Immunotherapy in Head and Neck Cancer When, How, and Why?

Head and neck cancer (HNC) is one of the most common cancers worldwide. Alcohol and tobacco consumption, besides viral infections, are the main risk factors associated with this cancer. When diagnosed in advanced stages, HNC patients present a higher probability of recurrence or metastasising. The complexity of therapeutic options and post-treatment surveillance is associated with poor prognosis and reduced overall survival (OS). This review aims to explore immunotherapy (immune checkpoint inhibitors (ICI), therapeutic vaccines, and oncolytic viruses) in HNC patients' treatment, and to explore when, how, and why patients can benefit from it. The monotherapy with ICI or in combination with chemotherapy (QT) shows the most promising results. Compared to standard therapy, ICI are able to increase OS and patients' quality of life. QT in combination with ICI demonstrates significant response rates and considerable long-term clinical benefits. However, the toxicity associated with this approach is still a hurdle to overcome. In parallel, the therapeutic vaccines directed to the Human Papilloma Virus are also efficient in increasing the antitumour response, inducing cellular and humoral immunity. Although these results demonstrate clinical benefits compared to standard therapy, it is also important to unravel the resistance mechanisms in order to predict the clinical benefit of immunotherapy.

Resistance to endocrine therapy in HR + and/or HER2 + breast cancer: the most promising predictive biomarkers.

Breast cancer is the most common cancer in women. It is a heterogeneous disease, encompassing different biological subtypes that differ in histological features, outcomes, clinical behaviour and different molecular subtypes. Therapy has progressed substantially over the past years with a reduction both for locoregional and systemic therapy. Endocrine therapies have considerably reduced cancer recurrence and mortality. Despite the major diagnostic and therapeutic innovations, resistance to therapy has become a main challenge, especially in metastatic breast cancer, and became a major factor limiting the use of endocrine therapeutic agents in ER positive breast cancers. Approximately 50% of patients with ER positive metastatic disease achieve a complete or partial response with endocrine therapy. However, in the remaining patients, the benefit is limited due to resistance, intrinsic or acquired, resulting in disease progression and poor outcome.Tumour heterogeneity as well as acquired genetic changes and therapeutics pressure have been involved in the endocrine therapy resistance. Nowadays, targeted sequencing of genes involved in cancer has provided insights about genomic tumour evolution throughout treatment and resistance driver mutations. Several studies have described multiple alterations in receptor tyrosine kinases, signalling pathways such as Phosphoinositide-3-kinase-protein kinase B/Akt/mTOR (PI3K/Akt/mTOR) and Mitogen-activated protein kinase (MAPK), cell cycle machinery and their implications in endocrine treatment failure.One of the current concern in cancer is personalized therapy. The focus has been the discovery of new potentially predictive biomarkers capable to identify reliably the most appropriate therapy regimen and which patients will experience disease relapse. The major concern is also to avoid overtreatment/undertreatment and development of resistance.This review focuses on the most promising predictive biomarkers of resistance in estrogen receptor-positive breast cancer and the emerging role of circulating free-DNA as a powerful tool for longitudinal monitoring of tumour molecular profile throughout treatment.

Immunotherapy in Breast Cancer: When, How, and What Challenges?

Breast Cancer (BC) is the second most frequent cause of cancer death among women worldwide and, although there have been significant advances in BC therapies, a significant percentage of patients develop metastasis and disease recurrence. Since BC was demonstrated to be an immunogenic tumor, immunotherapy has broken through as a significant therapy strategy against BC. Over the years, immunotherapy has improved the survival rate of HER2+ BC patients due to the approval of some monoclonal antibodies (mAbs) such as Trastuzumab, Pertuzumab and, recently, Margetuximab, along with the antibody-drug conjugates (ADC) Trastuzumab-Emtansine (T-DM1) and Trastuzumab Deruxtecan. Immune checkpoint inhibitors (ICI) showed promising efficacy in triple-negative breast cancer (TNBC) treatment, namely Atezolizumab and Pembrolizumab. Despite the success of immunotherapy, some patients do not respond to immunotherapy or those who respond to the treatment relapse or progress. The main causes of these adverse events are the complex, intrinsic or extrinsic resistance mechanisms. In this review, we address the different immunotherapy approaches approved for BC and some of the mechanisms responsible for resistance to immunotherapy.

Oxidative stress in bladder cancer: an ally or an enemy?

