Single-fraction stereotactic ablative body radiation therapy for primary and metastasic lung tumor: A new paradigm?

Stereotactic ablative body radiotherapy (SABR) is an effective technique comparable to surgery in terms of local control and efficacy in early stages of non-small cell lung cancer (NSCLC) and pulmonary metastasis. Several fractionation schemes have proven to be safe and effective, including the single fraction (SF) scheme. SF is an option cost-effectiveness, more convenience and comfortable for the patient and flexible in terms of its management combined with systemic treatments. The outbreak of the severe acute respiratory syndrome coronavirus 2 pandemic has driven this not new but underutilized paradigm, recommending this option to minimize patients' visits to hospital. SF SABR already has a long experience, strong evidence and sufficient maturity to reliably evaluate outcomes in peripheral primary NSCLC and there are promising outcomes in pulmonary metastases, making it a valid treatment option; although its use in central locations, synchronous and recurrencies tumors requires more prospective safety and efficacy studies. The SABR radiobiology study, together with the combination with systemic therapies, (targeted therapies and immunotherapy) is a direction of research in both advanced disease and early stages whose future includes SF.

A Promising Thermodynamic Study of Hole Transport Materials to Develop Solar Cells: 1,3-Bis(N-carbazolyl)benzene and 1,4-Bis(diphenylamino)benzene.

The thermochemical study of the 1,3-bis(N-carbazolyl)benzene (NCB) and 1,4-bis(diphenylamino)benzene (DAB) involved the combination of combustion calorimetric (CC) and thermogravimetric techniques. The molar heat capacities over the temperature range of (274.15 to 332.15) K, as well as the melting temperatures and enthalpies of fusion were measured for both compounds by differential scanning calorimetry (DSC). The standard molar enthalpies of formation in the crystalline phase were calculated from the values of combustion energy, which in turn were measured using a semi-micro combustion calorimeter. From the thermogravimetric analysis (TGA), the rate of mass loss as a function of the temperature was measured, which was then correlated with Langmuir's equation to derive the vaporization enthalpies for both compounds. From the combination of experimental thermodynamic parameters, it was possible to derive the enthalpy of formation in the gaseous state of each of the title compounds. This parameter was also estimated from computational studies using the G3MP2B3 composite method. To prove the identity of the compounds, the 1H and 13C spectra were determined by nuclear magnetic resonance (NMR), and the Raman spectra of the study compounds of this work were obtained.

Quantifying Variations in Metal-Ligand Cooperative Binding Strength with Cyclic Voltammetry and Redox-Active Ligands.

Metal-ligand cooperativity (MLC), a phenomenon that leverages reactive ligands to promote synergistic reactions with metals, has proven to be a powerful approach to achieving new and unprecedented chemical transformations with metal complexes. While many examples of MLC are known with a wide range of substrates, experimentally quantifying how ligand modifications affect MLC binding strength remains a challenge. Here we describe how cyclic voltammetry (CV) was used to quantify differences in MLC binding strength in a series of square-pyramidal Ru complexes. This method relies on using multifunctional ligands (those capable of both MLC and ligand-centered redox activity) as electrochemical reporters of MLC binding strength. The synthesis and characterization of Ru complexes with three different redox-active tetradentate ligands and two different ancillary phosphines (PPh3 and PCy3) are described. Titration CV studies conducted using BH3·THF with BH3 as a model MLC substrate allowed ΔGMLC to be quantified for each complex. Compared to our base triaryl ligand, increasing π conjugation in the backbone of the redox-active ligand enhanced MLC binding, whereas increasing π conjugation in the flanking groups decreased the MLC binding strength. Structures and spectroscopic data collected for the isolated MLC complexes are also described along with supporting DFT calculations that were used to illuminate electronic factors that likely account for the observed differences in the MLC binding strength. These results demonstrate how redox-active ligands and CV can be used to quantify subtle differences in the MLC binding strength across a series of structurally related complexes with different ligand modifications.

New challenges in the combination of radiotherapy and immunotherapy in non-small cell lung cancer.

