Agnostic drug development revisited.

The advent of molecular profiling and the generalization of next generation sequencing in oncology has enabled the identification of patients who could benefit from targeted agents. Since the tumor-agnostic approval of pembrolizumab for patients with MSI-High tumors in 2017, different molecularly-guided therapeutics have been awarded approvals and progressively incorporated in the treatment landscape across multiple tumor types. As the number of tumor-agnostic targets considered druggable expands in the clinic, novel challenges will reshape the drug development field involving all the stakeholders in oncology. In this review, we provide an overview of current tumor-agnostic approvals and discuss promising candidate therapeutics for tumor-agnostic designation and challenges for their broad implementation.

Intratumoral therapies in head and neck squamous cell carcinoma: A systematic review and future perspectives.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) presents an ideal scenario for intratumoral therapies (IT), due to its local recurrence pattern and frequent superficial extension. IT therapies aim to effect tumor regression by directly injecting antineoplastic agents into lesions. However, there is a lack of updated evidence regarding IT therapies in HNSCC. PATIENTS AND METHODS: A systematic literature search (CRD42023462291) was conducted using WebOfScience, ClinicalTrials.gov, and conference abstracts from ESMO and ASCO, identifying for IT clinical trials in patients with HNSCC, from database creation to September 12th, 2023. Efficacy as well as safety (grade ≥ 3 treatment-related adverse events[trAEs]) were reported. RESULTS: After evaluation of 1180 articles identified by the systematic search, 31 studies treating 948 patients were included. IT injectables were categorized as chemotherapies with or without electroporation (k = 4, N = 268), oncolytic viruses, plasmids, and bacteria-based (k = 16, N = 446), immunotherapies and EGFR-based therapies (k = 5, N = 160), radioenhancer particles (k = 2, N = 68), and calcium electroporation (k = 1, n = 6). EGFR-antisense plasmids, NBTXR3 radioenhancer and immune innate agonists show best overall response rates, at 83 %, 81 % and 44 % respectively. Eleven (35 %) studies added systemic therapy or radiotherapy to the IT injections. No study used predictive biomarkers to guide patient selection. 97 % studies were phase I-II. Safety-wise, electroporation and epinephrine-based injectable trials had significant local symptoms such as necrosis, fistula formation and post-injection dysphagia. Treatment-related tumor haemorrhages of various grades were described in several trials. Grade ≥ 3 trAEs attributable to the other therapies mainly comprised general symptoms such as fatigue. There were 3 injectable-related deaths across the systematic review. CONCLUSION: This is the first review to summarize all available evidence of IT in HNSCC. As of today, IT therapies lack sufficient evidence to recommend their use in clinical practice. Continuing research on potential molecules, patient selection, safe administration of injections and controlled randomized trials are needed to assess their added benefit.

Effect of Tumor Regression Grade on Survival and Disease-Free Interval in Patients Operated on for Locally Advanced Rectal Cancer.

INTRODUCTION: Colorectal cancer is the fourth leading cause of cancer-related death in both men and women in our population. In this regard, rectal cancer accounts for more than half of colorectal cancer deaths, and its incidence is expected to increase in the coming years. There have been significant changes in neoadjuvant therapy regimens, with promising results, as demonstrated by the recent RAPIDO and PRODIGE23 studies. Around 40% of patients diagnosed with locally advanced rectal cancer show some degree of response to neoadjuvant treatment, with complete tumor regression observed in up to one in five patients. MATERIALS AND METHODS: Retrospective observational study. A total of 181 patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy followed by surgery were analyzed. Clinical and pathological data were collected from the patients, including assessment of tumor regression through histopathological studies after surgery. The Mandard tumor regression grading system was used to categorize tumor response into different grades. RESULTS: The results showed a significant association between the degree of tumor regression and several important clinical outcomes. Specifically, patients with higher tumor regression had significantly better disease-free survival than those with less regression (p = 0.004). In addition, tumor regression was also correlated with the incidence of local recurrence (p = 0.018) and distant metastasis (p = 0.032). These associations suggest that tumor responsiveness to neoadjuvant therapy may influence the long-term progression of the disease. Regarding tumor deposits and the presence of lymphadenopathy, these factors were also found to be significantly associated with clinical outcomes. Patients with tumor deposits had a higher incidence of local recurrence (p = 0.025) and distant metastases (p = 0.041), while the presence of lymphadenopathy increased the risk of local recurrence (p = 0.013). These findings highlight the importance of evaluating not only tumor regression but also other pathological markers to predict prognosis and guide clinical management. CONCLUSIONS: The degree of tumor regression was not an independent predictor of survival compared to other variables such as nodal stage and presence of tumor deposits. This indicates that while tumor regression is an important factor, other elements also play a crucial role in determining the prognosis of patients with locally advanced rectal cancer. This study provides additional evidence for the importance of tumor regression, tumor deposits, and lymphadenopathy as predictors of clinical outcomes in patients with rectal cancer treated with neoadjuvant chemoradiotherapy.

