Low-Level Expression of p-S6 Is Associated with Nodal Metastasis in Patients with Head and Neck Cutaneous Squamous Cell Carcinoma.

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer. The incidence of metastasis for cSCC is estimated to be around 1.2-5%. Ribosomal protein S6 (p-S6) and the p21 protein (p21) are two proteins that play central roles in other cancers. These proteins may be equally important in cSCC, and together, these could constitute a good candidate for metastasis risk assessment of these patients. We investigate the relationship of p-S6 and p21 expression with the impact on the prognosis of head and neck cSCC (cSCCHN). p-S6 and p21 expression was analyzed by immunohistochemistry on paraffin-embedded tissue samples from 116 patients with cSCCHN and associations sought with clinical characteristics. Kaplan-Meier estimators and Cox proportional hazard regression models were also used. The expression of p-S6 was significantly inversely associated with tumor thickness, tumor size, desmoplastic growth, pathological stage, perineural invasion and tumor buds. p21 expression was significantly inversely correlated with >6 mm tumor thickness, desmoplastic growth, and perineural invasion. p-S6-negative expression significantly predicted an increased risk of nodal metastasis (HR = 2.63, 95% CI 1.51-4.54; p < 0.001). p21 expression was not found to be a significant risk factor for nodal metastasis. These findings demonstrate that p-S6-negative expression is an independent predictor of nodal metastasis. The immunohistochemical expression of p-S6 might aid in better risk stratification and management of patients with cSCCHN.

Leukemic Involvement Is a Common Feature in Waldenström Macroglobulinemia at Diagnosis.

Waldenström Macroglobulinemia (WM) is a lymphoplasmacytic lymphoma with bone marrow (BM) involvement and IgM monoclonal gammopathy. To date, no studies have focused specifically on peripheral blood (PB) involvement. In this study, 100 patients diagnosed with WM according to the World Health Organization (WHO) criteria were included based on the demonstration of MYD88mut in BM and the availability of PB multiparametric flow cytometry (MFC) analysis. Leukemic involvement by MFC was detected in 50/100 patients. A low percentage of mature small lymphocytes in PB smears was observed in only 15 cases. MYD88mut by AS-qPCR was detected in PB in 65/100 cases. In cases with leukemic expression by MFC, MYD88mut was detected in all cases, and IGH was rearranged in 44/49 cases. In 21/50 patients without PB involvement by MFC, molecular data were consistent with circulating disease (MYD88mut by AS-qPCR 3/50, IGH rearranged 6/50, both 12/50). Therefore, PB involvement by standard techniques was detected in 71/100 patients. MYD88mut was detected in PB by dPCR in 9/29 triple negative cases. Overall, 80% of the patients presented PB involvement by any technique. Our findings support the role of PB MFC in the evaluation of patients with IgM monoclonal gammopathy and provide reliable information on correlation with molecular features. The development of a feasible MFC assay may stand as an objective tool in the classification of mature B cell neoplasms presenting with IgM monoclonal gammopathy.

Combining Ultrafiltration and Nanofiltration to Obtain a Concentrated Extract of Purified Polyphenols from Wet Olive Pomace.

Despite the environmental concerns raised every year by the generation of high volumes of wet olive pomace, it contains valuable phenolic compounds that are essential for the valorization of this by-product. In this work, an integrated process to recover phenolic compounds from wet olive pomace is proposed. It consists of ultrasound-assisted solid-liquid extraction, followed by ultrafiltration and nanofiltration. Several commercial membranes were studied at different operational conditions. The ultrafiltration stage allowed the purification of biophenols, which were obtained in the permeate stream. Regarding organic matter, satisfactory rejection values were obtained with both commercial UH030 and UP005 membranes (Microdyn Nadir), but the latter provided more efficient purification and higher values of permeate flux, above 18 L·h-1·m-2 at 2.5 bar and 1.5 m·s-1. Later, this permeate stream was concentrated by means of a nanofiltration process, obtaining polyphenol rejection values that surpassed 85% with the commercial NF270 membrane (DuPont), then achieving the concentration of the previously purified polyphenols.