Immunotherapy has represented one of the main medical revolutions of recent decades, and is currently a consolidated treatment for different types of tumors at different stages and scenarios, and is present in a multitude of clinical trials. One of the diseases in which it is most developed is non-small cell lung cancer. The combination of radiotherapy and immunotherapy in cancer in general and lung cancer in particular currently represents one of the main focuses of basic and clinical research in oncology, due to the synergy of this interaction, which can improve tumor response, resulting in improved survival and disease control. In this review we present the biochemical and molecular basis of the interaction between radiotherapy and immunotherapy. We also present the current clinical status of this interaction in each of the stages and cases of non-small cell lung cancer, with the main results obtained in the different studies both in terms of tumor response and survival as well as toxicity. Finally, we mention the main studies underway and the challenges of this interaction in the coming years, including how these treatments should be combined to achieve the greatest efficacy with the fewest possible side effects (dose, type of radiotherapy and drugs, sequence of treatments).

Management of Resectable Stage III-N2 Non-Small-Cell Lung Cancer (NSCLC) in the Age of Immunotherapy.

Stage III non-small-cell lung cancer (NSCLC) with N2 lymph node involvement is a heterogeneous group with different potential therapeutic approaches. Patients with potentially resectable III-N2 NSCLC are those who are considered to be able to receive a multimodality treatment that includes tumour resection after neoadjuvant therapy. Current treatment for these patients is based on neoadjuvant chemotherapy +/- radiotherapy followed by surgery and subsequent assessment for adjuvant chemotherapy and/or radiotherapy. In addition, some selected III-N2 patients could receive upfront surgery or pathologic N2 incidental involvement can be found a posteriori during analysis of the surgical specimen. The standard treatment for these patients is adjuvant chemotherapy and evaluation for complementary radiotherapy. Despite being a locally advanced stage, the cure rate for these patients continues to be low, with a broad improvement margin. The most immediate hope for improving survival data and curing these patients relies on integrating immunotherapy into perioperative treatment. Immunotherapy based on anti-PD1/PD-L1 immune checkpoint inhibitors is already a standard treatment in stage III unresectable and advanced NSCLC. Data from the first phase II studies in monotherapy neoadjuvant therapy and, in particular, in combination with chemotherapy, are highly promising, with impressive improved and complete pathological response rates. Despite the lack of confirmatory data from phase III trials and long-term survival data, and in spite of various unresolved questions, immunotherapy will soon be incorporated into the armamentarium for treating stage III-N2 NSCLC. In this article, we review all therapeutic approaches to stage III-N2 NSCLC, analysing both completed and ongoing studies that evaluate the addition of immunotherapy with or without chemotherapy and/or radiotherapy.

Effective Approach to Render Stable Dynamic Omniphobicity and Icephobicity to Ultrasmooth Metal Surfaces.

Surface modifications for easy removal of liquids and solids from various metal surfaces are much less established than for silicon (Si) or glass substrates. Trimethylsiloxy-terminated polymethylhydrosiloxane (PMHS) is very promising because it can be directly immobilized covalently to a wide variety of metal surfaces by simply heating neat PMHS liquid, resulting in a film showing excellent dynamic omniphobicity. However, such PMHS films are easily degraded by hydrolytic attack in an aqueous environment. In this study, we have successfully improved the hydrolytic stability of the PMHS-covered ultrasmooth metal (Ti, Al, Cr, Ni, and Cu) surfaces by end-capping of the residual Si-H groups of the PMHS films with vinyl-terminated organosilanes, for example, trimethylvinylsilane (TMVS), through a platinum-catalyzed hydrosilylation reaction. The resulting TMVS-capped PMHS film surfaces showed significantly greater stability even after submersion in water for 6 days, with their excellent dynamic dewetting behavior toward water, toluene, n-hexadecane, and ethanol changing little. In addition, they also showed reasonable anti-icing (icephobic) properties with low ice-adhesion strength of less than 50 kPa even after 20 cycles of testing at -15 °C.

GOECP/SEOR clinical guidelines on radiotherapy for malignant pleural mesothelioma.