Perceived quality of life by patients with immune-mediated inflammatory diseases treated with biological therapies. SACVINFA study.

OBJECTIVES: To evaluate health-related quality of life perceived by patients with the most prevalent immune-mediated inflammatory diseases in Spain: inflammatory bowel disease (IBD), psoriasis (Ps), psoriatic arthritis (AP), rheumatoid arthritis (RA), and spondyloarthropathies (SpAs), and to determine the factors that influence patient quality of life. METHODS: The SACVINFA study (SA=satisfaction, CV=quality of life, IN=immune-mediated, FA=pharmacy) consisted of an observational study conducted in 4 hospitals in the Community of Madrid. A cross-sectional analysis was made for adult patients diagnosed with an immune-mediated inflammatory disease who attended the Pharmacy Service. Quality of life was assessed using the EQ-5D-5L questionnaire (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression) and specific questionnaires: SIBDQ-9, DLQI, PsAQoL, QoL-RA, and ASQoL. RESULTS: A total of 578 patients were analysed (inflammatory bowel disease=25.3%; psoriasis=19.7%; spondyloarthropathies=18.7%; rheumatoid arthritis=18.5%; psoriatic arthritis=17.8%). The mean age (standard deviation) was 49.8 (12.3) years and 50.7% were male. The average score (standard deviation) for the global EQ-5D-5L was 0.771 (0.2) and the mean (standard deviation) visual analogue scale score was 71.5 (20.0). Type of immune-mediated inflammatory diseases was associated with differences in quality of life showing psoriasis and inflammatory bowel disease higher values of EQ5D-5L than psoriatic arthritis, rheumatoid arthritis, and spondyloarthropathies, p<.05 in all comparisons. Patients with RA, IBD, and Ps achieved 70% of the maximum score, while patients with PsA and SpAs did not reach 50% of the maximum possible score. Female gender, a state of moderate/severe disease severity, an older age, and a higher number of previous treatments were correlated with worse quality of life. Conversely, persistence to current treatment correlated with better quality of life. CONCLUSIONS: Patients with immune-mediated inflammatory diseases have markedly affected quality of life, mainly in the pain/discomfort dimension, especially in those immune-mediated inflammatory diseases with a rheumatological component.

Prognostic Value of Histone Acetyl Transferase 1 (HAT-1) and Inflammatory Signatures in Pancreatic Cancer.