Native Spleen Preservation During Visceral Transplantation Inhibits Graft-Versus-Host-Disease Development: Clinical and Experimental Study.

OBJECTIVE: We aimed to assess whether native spleen preservation during visceral transplantation (VT) affects graft-versus-host-disease (GVHD) incidence. SUMMARY BACKGROUND DATA: GVHD is one of the most severe and frequently lethal hematological complications after VT procedures. Because there is no specific treatment for GVHD, it is imperative to develop a strategy to reduce donor lymphocyte engraftment and proliferation. METHODS: Our study included both clinical and experimental data. A total of 108 patients were divided into 3 groups: a native spleen preservation group, a native spleen removal with no donor spleen group, and a donor spleen included (allogeneic spleen) group. We also used an allogeneic VT rat model, in which recipients were divided into 2 groups: a native spleen preservation (+SP) group and a native spleen removal (-S) group. Skin rash appearance, histopathological changes, chimerism, and spleen effects on circulating allogeneic T-cells were assessed. RESULTS: The patients with native spleen preservation showed a lower rate of GVHD ( P <.001) and better survival ( P <.05) than those in the other groups. Skin and histological signs of GVHD were lower in the rats in the +SP group ( P <.05). The donor T-cell frequency in the bloodstream and skin was also significantly reduced when the native spleen was preserved ( P <.01 and P <.0001, respectively). CONCLUSIONS: The clinical and experimental data indicate that recipient spleen preservation protects against GVHD after VT, and donor cell clearance from the bloodstream by spleen macrophages could be the underlying mechanism. Therefore, spleen preservation should be considered in VT procedures, whenever possible.

Treatment of impacted or retained second molars with the miniscrew-supported pole technique: a prospective follow-up study.

BACKGROUND: Eruption disturbances of permanent molars are uncommon; however, it is important to treat them as soon as they are diagnosed. The main objective was to analyze the effectiveness of the "miniscrew-supported pole technique," a surgically assisted orthodontic procedure to force the eruption of impacted/retained second molars (M2s) when there are indicators of complex molar inclusion. An observational prospective study was carried out during a 2-year period. Sociodemographic, clinical and low-dose scanner variables were taken at baseline (T0). Follow-up variables (T1) were the time between surgery and tooth eruption, radiographic measurements, debonding of buttons, failure rate of miniscrews and success rate of eruption. RESULTS: A total of 21 patients (mean age of 13.9 years) with 24 retained/impacted M2s were recruited; 13 molars were maxillary (54.2%) and 11 (45.8%) were mandibular. Six (25%) were impacted molars and 18 (75%) primarily retained. At T0, molar angulation was mesial in six molars (25%), distal in five molars (20.8%) and 13 molars were vertically positioned (54.2%). Infraocclusion degree was moderate in four (16.7%) molars and severe in 20 (83.3%). Only three (12.5%) third molars were removed due to lack of space. All M2s managed to erupt, achieving a success rate of 100%; however, two molars of the same patient did not achieve occlusion. The period of eruption after surgery was 126.8 (117.3) days. Anatomical radicular alteration was the only variable independently related to a longer time of treatment (p = 0.027). CONCLUSIONS: The pole technique, using one mesial miniscrew and simple orthodontic mechanics, applies forces that succeed in erupting complicated retained/impacted M2s in a short period of time and with a low failure rate.

Pulmonary artery sarcoma with extensive leiomyosarcoma differentiation and heterologous osteosarcomatous elements.

Pulmonary artery sarcomas are exceptionally unusual. Their clinic, diagnosis and treatment play a very important role in the ultimate outcome and long-term survival. We present the case of a 70-year-old gentleman diagnosed with a leiomyosarcoma of the pulmonary artery with osteosarcoma differentiation that underwent surgical resection and subsequent chemotherapy, with good recovery at 9 months follow-up. Late diagnosis and incomplete surgical resection will worsen the short- and long-term prognosis of these patients.

PLCγ1/PKCθ Downstream Signaling Controls Cutaneous T-Cell Lymphoma Development and Progression.