Bladder cancer (BC) is the most common cancer of the urinary tract and despite all innovations, remains a major challenge due to high morbidity and mortality. Genomic and epigenetic analyses allowed the discovery of new genes and pathways involved in the pathogenesis and regulation of BC. However, the effect on mortality has been modest and the development of new targets for BC treatment are needed. Recent evidence suggests that cancer cells are under increased stress associated with oncogenic transformation, with changes in metabolic activity and increased generation of reactive oxygen species (ROS). The increased amounts of ROS in cancer cells are associated with stimulation of cellular proliferation, promotion of mutations and genetic instability, as well as alterations in cellular sensitivity to anticancer agents. Since these mechanisms occur in cancer cells, there is a close link between oxidative stress (OS) and BC with implications in prevention, carcinogenesis, prognosis, and treatment. We address the role of OS as an enemy towards BC development, as well as an ally to fight against BC. This review promises to expand our treatment options for BC with OS-based therapies and launches this approach as an opportunity to improve our ability to select patients most likely to respond to personalized therapy.

Cold Atmospheric Plasma, a Novel Approach against Bladder Cancer, with Higher Sensitivity for the High-Grade Cell Line.

Antitumor therapies based on Cold Atmospheric Plasma (CAP) are an emerging medical field. In this work, we evaluated CAP effects on bladder cancer. Two bladder cancer cell lines were used, HT-1376 (stage III) and TCCSUP (stage IV). Cell proliferation assays were performed evaluating metabolic activity (MTT assay) and protein content (SRB assay). Cell viability, cell cycle, and mitochondrial membrane potential (Δψm) were assessed using flow cytometry. Reactive oxygen and nitrogen species (RONS) and reduced glutathione (GSH) were evaluated by fluorescence. The assays were carried out with different CAP exposure times. For both cell lines, we obtained a significant reduction in metabolic activity and protein content. There was a decrease in cell viability, as well as a cell cycle arrest in S phase. The Δψm was significantly reduced. There was an increase in superoxide and nitric oxide and a decrease in peroxide contents, while GSH content did not change. These results were dependent on the exposure time, with small differences for both cell lines, but overall, they were more pronounced in the TCCSUP cell line. CAP showed to have a promising antitumor effect on bladder cancer, with higher sensitivity for the high-grade cell line.

Microbiome: A Supportive or a Leading Actor in Lung Cancer?

Lung cancer is still the leading cause of cancer death worldwide. Despite the major diagnostic and therapeutic innovations, the effect on mortality has been modest and the overall survival is still poor. Better understanding of the pathology of these tumors is necessary in order to develop personalized therapeutic strategies in lung cancer patients. Human microbiome has been associated with normal physiology and function, and increasing evidence points towards a key role of the microbiome in promoting the progression of lung disease. Studies have shown that although poorly understood, lung has a distinctive microbiome that may an important role in lung cancer development and progression, and interactions between microbial populations have the potential to influence disease, suggesting that microbiome can be an emerging target in cancer therapeutics. We will review mechanisms how the lung microbiota influences carcinogenesis, focusing on the bacterial dysbiosis and inflammation. Moreover, we will discuss the link between the microbiome and cancer and the consequences induced by the immune system, as the host microbiota plays an essential role in activating and modulating the immune response. We summarize current research advances in the lung microbiome and demonstrate the potential to exploit microbiome as a mechanism to prevent carcinogenesis and modulate therapeutic strategy, suggesting microbiome as a valuable approach in lung cancer patients.

Practical considerations in the use of a porcine model (Sus scrofa domesticus) to assess prevention of postoperative peritubal adhesions.