Malignant pleural mesothelioma (MPM) is a rare tumor with poor prognosis and rising incidence. Palliative care is common in MPM as radical treatment with curative intent is often not possible due to metastasis or extensive locoregional involvement. Numerous therapeutic advances have been made in recent years, including the use of less aggressive surgical techniques associated with lower morbidity and mortality (e.g., pleurectomy/decortication), technological advancements in the field of radiotherapy (intensity-modulated radiotherapy, image-guided radiotherapy, stereotactic body radiotherapy, proton therapy), and developments in systemic therapies (chemotherapy and immunotherapy). These improvements have had as yet only a modest effect on local control and survival. Advances in the management of MPM and standardization of care are hampered by the evidence to date, limited by high heterogeneity among studies and small sample sizes. In this clinical guideline prepared by the oncological group for the study of lung cancer of the Spanish Society of Radiation Oncology, we review clinical, histologic, and therapeutic aspects of MPM, with a particular focus on all aspects relating to radiotherapy, including the current evidence base, associations with chemotherapy and surgery, treatment volumes and planning, technological advances, and reradiation.

Targeted therapy moves to earlier stages of non-small-cell lung cancer: emerging evidence, controversies and future challenges.

Lung cancer continues to be the leading cause of cancer mortality and a serious health problem despite the numerous advances made in the last decade and the rapid advance of research in this field. In recent years, there has been a decrease in mortality from lung cancer coinciding with the approval times of targeted therapy. To date, targeted therapy has been used in the context of advanced disease in clinical practice, with great benefits in survival and quality of life. The next step will be to incorporate targeted therapy into the treatment of earlier stages of non-small-cell lung cancer, and there is already a randomized trial showing a disease-free survival benefit. However, there are many questions that need to be resolved first. In the present review, the authors discuss the findings of published reports and ongoing clinical trials assessing the role of targeted therapies in nonmetastatic disease.

Lay abstract Despite major therapeutic advances over the last decade, lung cancer continues to present the highest mortality rate of all cancers. Precision and personalized therapy directed at specific alterations in the genetic material of the tumor as well as immunotherapy has significantly improved survival in metastatic non-small-cell lung cancer. The next step will be to incorporate precision medicine into the treatment of earlier stages of non-small-cell lung cancer. The recent publication of the results of the ADAURA phase III trial showing a significant improvement in disease-free survival in patients with resected EGFR-mutated non-small-cell lung cancer who received an adjuvant EGFR-directed tyrosine kinase inhibitor called osimertinib has opened the doors to the incorporation of this novel agent into routine clinical practice. However, there are many questions that need to be resolved first. In the present review, the authors discuss the findings of published reports and ongoing clinical trials assessing the role of precision medicine in nonmetastatic disease.

Randomized Phase III Trial of Prophylactic Cranial Irradiation With or Without Hippocampal Avoidance for Small-Cell Lung Cancer (PREMER): A GICOR-GOECP-SEOR Study.

PURPOSE: Radiation dose received by the neural stem cells of the hippocampus during whole-brain radiotherapy has been associated with neurocognitive decline. The key concern using hippocampal avoidance-prophylactic cranial irradiation (HA-PCI) in patients with small-cell lung cancer (SCLC) is the incidence of brain metastasis within the hippocampal avoidance zone. METHODS: This phase III trial enrolled 150 patients with SCLC (71.3% with limited disease) to standard prophylactic cranial irradiation (PCI; 25 Gy in 10 fractions) or HA-PCI. The primary objective was the delayed free recall (DFR) on the Free and Cued Selective Reminding Test (FCSRT) at 3 months; a decrease of 3 points or greater from baseline was considered a decline. Secondary end points included other FCSRT scores, quality of life (QoL), evaluation of the incidence and location of brain metastases, and overall survival (OS). Data were recorded at baseline, and 3, 6, 12, and 24 months after PCI. RESULTS: Participants' baseline characteristics were well balanced between the two groups. The median follow-up time for living patients was 40.4 months. Decline on DFR from baseline to 3 months was lower in the HA-PCI arm (5.8%) compared with the PCI arm (23.5%; odds ratio, 5; 95% CI, 1.57 to 15.86; P = .003). Analysis of all FCSRT scores showed a decline on the total recall (TR; 8.7% v 20.6%) at 3 months; DFR (11.1% v 33.3%), TR (20.3% v 38.9%), and total free recall (14.8% v 31.5%) at 6 months, and TR (14.2% v 47.6%) at 24 months. The incidence of brain metastases, OS, and QoL were not significantly different. CONCLUSION: Sparing the hippocampus during PCI better preserves cognitive function in patients with SCLC. No differences were observed with regard to brain failure, OS, and QoL compared with standard PCI.