Developing mechanistic rationales can improve the clinical management of cutaneous T-cell lymphomas. There is considerable genetic and biological evidence of a malignant network of signaling mechanisms, highly influenced by deregulated TCR/PLCγ1 activity, controlling the biology of these lesions. In addition, activated signal transducer and activator of transcription 3 is associated with clinical progression, although the alterations responsible for this have not been fully elucidated. Here, we studied PLCγ1-dependent mechanisms that can mediate STAT3 activation and control tumor growth and progression. Downstream of PLCγ1, the pharmacological inhibition and genetic knockdown of protein kinase C theta (PKCθ) inhibited signal transducer and activator of transcription 3 activation, impaired proliferation, and promoted apoptosis in cutaneous T-cell lymphoma cells. A PKCθ-dependent transcriptome in mycosis fungoides/Sézary syndrome cells revealed potential effector genes controlling cytokine signaling, TP53, and actin cytoskeleton dynamics. Consistently, an in vivo chicken embryo model xenografted with mycosis fungoides cells showed that PKCθ blockage abrogates tumor growth and spread to distant organs. Finally, the expression of a number of PKCθ target genes found in mycosis fungoides cells significantly correlated with that of PRKCQ (PKCθ) in 81 human mycosis fungoides samples. In summary, PKCθ can play a central role in the activation of malignant cutaneous T-cell lymphoma mechanisms via multiple routes, including, but not restricted to, STAT3. These mechanisms may, in turn, serve as targets for specific therapies.

Anticoagulation in syncardia total artificial heart recipients: anti-factor Xa or activated partial thromboplastin time?

Although the activated partial thromboplastin time (aPTT) has historically been the method of choice for anticoagulation monitoring in patients undergoing mechanical circulatory support with intravenous unfractionated heparin, it is being progressively superseded by the anti-factor Xa (anti-Xa) method. A retrospective single-arm, single-centre analysis of 20 patients who underwent total artificial heart implantation entailed simultaneous determinations of aPTT and anti-Xa. Agreement between these parameters was assessed using the Bland-Altman method. Despite a positive correlation between aPTT and anti-Xa, normal target ranges were poorly aligned: from 5th to 30th postoperative day, for anti-Xa values of 0.2 and 0.4 U/ml corresponding aPTT values were 52.1 and 65.2 s, 7.9 and 14.8 lower than predicted values, respectively. This was not associated with thromboembolic sequalae. It was not possible to demonstrate a significant relationship between the predictor variables (postoperative day; white blood cell count; C-reactive protein concentration; alanine transaminase and alkaline phosphatase level; bilirubin; haemoglobin; albumin and total protein concentration) and the agreement between aPTT and anti-Xa levels. In summary, when anti-Xa levels were used to guide anticoagulation therapy, corresponding aPTT levels were low with respect to target range. Methodology applied in this study is generalizable to other forms of mechanical circulatory support.

Sternal sparing bilateral symmetrical thoracotomy for implantation of left ventricular assist device.

Reopening the chest in patients with left ventricular assist devices at the time of a heart transplant is challenging due to adhesions and the possibility of injury to vital structures. The sternal sparing bilateral thoracotomy approach utilized to implant a left ventricular assist device minimizes the chances of such injuries and offers a cosmetically better outcome. We demonstrate a procedure for implanting a left ventricular assist device in a 54-year-old man diagnosed with dilated cardiomyopathy who suffered rapid decompensation despite maximum medical therapy.

Is the quality-of-life improvement after transcatheter aortic valve implantation equivalent to that achieved by surgical aortic valve replacement?

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was 'is the quality-of-life (QoL) improvement after transcatheter aortic valve implantation (TAVI) equivalent to that achieved by surgical aortic valve replacement (sAVR)?' Literature search revealed 189 papers with reference to QoL after TAVI, of which 7 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers were tabulated. QoL plays a crucial role in the decision-making process for procedures such as TAVI and sAVR. Current evidence included and analysed in this review have shown a clear improvement in QoL after both TAVI and sAVR. TAVI offers a rapid improvement of QoL, evident within the first 30 days. There is no difference in QoL at 2- and 5-year follow-up between TAVI and sAVR. There are currently paucity of data on long-term QoL and the potential impact of structural valve degeneration following TAVI.