Pancreatic cancer is a type of gastrointestinal tumor with a growing incidence and mortality worldwide. Pancreatic ductal adenocarcinoma (PDAC) constitutes 90% of cases, and late-stage diagnosis is common, leading to a 5-year survival rate of less than 10% in high-income countries. The use of biomarkers has different proven translational applications, facilitating early diagnosis, accurate prognosis and identification of potential therapeutic targets. Several studies have shown a correlation between the tissue expression levels of various molecules, measured through immunohistochemistry (IHC), and survival rates in PDAC. Following the hallmarks of cancer, epigenetic and metabolic reprogramming, together with immune evasion and tumor-promoted inflammation, plays a critical role in cancer initiation and development. In this study, we aim to explore via IHC and Kaplan-Meier analyses the prognostic value of various epigenetic-related markers (histones 3 and 4 (H3/H4), histone acetyl transferase 1 (HAT-1), Anti-Silencing Function 1 protein (ASF1), Nuclear Autoantigenic Sperm Protein (NASP), Retinol Binding Protein 7 (RBBP7), importin 4 (IPO4) and IPO5), metabolic regulators (Phosphoglycerate mutase (PGAM)) and inflammatory mediators (allograft inflammatory factor 1 (AIF-1), interleukin 10 (IL-10), IL-12A and IL-18) in patients with PDAC. Also, through a correlation analysis, we have explored the possible interconnections in the expression levels of these molecules. Our results show that higher expression levels of these molecules are directly associated with poorer survival rates in PDAC patients, except in the case of IL-10, which shows an inverse association with mortality. HAT1 was the molecule more clearly associated with mortality, with a hazard risk of 21.74. The correlogram demonstrates an important correlation between almost all molecules studied (except in the case of IL-18), highlighting potential interactions between these molecules. Overall, our study demonstrates the relevance of including different markers from IHC techniques in order to identify unexplored molecules to develop more accurate prognosis methods and possible targeted therapies. Additionally, our correlation analysis reveals potential interactions among these markers, offering insights into PDAC's pathogenesis and paving the way for targeted therapies tailored to individual patient profiles. Future studies should be conducted to confirm the prognostic value of these components in PDAC in a broader sample size, as well as to evaluate the possible biological networks connecting them.

Place Matters: A Study on the Influence of Birthplace and the Place of Development on Soccer Academy Players' Careers.

The effect of birthplace (the place where a player is born and grows up) is one of the key variables associated with soccer player development and achievement. However, recent studies have questioned the influence of contextual variables on selection and promotion processes related to birthplace. The main purposes of this study were: (1) establish whether there is a difference between the birthplace and sporting growth according to the stages of entry into the academy, (2) to evaluate the influence of geographical and contextual variables on sporting development, and (3) assess the chances of making a professional team debut. Applied logistic regression was used in order to analyse the birthplace and growth of 1411 male soccer players, of which 40.1% are incorporated in the U-12 category from a Spanish First division club, and the results showed a statistically significant association between a change from one's birthplace to the place of sporting growth and later success (79%). Key contextual variables such as number of inhabitants, population density, proximity to sports facilities, average household income and presence of sports clubs have been considered. The analysis of the contextual variables revealed that there was a positive relationship between certain variables, like a higher population, and being selected for the academy (p < 0.01; r = 0.28). Finally, the findings showed that players who experienced a geographical transition were 38% more likely to make a professional debut. The importance of considering the place of sporting growth when analysing the "birthplace effect" has therefore been demonstrated.

Thyroid abscess, an uncommon diagnosis: A case report and mini­review of the literature.

Thyroid abscess is a rare entity, commonly experienced by immunocompromised patients, or those who have anatomical abnormalities or a pre-existing thyroid disease. An early diagnosis continued by treatment with antibiotics and drainage of the abscess is the recommended therapeutic strategy for such cases. The present study describes a clinical case of this rare event, and also provides a brief literature review. The present study describes the case of a 48-year-old healthy male with no medical antecedents, apart from acute prostatitis treated with antibiotics for 6 days prior, who visited the Emergency Department of the authors' hospital with neck pain and progressive swelling of the mass. Diagnostic imaging confirmed the authors' suspicion of an abscess and revealed the lesion displacing the airway to the contralateral side. This restricted the mobility of the neck of the patient. As an emergency measure, the patient was then taken to the operating room for a neck examination. A hemithyroidectomy was finally performed. Following a prolonged hospital duration, he was discharged from the hospital and his recovery was uneventful without any voice alterations, hypocalcemia or recurrence.

Anodizing Tungsten Foil with Ionic Liquids for Enhanced Photoelectrochemical Applications.