Infertility has been a common postoperative problem caused by peritoneal adhesions. Since several prophylactic agents have recently shown promising preliminary results, more complete studies comparing their real efficacy and safety are needed urgently. The aim of this study was to investigate and describe practical considerations of a porcine model that can be used to assess such prophylactic agents. First, 10 healthy 5½ months old female pigs (24.3-31.3 Kg) underwent a standardized laparoscopy to provoke peritubal adhesion formation without prophylactic agents. After 30 days, a second-look laparoscopy was performed to evaluate adhesions and perform adnexectomy for histopathological evaluation. Adhesions at different sites were classified by grade, for which the scores range from 0 (no adhesion) to 3 (very strong vascularized adhesions), and also by area, with scores ranging from 0 (no adhesion) to 4 (>75% of the injured area). The histopathological evaluation of the distal uterine horns, oviducts and ovaries were compared withthose from a control group of six healthy pigs with no previous surgery. Biological samples were collected to assess vitality, inflammation and renal, hepatic and hematopoietic systems. There were small (but significant) changes in serum albumin (P = 0.07), globulin (P = 0.07), C-reactive protein (P = 0.011), fibrinogen (P = 0.023) and bilirubin (P<0.01) after 30 days, but all values were within the normal range. No inflammation or abscess formation was observed, but different degrees of adhesion were identified. The estimated occurrence of adhesion (scores >0) and of strong / very strong adhesion (scores >1) was 75% (95% CI: 55-94.9) and 65% (95% CI: 45-85), respectively. The porcine model represents a useful animal platform that can be used to test the efficacy and safety of candidate prophylactic agents intended to prevent postoperative peritubal adhesions formation. We present several practical considerations and measures that can help to minimize animal suffering and avoid problems during such experiments.

Trabecular trichoblastoma in a domestic cat (Felis catus domesticus, Linnaeus 1758): Case report / Tricoblastoma trabecular em gato doméstico (Felis catus domesticus, Linnaeus 1758): Relato de caso

Trichoblastoma is characterized as a benign cutaneous neoplasm that originates in the trichoblastic epithelium of the hair bulb. The present report describes the case of a 4-year-old cross breed neutered male cat that had a history of a slow, freely movable, ulcerated, slow growing, solitary cutaneous nodule located on the left scapular region. Histopathological evaluation showed neoplastic cells arranged in cohesive nests or palisades with eosinophilic and scant cytoplasm. Based on the microscopic findings, a diagnosis of trabecular trichoblastoma was made. The treatment of choice consisted of total surgical excision of the mass with safe surgical margins. Tumor recurrence was not observed.(AU)

O Tricoblastoma se caracteriza como uma neoplasia benigna cutânea que tem origem no epitélio tricoblástico do bulbo piloso. O presente relato descreve o caso de felino macho, sem raça definida (SRD), com histórico de nódulo solitário de crescimento lento, não aderido e ulcerado, localizado na região escapular esquerda. A histopatologia evidenciou células neoplásicas organizadas em ninhos coesos, em paliçadas com citoplasma eosinofílico e escasso, os achados foram compatíveis com a descrição de tricoblastoma trabecular. O tratamento de eleição consistiu na exérese cirúrgica total da massa com ampla margem de segurança e recidivas não foram observadas(AU)

Trabecular trichoblastoma in a domestic cat (Felis catus domesticus, Linnaeus 1758) / Tricoblastoma trabecular em gato doméstico (Felis catus domesticus, Linnaeus 1758)

Trichoblastoma is characterized as a benign cutaneous neoplasm that originates in the trichoblastic epithelium of the hair bulb. The present report describes the case of a 4-year-old cross breed neutered male cat that had a history of a slow, freely movable, ulcerated, slow growing, solitary cutaneous nodule located on the left scapular region. Histopathological evaluation showed neoplastic cells arranged in cohesive nests or palisades with eosinophilic and scant cytoplasm. Based on the microscopic findings, a diagnosis of trabecular trichoblastoma was made. The treatment of choice consisted of total surgical excision of the mass with safe surgical margins. Tumor recurrence was not observed.(AU)

O Tricoblastoma se caracteriza como uma neoplasia benigna cutânea que tem origem no epitélio tricoblástico do bulbo piloso. O presente relato descreve o caso de felino macho, sem raça definida (SRD), com histórico de nódulo solitário de crescimento lento, não aderido e ulcerado, localizado na região escapular esquerda. A histopatologia evidenciou células neoplásicas organizadas em ninhos coesos, em paliçadas com citoplasma eosinofílico e escasso, os achados foram compatíveis com a descrição de tricoblastoma trabecular. O tratamento de eleição consistiu na exérese cirúrgica total da massa com ampla margem de segurança e recidivas não foram observadas.(AU)

Hemostasis with the Ultrasonic Scalpel.