Diagnostic Value of Genotypic Analysis in Primary Cutaneous Lymphomas using Standardized BIOMED-2 Polymerase Chain Reaction Protocols: Experience in Daily Clinical Practice.

BIOMED-2 Concerted Action BMH4-CT98-3936 (BIOMED-2) PCR protocols are an important diagnostic tool in the evaluation of cutaneous lymphomas. The aim of this study was to assess the diagnostic value of the genotyping results obtained by these techniques in daily clinical practice. A total of 360 paraffin-embedded skin samples were retrospectively reviewed from 114 cutaneous T-cell lymphomas and 35 cutaneous B-cell lym-phomas. A total of 249 biopsies from 180 patients with benign lymphoid infiltrates served as controls. T-cell receptor and immunoglobulin gene rearrangements were assessed using the BIOMED-2 method. A combined T-cell receptor gamma and beta assay approach reliably distinguished cutaneous T-cell lymphomas from benign skin T-cell infiltrates (sensitivity 89.4%; specificity 81.5%). Analysis of complete immunoglobulin heavy chain rearrangements also differentiated cutaneous B-cell lymphomas from benign B-cell infiltrates (sensitivity 85.7%; specificity 82.4%). In conclusion, the full BIOMED-2 protocol is a useful aid combined with clinical, histological and immunophenotypical findings for assessment of lymphoid clonality in skin lymphoid proliferations.

Optimizing the Procedure to Manufacture Clinical-Grade NK Cells for Adoptive Immunotherapy.

Natural killer (NK) cells represent promising tools for cancer immunotherapy. We report the optimization of an NK cell activation-expansion process and its validation on clinical-scale. METHODS: RPMI-1640, stem cell growth medium (SCGM), NK MACS and TexMACS were used as culture mediums. Activated and expanded NK cells (NKAE) were obtained by coculturing total peripheral blood mononuclear cells (PBMC) or CD45RA+ cells with irradiated K562mbIL15-41BBL or K562mbIL21-41BBL. Fold increase, NK cell purity, activation status, cytotoxicity and transcriptome profile were analyzed. Clinical-grade NKAE cells were manufactured in CliniMACS Prodigy. RESULTS: NK MACS and TexMACs achieved the highest NK cell purity and lowest T cell contamination. Obtaining NKAE cells from CD45RA+ cells was feasible although PBMC yielded higher total cell numbers and NK cell purity than CD45RA+ cells. The highest fold expansion and NK purity were achieved by using PBMC and K562mbIL21-41BBL cells. However, no differences in activation and cytotoxicity were found when using either NK cell source or activating cell line. Transcriptome profile showed to be different between basal NK cells and NKAE cells expanded with K562mbIL21-41BBL or K562mbIL15-41BBL. Clinical-grade manufactured NKAE cells complied with the specifications from the Spanish Regulatory Agency. CONCLUSIONS: GMP-grade NK cells for clinical use can be obtained by using different starting cells and aAPC.

Phase 2 Clinical Trial of Infusing Haploidentical K562-mb15-41BBL-Activated and Expanded Natural Killer Cells as Consolidation Therapy for Pediatric Acute Myeloblastic Leukemia.