Recent advances in early stage lung cancer.

Treatment of early-stage non-small cell lung cancer has undergone considerable change in recent years. Areas of great interest to researchers include less invasive surgical methods with lower associated morbidity, indications for adjuvant chemotherapy and radiotherapy, the emergence of stereotactic body radiotherapy (SBRT) for peripheral and central or ultracentral tumors, and the probable role of adjuvant immunotherapy following surgery and SBRT, all of which may influence the management of these patients. RELEVANCE FOR PATIENTS: At present, the treatment of early stage non-small cell lung cancer is undergoing changes associated with the evolution of existing treatments and the advent of new treatments.

Immunotherapy Moves to the Early-Stage Setting in Non-Small Cell Lung Cancer: Emerging Evidence and the Role of Biomarkers.

Despite numerous advances in targeted therapy and immunotherapy in the last decade, lung cancer continues to present the highest mortality rate of all cancers. Targeted therapy based on specific genomic alterations, together with PD-1 and CTLA-4 axis blocking-based immunotherapy, have significantly improved survival in advanced non-small cell lung cancer (NSCLC) and both therapies are now well-established in this clinical setting. However, it is time for immunotherapy to be applied in patients with early-stage disease, which would be an important qualitative leap in the treatment of lung cancer patients with curative intent. Preliminary data from a multitude of studies are highly promising, but therapeutic decision-making should be guided by an understanding of the molecular features of the tumour and host. In the present review, we discuss the most recently published studies and ongoing clinical trials, controversies, future challenges and the role of biomarkers in the selection of best therapeutic options.

GOECP/SEOR clinical recommendations for lung cancer radiotherapy during the COVID-19 pandemic.

The coronavirus disease 2019 crisis has had a major and highly complex impact on the clinical practice of radiation oncology worldwide. Spain is one of the countries hardest hit by the virus, with devastating consequences. There is an urgent need to share experiences and offer guidance on decision-making with regard to the indications and standards for radiation therapy in the treatment of lung cancer. In the present article, the Oncological Group for the Study of Lung Cancer of the Spanish Society of Radiation Oncology reviews the literature and establishes a series of consensus-based recommendations for the treatment of patients with lung cancer in different clinical scenarios during the present pandemic.

Influence of Multisite Metal-Ligand Cooperativity on the Redox Activity of Noninnocent N2S2 Ligands.

Metal-ligand cooperativity (MLC) relies on chemically reactive ligands to assist metals with small-molecule binding and activation, and it has facilitated unprecedented examples of catalysis with metal complexes. Despite growing interest in combining ligand-centered chemical and redox reactions for chemical transformations, there are few studies demonstrating how chemically engaging redox active ligands in MLC affects their electrochemical properties when bound to metals. Here we report stepwise changes in the redox activity of model Ru complexes as zero, one, and two BH3 molecules undergo MLC binding with a triaryl noninnocent N2S2 ligand derived from o-phenylenediamine (L1). A similar series of Ru complexes with a diaryl N2S2 ligand with ethylene substituted in place of phenylene (L2) is also described to evaluate the influence of the o-phenylenediamine subunit on redox activity and MLC. Cyclic voltammetry (CV) studies and density functional theory (DFT) calculations show that MLC attenuates ligand-centered redox activity in both series of complexes, but electron transfer is still achieved when only one of the two redox-active sites on the ligands is chemically engaged. The results demonstrate how incorporating more than one multifunctional reactive site could be an effective strategy for maintaining redox noninnocence in ligands that are also chemically reactive and competent for MLC.

Alternative management for gynecological cancer care during the COVID-2019 pandemic: A Latin American survey.