This research examines the influence of adding a commercial ionic liquid to the electrolyte during the electrochemical anodization of tungsten for the fabrication of WO3 nanostructures for photoelectrochemical applications. An aqueous electrolyte composed of 1.5 M methanesulfonic acid and 5% v/v [BMIM][BF4] or [EMIM][BF4] was used. A nanostructure synthesized in an ionic-liquid-free electrolyte was taken as a reference. Morphological and structural studies of the nanostructures were performed via field emission scanning electron microscopy and X-ray diffraction analyses. Electrochemical characterization was carried out using electrochemical impedance spectroscopy and a Mott-Schottky analysis. From the results, it is highlighted that, by adding either of the two ionic liquids to the electrolyte, well-defined WO3 nanoplates with improved morphological, structural, and electrochemical properties are obtained compared to samples synthesized without ionic liquid. In order to evaluate their photoelectrocatalytic performance, the samples were used as photocatalysts to generate hydrogen by splitting water molecules and in the photoelectrochemical degradation of methyl red dye. In both applications, the nanostructures synthesized with the addition of either of the ionic liquids showed a better performance. These findings confirm the suitability of ionic liquids, such as [BMIM][BF4] and [EMIM][BF4], for the synthesis of highly efficient photoelectrocatalysts via electrochemical anodization.

Repeated pancreatic resection for pancreatic metastases from renal cell Carcinoma: A Spanish multicenter study (PANMEKID).

BACKGROUND AND OBJECTIVES: Recurrent isolated pancreatic metastasis from Renal Cell Carcinoma (RCC) after pancreatic resection is rare. The purpose of our study is to describe a series of cases of relapse of pancreatic metastasis from renal cancer in the pancreatic remnant and its surgical treatment with a repeated pancreatic resection, and to analyse the results of both overall and disease-free survival. METHODS: Multicenter retrospective study of patients undergoing pancreatic resection for RCC pancreatic metastases, from January 2010 to May 2020. Patients were grouped into two groups depending on whether they received a single pancreatic resection (SPS) or iterative pancreatic resection. Data on short and long-term outcome after pancreatic resection were collected. RESULTS: The study included 131 pancreatic resections performed in 116 patients. Thus, iterative pancreatic surgery (IPS) was performed in 15 patients. The mean length of time between the first pancreatic surgery and the second was 48.9 months (95 % CI: 22.2-56.9). There were no differences in the rate of postoperative complications. The DFS rates at 1, 3 and 5 years were 86 %, 78 % and 78 % vs 75 %, 50 % and 37 % in the IPS and SPS group respectively (p = 0.179). OS rates at 1, 3, 5 and 7 years were 100 %, 100 %, 100 % and 75 % in the IPS group vs 95 %, 85 %, 80 % and 68 % in the SPS group (p = 0.895). CONCLUSION: Repeated pancreatic resection in case of relapse of pancreatic metastasis of RCC in the pancreatic remnant is justified, since it achieves OS results similar to those obtained after the first resection.

Impact on costs and outcomes of multi-gene panel testing for advanced solid malignancies: a cost-consequence analysis using linked administrative data.