BACKGROUND: Acute myeloid leukemia (AML) accounts for approximately 20% of pediatric leukemia cases; 30% of these patients experience relapse. The antileukemia properties of natural killer (NK) cells and their safety profile have been reported in AML therapy. We proposed a phase 2, open, prospective, multicenter, nonrandomized clinical trial for the adoptive infusion of haploidentical K562-mb15-41BBL-activated and expanded NK (NKAE) cells as a consolidation strategy for children with favorable and intermediate risk AML in first complete remission after chemotherapy (NCT02763475). PATIENTS AND METHODS: Before the NKAE cell infusion, patients underwent a lymphodepleting regimen. After the NKAE cell infusion, patients were administered low doses (1 × 106/IU/m2) of subcutaneous interleukin-2. The primary study endpoint was AML relapse-free survival. We needed to include 35 patients to demonstrate a 50% reduction in relapses. RESULTS: Seven patients (median age, 7.4 years; range, 0.78-15.98 years) were administered 13 infusions of NKAE cells, with a median of 36.44 × 106 cells/kg (range, 6.92 × 106 to 193.2 × 106 cells/kg). We observed chimerism in 4 patients (median chimerism, 0.065%; range, 0.05-0.27%). After a median follow-up of 33 months, the disease of 6 patients (85.7%) remained in complete remission. The 3-year overall survival was 83.3% (95% confidence interval, 68.1-98.5), and the cumulative 3-year relapse rate was 28.6% (95% confidence interval, 11.5-45.7). The study was terminated early because of low patient recruitment. CONCLUSION: This study emphasizes the difficulties in recruiting patients for cell therapy trials, though NKAE cell infusion is safe and feasible. However, we cannot draw any conclusions regarding efficacy because of the small number of included patients and insufficient biological markers.

Secondary hypereosinophilic syndrome: an unusual manifestation in a patient with syringotropic mycosis fungoides and human immunodeficiency virus infection.

Syringotropic mycosis fungoides is a very rare variant of cutaneous T-cell lymphomas characterised by prominent involvement of the eccrine glands. Hypereosinophilic syndrome refers to a rare group of conditions that are associated with persistent eosinophilia with organ involvement. It is classified into idiopathic, primary and secondary (reactive). We report herein an unusual case of hypereosinophilic syndrome with great impact on morbidity, which developed in a patient with human immunodeficiency virus infection and long-time misdiagnosed syringotropic mycosis fungoides.

Miniscrew-supported pole technique: Surgical-orthodontic approach for impacted or retained second molars in adolescents.

BACKGROUND: Several treatment options have been proposed for the treatment of eruption disturbances of permanent molars. Despite being an infrequent condition, these disturbances should be solved as they can lead to important complications and play a relevant role in completing the occlusion. FINDINGS: The presented cases involved maxillary and mandibular included second molars (M2s) respectively. Both teeth erupted successfully after the application of the miniscrew-supported pole technique, and a functional occlusion was established. CONCLUSIONS: This technique is a surgically assisted orthodontic procedure performed to force the eruption of impacted/retained M2s. This device uses one mesial miniscrew which allows the application of relevant force to achieve the eruption of complicated retained/impacted M2s within a short period of time.

A detailed explantation assessment protocol for patients with left ventricular assist devices with myocardial recovery.

OBJECTIVES: Left ventricular assist device (LVAD) implantation for end-stage heart failure patients has been on the rise, providing a reliable long-term option. For some LVAD patients, longer term LV unloading leads to recovery; hence, the need for evaluating potential myocardial recovery and weaning eligibility has emerged. METHODS: All patients who underwent contemporary LVAD explantation at our institution between 2009 and 2020 were included in the study. Patients in New York Heart Association I, left ventricular ejection fraction >40%, a cardiac index >2.4 l/min and a peak oxygen intake >50% predicted underwent a 4-phase weaning assessment. A minimally invasive approach using a titanium plug was the surgery of choice in the most recent explants. Kaplan-Meier curves were used to estimate the survival at 1 and 5 years. RESULTS: Twenty-six patients (17 HeartMate II, 9 HeartWare) underwent LVAD explantation after a median 317 days of support [IQ (212-518)], range 131-1437. Mean age at explant was 35.8 ± 12.7 years and 85% were males. Idiopathic dilated cardiomyopathy was the underlying diagnosis in 70% of cases. Thirteen (48%) patients were on short-term mechanical circulatory support and 60% required intensive care unit admission prior to the LVAD implantation. At 1 year, Kaplan-Meier estimated survival was 88%, whereas at 6 years, it was 77%. The average left ventricular ejection fraction at 1 year post-explant was 44.25% ± 8.44. CONCLUSIONS: The use of a standardized weaning protocol (echocardiographic and invasive) and a minimally invasive LVAD explant technique minimizes periprocedural complications and leads to good long-term device-free survival rates.

Sarcoma treatment in the era of molecular medicine.