OBJECTIVE: To determine the acceptance rate of treatment alternatives for women with either preinvasive conditions or gynecologic cancers during the COVID-19 pandemic among Latin American gynecological cancer specialists. METHODS: Twelve experts in gynecological cancer designed an electronic survey, according to recommendations from international societies, using an online platform. The survey included 22 questions on five topics: consultation care, preinvasive cervical pathology, and cervical, ovarian, and endometrial cancer. The questionnaire was distributed to 1052 specialists in 14 Latin American countries. A descriptive analysis was carried out using statistical software. RESULTS: A total of 610 responses were received, for an overall response rate of 58.0%. Respondents favored offering teleconsultation as triage for post-cancer treatment follow-up (94.6%), neoadjuvant chemotherapy in advanced stage epithelial ovarian cancer (95.6%), and total hysterectomy with bilateral salpingo-oophorectomy and defining adjuvant treatment with histopathological features in early stage endometrial cancer (85.4%). Other questions showed agreement rates of over 64%, except for review of pathology results in person and use of upfront concurrent chemoradiation for early stage cervical cancer (disagreement 56.4% and 58.9%, respectively). CONCLUSION: Latin American specialists accepted some alternative management strategies for gynecological cancer care during the COVID-19 pandemic, which may reflect the region's particularities. The COVID-19 pandemic led Latin American specialists to accept alternative management strategies for gynecological cancer care, especially regarding surgical decisions.

Cambiarenes: Single-Step Synthesis and Selective Zwitterion Binding of a Clip-Shaped Macrocycle with a Redox-Active Core.

A novel macrocyclic host molecule was synthesized that forms in a single step from commercially available starting materials. The core of the macrocycle backbone possesses two quinone rings and, thus, it is redox-active. Host-guest binding involving the clip-shaped cavity indicates selective binding of pyridine N-oxides based on the electron density of and steric bulk around the anionic oxygen.

Management of oligometastatic non-small cell lung cancer patients: Current controversies and future directions.

Oligometastatic non-small cell lung cancer (NSCLC) describes an intermediate stage of NSCLC between localized and widely-disseminated disease. This stage of NSCLC is characterized by a limited number of metastases and a more indolent tumor biology. Currently, the management of oligometastatic NSCLC involves radical treatment (radiotherapy or surgery) that targets the metastatic lesions and the primary tumor to achieve disease control. This approach offers the potential to achieve prolonged survival in patients who, in the past, would have only received palliative measures. The optimal therapeutic strategies for the different scenarios of oligometastatic disease (intracranial vs extracranial disease, synchronous vs metachronous) remain undefined. Given the lack of head-to-head studies comparing radiotherapy to surgery in these patients, the decision to apply surgery or radiotherapy (with or without systemic treatment) must be based on prognostic factors that allow us to classify patients. This classification will allow us to select the most appropriate therapeutic strategy on an individualized basis. In the future, the molecular or microRNA profiles will likely improve the treatment selection process. The objective of the present article is to review the most relevant scientific evidence on the management of patients with oligometastatic NSCLC, focusing on the role of radiotherapy and surgery. We also discuss areas of controversy and future directions.

Obturator nerve injury and repair during laparoscopic lymphadenectomy. Case report and review of the literature / Lesión y reparación laparoscópica de nervio obturador en linfadenectomía laparoscópica. Reporte de un caso y revisión de la literatura

Objective: To report a case of obturator nerve injury during laparoscopic lymphadenectomy and repair through the same approach during the same surgical procedure; and to present a review of the literature on this type of injury, techniques used, timing of the repair, and rehabilitation outcomes. Materials and Methods: Case presentation of a 29-year-old woman seen at the National Cancer Institute (Instituto Nacional de Cancerología) in Bogotá, Colombia. The patient had a clinical diagnosis of stage Ib1 squamous cell carcinoma of the cervix and was taken to radical trachelectomy plus bilateral pelvic lymphadenectomy because of her wish to preserve fertility. During the procedure, a complete dissection of the obturator nerve was recognized and repaired immediately through the laparoscopic approach. A literature search was conducted in the Medline database via PubMed. The terms used for the search were "Obturator Nerve," "Lymph Node Excision," "Trauma," "Nervous System". The search was limited to publications in Spanish and English and included case series and reports, cohorts and review articles published between 1968 and September 2018. Results: Eight studies were included, all of them case reports. In six cases, complete sectioning of the nerve was recognized during surgery. In four cases, end-to-end anastomosis was used for repair; three cases were reconstructed using sural nerve grafting; and one case was managed with neurolysis and end-to-end anastomosis. All cases were approached laparoscopically. Over a nine-month follow-up period, three patients recovered full nerve function. Conclusion: The studies retrieved were all case reports, the most frequent injury being complete nerve sectioning. Several nerve repair techniques were used. Recovery after one year was not complete in a significant number of the cases reported.