Background: To date, economic analyses of tissue-based next generation sequencing genomic profiling (NGS) for advanced solid tumors have typically required models with assumptions, with little real-world evidence on overall survival (OS), clinical trial enrollment or end-of-life quality of care. Methods: Cost consequence analysis of NGS testing (555 or 161-gene panels) for advanced solid tumors through the OCTANE clinical trial (NCT02906943). This is a longitudinal, propensity score-matched retrospective cohort study in Ontario, Canada using linked administrative data. Patients enrolled in OCTANE at Princess Margaret Cancer Centre from August 2016 until March 2019 were matched with contemporary patients without large gene panel testing from across Ontario not enrolled in OCTANE. Patients were matched according to 19 patient, disease and treatment variables. Full 2-year follow-up data was available. Sensitivity analyses considered alternative matched cohorts. Main Outcomes were mean per capita costs (2019 Canadian dollars) from a public payer's perspective, OS, clinical trial enrollment and end-of-life quality metrics. Findings: There were 782 OCTANE patients with 782 matched controls. Variables were balanced after matching (standardized difference <0.10). There were higher mean health-care costs with OCTANE ($79,702 vs. $59,550), mainly due to outpatient and specialist visits. Publicly funded drug costs were less with OCTANE ($20,015 vs. $24,465). OCTANE enrollment was not associated with improved OS (restricted mean survival time [standard error]: 1.50 (±0.03) vs. 1.44 (±0.03) years, log-rank p = 0.153), varying by tumor type. In five tumor types with ≥35 OCTANE patients, OS was similar in three (breast, colon, uterus, all p > 0.40), and greater in two (ovary, biliary, both p < 0.05). OCTANE was associated with greater clinical trial enrollment (25.4% vs. 9.5%, p < 0.001) and better end-of-life quality due to less death in hospital (10.2% vs. 16.4%, p = 0.003). Results were robust in sensitivity analysis. Interpretation: We found an increase in healthcare costs associated with multi-gene panel testing for advanced cancer treatment. The impact on OS was not significant, but varied across tumor types. OCTANE was associated with greater trial enrollment, lower publicly funded drug costs and fewer in-hospital deaths suggesting important considerations in determining the value of NGS panel testing for advanced cancers. Funding: T.P H holds a research grant provided by the Ontario Institute for Cancer Research through funding provided by the Government of Ontario (#IA-035 and P.HSR.158) and through funding of the Canadian Network for Learning Healthcare Systems and Cost-Effective 'Omics Innovation (CLEO) via Genome Canada (G05CHS).

Single metachronous bone metastasis following rectal adenocarcinoma: A case report.

Colorectal cancer (CRC) ranks as the third leading cause of cancer-related mortality in developed countries. While its incidence in early stages has increased due to screening programs, a significant number of patients experience the development of metastases either at the time of diagnosis or during follow-ups. Unlike certain other types of cancer, such as breast, prostate, or lung cancer, where bone tissue is a common site for secondary dissemination, CRC primarily spreads to the lymph nodes, liver and lungs. The occurrence of bone metastases from CRC is rare and usually coincides with tumor involvement in other locations. Risk factors for bone metastases include the location of the primary tumor, the age of the patients, KRAS mutations and the degree of tumor differentiation. Unlike metastases to the liver and lungs, bone metastases tend to be symptomatic, affecting the patient's quality of life and resulting in a poorer prognosis with shorter survival rates. The approach to patient management needs to be personalized. The present study describes the of a patient who underwent surgery for stage IV rectal adenocarcinoma and later developed a metastasis in the costal wall 79 months post-intervention, with no evidence of recurrence at other sites.

Spontaneous cervical hematoma caused by giant parathyroid adenoma in an elderly patient: A case report.

Spontaneous cervical hematoma usually occurs as a consequence of extracapsular bleeding from a parathyroid gland, generally due to the presence of an adenoma (giant adenoma), glandular hyperplasia, cystic component, or, less frequently, due to the existence of a carcinoma. The hematoma can be confined to the cervical compartment or extend to the mediastinum, potentially causing airway compression. Despite this, the recommended management in hemodynamically stable patients consists of surveillance and hospital monitoring with delayed surgery after a few weeks. On the other hand, in those patients with airway compromise and instability, emergency surgery, consisting of cervicotomy and drainage, is mandatory. The present study describes the case of a 78-year-old patient with a medical history of high blood pressure, non-insulin-dependent diabetes mellitus, dyslipidemia, moderate aortic stenosis, chronic kidney disease and sarcoidosis under pharmacological treatment who attended the emergency department due to symptoms of neck pain, an increase in soft tissue, and dyspnea on moderate exertion with an evolution leading to respiratory failure. This was secondary to a diagnosis of spontaneous cervical hematoma that required urgent surgical intervention. The results of histopathological analysis revealed that a giant parathyroid adenoma was responsible for the bleeding. The patient had a complicated post-operative period with a prolonged admission to the intensive care unit.

Peritoneal Metastases: Evolution from a Dark Horizon to an Encouraging Present and a Promising Future.

Peritoneal metastasis (PM) is the primary pattern of metastasis for primary tumours of the appendix, ovary, and peritoneal mesothelioma [...].

Basketball talent identification: a systematic review and meta-analysis of the anthropometric, physiological and physical performance factors.