Sarcomas are heterogeneous and clinically challenging soft tissue and bone cancers. Although constituting only 1% of all human malignancies, sarcomas represent the second most common type of solid tumors in children and adolescents and comprise an important group of secondary malignancies. More than 100 histological subtypes have been characterized to date, and many more are being discovered due to molecular profiling. Owing to their mostly aggressive biological behavior, relative rarity, and occurrence at virtually every anatomical site, many sarcoma subtypes are in particular difficult-to-treat categories. Current multimodal treatment concepts combine surgery, polychemotherapy (with/without local hyperthermia), irradiation, immunotherapy, and/or targeted therapeutics. Recent scientific advancements have enabled a more precise molecular characterization of sarcoma subtypes and revealed novel therapeutic targets and prognostic/predictive biomarkers. This review aims at providing a comprehensive overview of the latest advances in the molecular biology of sarcomas and their effects on clinical oncology; it is meant for a broad readership ranging from novices to experts in the field of sarcoma.

Síndrome de Austrian: quien no sabe lo que busca, no entiende lo que encuentra / Austrian Syndrome: he who does not know what he is looking for will not understand what he finds

Resumen El síndrome de Austrian es una tríada que engloba neumonía, meningitis y endocarditis causadas por Staphylococcus pneumoniae. Dado el aumento en el uso de antibióticos, cada vez vemos esta enfermedad de forma menos frecuente en la práctica clínica diaria. No obstante, se debe recordar su existencia ya que el conocimiento de esta entidad puede ser crucial en el pronóstico de estos enfermos. Desconocer algunos síndromes por presentar una frecuencia menor en los tiempos actuales no exime de mantener la buena práctica clínica ya que de ello puede depender el devenir del paciente. Se presenta un caso de síndrome de Austrian en un paciente joven, quien tuvo evolución tórpida los primeros días de ingreso; finalmente, tras la realización de varias pruebas, se solicitó un ecocardiograma que fue la clave para el diagnóstico. Se trata de un caso de interés para reflexionar en que, a pesar de poseer nuevas tecnologías a nuestro alcance en la actualidad, es preciso recordar la importancia de una buena exploración física.

Abstract Austrian syndrome is a triad that includes pneumonia, meningitis, and endocarditis caused by Staphylococcus pneumoniae. Given the increase in the use of antibiotics, it is becoming less common to see this disease in daily clinical practice. However, it should be remembered that it exists since knowledge of this condition could be crucial in the prognosis of these patients. To not recognise some syndromes due to currently having a lower frequency does not exempt maintaining good clinical practice, since the outcome of the patient may depend on this. A case of Austrian syndrome is presented in a young patient, who had a slow response in the first days of admission. Finally, after performing several tests, a cardiac ultrasound was requested, which was key for the diagnosis. It is an interesting case to reflect that, despite currently having new technologies within our reach, it is essential to remember the importance of a good physical examination.

Cardiac tumors invading the right ventricle; Aggressive Surgical Management with backup mechanical circulatory support if necessary.

BACKGROUND: Primary cardiac tumors are exceedingly rare. Amongst the malignant types, sarcomas are the most frequently encountered. Treatment includes attempted aggressive surgical resection as the only curative option. We report our experience. METHODS: During the last five years, six patients presented at our institution with complex cardiac tumors with different underlying diagnoses and were at different stages of their disease. RESULTS: 6 patients with median age of 30-years-old underwent surgery in our centre. 3 patients had undergone debulking prior to surgery at our institution. In all patients, the tumor involved the right ventricle. One patient had biventricular involvement, the septum was involved in 4 patients, 2 patients had extracardiac growth, one invading both great vessels, one involving the pericardium and the hilar structures on the right side. Complete resection was achieved in 4 cases, 3 with successful resection-reconstruction, one with cardiectomy and implantation of a total artificial heart. 5 patients are currently alive, 4 free of recurrence. CONCLUSIONS: Complete radical surgery is the only curative treatment for patients suffering from cardiac tumors. The availability of mechanical circulatory support allows for a more radical surgical approach even including total cardiectomy, possibly resulting in a significant increase in R0 resections.