BACKGROUND AND OBJECTIVES: The ultrasonically activated scalpel is a surgical instrument that is used in minimally invasive surgery to safely cut and seal vessels. This study reported the experimental observations of the use of a laparoscopic ultrasonic scalpel, including its safety and feasibility. in sealing vessels of different diameters in an in vivo animal model during both physiological and supraphysiological blood pressure (BP) conditions. METHODS: One healthy female swine was used. We performed resections of the omentum, biopsies in different regions of the liver, and a hysterectomy. Vessels with diameters ranging from 2 to 10 mm were sealed with the ultrasonic scalpel under regular hemodynamic conditions and during pharmacologically induced arterial hypertension (BP challenge). RESULTS: For 10 random cuts made in the omentum and during the hysterectomy, the ultrasonic scalpel was effective and fast, with no immediate or delayed bleeding. Bipolar energy, sutures, and hemoclips were not required to control bleeding. No bleeding was observed in sealed vessels up to 8 mm, even during BP challenges sustained for longer than 5 minutes. When testing vessels of 10 mm, bleeding occurred in 1 common iliac vein before 10 minutes of waiting (the point of bleeding was easily identified) and bleeding occurred in 1 of the common iliac arteries during the BP challenge. CONCLUSION: Our findings corroborate that the ultrasonic scalpel can safely seal arteries up to 8 mm in diameter to prevent or control bleeding during laparoscopic procedures, even when BP exceeds normal levels.

Deslocamento espontâneo do núcleo do cristalino para câmara anterior / Spontaneous dislocation of the lens nucleus to the anterior chamber

Resumo Ruptura espontânea da cápsula anterior do cristalino, evoluindo com deslocamento anterior do núcleo é uma complicação rara da catarata hipermadura. Relatamos o caso de uma paciente do sexo feminino, 79 anos, que se apresentou com ruptura espontânea da cápsula anterior do cristalino com deslocamento anterior do núcleo em olho direito sem histórico de trauma ocular. O diagnóstico foi confirmado pela visualização das abas da cápsula anterior, principalmente quando o núcleo foi removido. Realizamos facoemulsificação do núcleo pelo risco de descompensar a córnea. É importante destacar a raridade do caso, sendo o primeiro relatado no Brasil.

Abstract Spontaneous rupture of the anterior lens capsule, evolving with anterior dislocation of the lens nucleus is a rare complication of hypermature cataract. We report a case of a female patient, 79 years old, who presented with spontaneous rupture of the anterior lens capsule with anterior dislocation of the nucleus in the right eye with no history of ocular trauma. The diagnosis was confirmed by the visualization of the tabs of the anterior capsule, especially when the nucleus was removed. We perform phacoemulsification of the nucleus by the risk of decompensating the cornea. It is important to highlight the rarity of the case, the first being reported in Brazil.

The role of immune system exhaustion on cancer cell escape and anti-tumor immune induction after irradiation.

Immune surveillance seems to represent an effective tumor suppressor mechanism. However, some cancer cells survive and become variants, being poorly immunogenic and able to enter a steady-state phase. These cells become functionally dormant or remain hidden clinically throughout. Neoplastic cells seem to be able to instruct immune cells to undergo changes promoting malignancy. Radiotherapy may act as a trigger of the immune response. After radiotherapy a sequence of reactions occurs, starting in the damage of oncogenic cells by multiple mechanisms, leading to the immune system positive feedback against the tumor. The link between radiotherapy and the immune system is evident. T cells, macrophages, Natural Killer cells and other immune cells seem to have a key role in controlling the tumor. T cells may be dysfunctional and remain in a state of T cell exhaustion, nonetheless, they often retain a high potential for successful defense against cancer, being able to be mobilized to become highly functional. The lack of clinical trials on a large scale makes data a little robust, in spite of promising information, there are still many variables in the studies relating to radiation and immune system. The clarification of the mechanisms underlying immune response to radiation exposure may contribute to treatment improvement, gain of life quality and span of patients.

Effects of X-radiation on lung cancer cells: the interplay between oxidative stress and P53 levels.

Lung cancer (LC) ranks as the most prevalent and deadliest cause of cancer death worldwide. Treatment options include surgery, chemotherapy and/or radiotherapy, depending on LC staging, without specific highlight. The aim was to evaluate the effects of X-radiation in three LC cell lines. H69, A549 and H1299 cell lines were cultured and irradiated with 0.5-60 Gy of X-radiation. Cell survival was evaluated by clonogenic assay. Cell death and the role of reactive oxygen species, mitochondrial membrane potential, BAX, BCL-2 and cell cycle were analyzed by flow cytometry. Total and phosphorylated P53 were assessed by western blotting. Ionizing radiation decreases cell proliferation and viability in a dose-, time- and cell line-dependent manner, inducing cell death preferentially by apoptosis with cell cycle arrest. These results may be related to differences in P53 expression and oxidative stress response. The results obtained indicate that sensibility and/or resistance to radiation may be dependent on molecular LC characteristics which could influence response to radiotherapy and treatment success.

