in a cribriform pattern; there were microcalcifications and a dark brown pigment, mostly extracellular. One case showed sarcomatoid transformation. All tumors were positive for epithelial membrane antigen (EMA), Claudin 7, and E-cadherin. Monosomy of 7 and 17 chromosomes was present in 1/36 cases and 2/37 cases, respectively. Polysomy of chromosome 7 and 17 was found in 26/36 cases and in 4/37, respectively. With a median follow-up of 74.05 months, 37 patients were alive without disease and two were alive with disease progression. PMChRCCs expand the morphologic spectrum of the ChRCC with an unusual immunohistochemical profile. Cytogenetically, they showed monosomy to chromosome (CHR) 17 as other ChRCCs and polysomy of CHR 7 infrequent to ChRCCs. We present the probably largest series of PMCRCC, confirming their low aggressive behavior, with exceptional sarcomatoid transformation and distant metastases.