TITULO: LESIÓN Y REPARACIÓN LAPAROSCÓPICA DE NERVIO OBTURADOR EN LINFADENECTOMÍA LAPAROSCÓPICA. REPORTE DE CASO Y REVISIÓN DE LA LITERATURA. Objetivo: presentar el caso de una lesión del nervio obturador durante linfadenectomía laparoscópica y su reparación por la misma vía en el mismo tiempo quirúrgico, y realizar una revisión de la literatura de la presentación de este tipo de lesiones, así como de la técnica utilizada, el momento de su reparación y los resultados de la rehabilitación. Materiales y métodos: se presenta el caso de una mujer de 29 años atendida en el Instituto Nacional de Cancerología en Bogotá, Colombia, con diagnóstico clínico de carcinoma escamocelular de cérvix estadio Ib1, a quien se le practicó traquelectomía radical más linfadenectomía pélvica bilateral por el deseo de preservar la fertilidad. Durante el procedimiento se advirtió una sección completa del nervio obturador, la cual se reparó inmediatamente por vía laparoscópica. Se realizó una búsqueda de la literatura en la base de datos Medline vía PubMed. Los términos utilizados para la búsqueda fueron: "Obturator Nerve", "Lymph Node Excision", "Trauma", "Nervous System". Se buscaron series y reportes de caso, cohortes y artículos de revisión desde 1968 hasta septiembre 2018. La búsqueda se limitó a idiomas español e inglés. Resultados: se incluyeron ocho estudios, todos reportes de caso. Un total de seis de los casos presentaron sección completa del nervio advertida intraquirúrgicamente. En cuatro casos se realizó la reparación por medio de anastomosis términoterminal, tres casos con reconstrucción utilizando injerto de nervio sural y un caso con neurolisis y anastomosis término-terminal, todos por vía laparoscópica. En el seguimiento a nueve meses, tres pacientes recuperaron totalmente la función. Conclusión: los estudios encontrados fueron reportes de caso, la lesión más frecuente es la sección completa del nervio; se encuentran varia técnicas de reparación del nervio. La recuperación al año no es total en un importante número de casos reportados.

The Influence of Redox-Innocent Donor Groups in Tetradentate Ligands Derived from o-Phenylenediamine: Electronic Structure Investigations with Nickel.

The continued development of redox-active ligands requires an understanding as to how ligand modifications and related factors affect the locus of redox activity and spin density in metal complexes. Here we describe the synthesis, characterization, and electronic structure of nickel complexes containing triaryl NNNN (1) and SNNS (2) ligands derived from o-phenylenediamine. The tetradentate ligands in 1 and 2 were investigated and compared to those in metal complexes with compositionally similar ligands to determine how ligand-centered redox properties change when redox-active flanking groups are replaced with redox-innocent NMe2 or SMe. A derivative of 2 in which the phenylene backbone was replaced with ethylene (3) was also prepared to interrogate the importance of o-phenylenediamine for ligand-centered redox activity. Cyclic voltammograms collected for 1 and 2 revealed two fully reversible ligand-centered redox events. Remarkably, several quasi-reversible ligand-centered redox waves were also observed for 3 despite the absence of the o-phenylenediamine subunit. Oxidizing 1 and 2 with silver salts containing different counteranions (BF4-, OTf-, NTf2-) allowed the electrochemically generated complexes to be analyzed as a function of different oxidation states using single-crystal X-ray diffraction (XRD), EPR spectroscopy, and S K-edge X-ray absorption spectroscopy. The experimental data are corroborated by DFT calculations, and together, they reveal how the location of unpaired spin density and electronic structure in singly and doubly oxidized salts of 1 and 2 varies depending on the coordinating ability of the counteranions and exogenous ligands such as pyridine.