The importance of radiotherapy on diffuse large B cell lymphoma treatment: a current review.

Diffuse large B cell lymphoma is recognized as a heterogeneous group of hematological malignancies; two main subtypes germinal center B and activated B cells are well defined although 15% of patients remain with unclassifiable disease. R-CHOP treatment has proven to provide very effective results in limited or advanced stage of the disease. However, treatment solely involving R-CHOP submits the patient to possible chemotherapy-induced toxicities, which may be avoided with the use of radiotherapy. Patients with early stage localized disease or who are particularly unresponsive to chemotherapy may be more suitable for mixed modality treatment with R-CHOP and consolidative radiotherapy. Although radiotherapy is being slowly phased out by other treatment strategies including chemotherapy and therapeutic drugs, it is still a highly important method of treatment. The different forms of radiotherapy can be used alongside these "new-age" treatment strategies to further improve prognostic outcomes and overall survival rates. The establishment of radiotherapy as a treatment strategy provides a highly beneficial prognostic advantage in early stage, localized disease.

Parental permissiveness, control, and affect and drug use among adolescents.

BACKGROUND: Parents play an important role in determining the risk of children's drug use. The aim of this study was to analyse how certain family-related variables (permissiveness toward drug use, and parental control and affect) were linked to the use of alcohol, tobacco and cannabis, based on young people's self-report of such variables. METHOD: The sample was composed of 1,428 school children (51.8% males) aged between 11 and 19 from Mallorca (Spain). RESULTS: We found that the young people who perceived their parents as permissive and those who perceived less maternal control and higher levels of both paternal and maternal affect were more likely to use alcohol, tobacco and cannabis. Sex differences were found within this pattern. Variables of maternal affect and control were not influential among males, whereas the general pattern was maintained among females. CONCLUSIONS: This study highlights the importance of perceived permissiveness and the need of considering parent's and children's gender when providing control and affect, as fathers will influence male children whereas mothers will influence female children.

Phenotypic and functional alterations on inflammatory peripheral blood cells after acute myocardial infarction.

The frequency and function of T cells, monocytes, and dendritic cell subsets were investigated in 12 patients after acute myocardial infarction (AMI)-(T0), 1 month after the episode (T1), and in 12 healthy individuals (HG). The cell characterization and the functional studies were performed by flow cytometry and by RT-PCR, after cell sorting. The most important findings at T0 moment, when compared with T1 and HG, were: a decrease in the frequency of IL-2-producing T cells; a lower frequency of TNF-α- and IL-6-producing monocytes, myeloid dendritic cells, and CD14(-/low)CD16(+)DCs; and a lower TNF-α mRNA expression, after sorting these cells. Moreover, the regulatory function of Treg cells, at T0 moment, was upregulated, based on the FoxP3, CTLA-4, and TGF-ß mRNA expression increase. The majority of these phenotypic and functional alterations disappeared at T1. Our data demonstrate that AMI induces a significant change in the immune system homeostasis.

Ultrasonography for measuring rectus abdominis muscles diastasis.

PURPOSE: Preoperative imaging evaluation may be useful for determining the position of recti abdominis muscles before their correction. The purpose of this study is to evaluate the accuracy of ultrasonography to measure the width of rectus abdominis muscle diastasis. METHODS: Rectus diastasis was measured by ultrasonography preoperatively in 20 females. Rectus diastasis was measured in seven levels along the anterior rectus sheath by ultrasound after sustained deep inspiration and after expiration. Rectus diastasis, at the same levels, was also measured after its exposition during abdominoplasty by two independent observers, using a surgical compass. These values were compared using Wilcoxon's statistical text, for non independent values. RESULTS: There was no significant difference between the values obtained by ultrasound and those measured during surgery in the supra-umbilical levels and at the level of the umbilicus. However, below the umbilicus these values differed significantly, showing smaller values in the imaging evaluation. CONCLUSION: Ultrasonography is an accurate method to measure rectus diastasis above the umbilicus and at the umbilical level.