Background: The purpose of this study was to do a systematic review and meta-analysis about the anthropometric, physiological, and physical performance that discriminate the physical talent in basketball. Methods: The search was conducted using the most relevant databases as Web of Science, PubMed, SPORTDiscus and Scopus, according to the PRISMA (2020) guideline. Keywords such as "basketball", "talented identification", "anthropometric", "physiology" and "physical performance" were used for the search, in English and following the "PICOS" question model. Eighteen articles' overall methodological quality was assessed using the Critical Review Forms. Results: The study found in basketball, height, body mass, Yo-Yo test, T-test, 20 m sprint, and jump performance had statistical significance between elite and non-elite groups, including different positions and levels. Conclusions: The reviewed literature highlighted a complicated relationship between anthropometric, physiological, and physical performance. Based on the results of the study, it's possible that height, body mass, agility, speed, endurance capacity, and lower lamb power could affect the early development of basketball.

Malignant Bowel Obstruction Due to Intraluminal Metastasis of Endometrial Adenocarcinoma Located in the Sigmoid Colon After Nine Years of Follow-Up.

Endometrial adenocarcinoma is currently the most common malignant tumor of the female genital tract. In the early stages, surgical or radiotherapy treatment offers high survival rates and excellent prognosis, although late recurrences have been described. Recurrences of endometrial adenocarcinoma are more frequent in the vaginal vault; however, implants are sometimes detected in the serosa of the colon and rectum, resulting in extrinsic compression. Here, we present the case of a 77-year-old patient with a clinical history of hysterectomy, lymphadenectomy, and double adnexectomy for endometrial adenocarcinoma (International Federation of Gynecology and Obstetrics (FIGO) Ia). Nine years after the initial treatment, she presented an endoluminal recurrence in the sigmoid colon, which is exceptional. The patient underwent surgery by performing an oncological sigmoidectomy. The immunohistochemical study revealed the tumor origin as metastasis of endometrial adenocarcinoma. The patient had a favorable postoperative period, subsequently receiving adjuvant therapy and being disease-free after 18 months of follow-up.

Gallbladder Volvulus in an Elderly Patient: A Case Report and Review of Literature.

Gallbladder volvulus is an uncommon cause of acute cholecystitis that results from the rotation of the gallbladder about its mesentery along the axis of the cystic pedicle. We present the case of an 87-year-old woman with acute abdominal pain in the right upper quadrant that began two days prior with no additional symptoms. The physical examination showed a large abdominal eventration on the right side and tenderness. A CT scan showed a distended gallbladder outside its liver bed and with a twist on its cystic pedicle, suggesting a gallbladder volvulus. Abdominal ultrasonography complementary revealed the gallbladder outside its vesicular fossa with incipient changes of acute cholecystitis but without evidence of gallstones. With the diagnosis of acute abdomen secondary to gallbladder volvulus, an emergency cholecystectomy was performed. The exact etiology of the gallbladder volvulus is unknown, although anatomical variants that predispose to its appearance have been described. The clinical presentation is similar to acute cholecystitis, so preoperative diagnosis can be challenging for both surgeons and radiologists and is often misdiagnosed. This is one of the few cases diagnosed with preoperative imaging techniques. Once diagnosed, the appropriate treatment is emergency cholecystectomy. Early diagnosis and surgical treatment are important before it progresses to necrosis, perforation, biliary peritonitis, and hemodynamic instability. Gallbladder volvulus is an uncommon condition. A high index of suspicion is required because the preoperative diagnosis is unusual. Once the diagnosis is established, the treatment is fundamentally surgical.

Selinexor for the treatment of recurrent or metastatic salivary gland tumors: Results from the GEMS-001 clinical trial.

OBJECTIVES: We aimed to evaluate the activity of selinexor, an oral selective inhibitor of nuclear export, in patients with recurrent or metastatic salivary gland tumors (SGT). METHODS: GEMS-001 is an open-label Phase 2 study for patients with recurrent or metastatic SGT with two parts. In Part 1 of the protocol, patients had tumor samples profiled with targeted next generation sequencing as well as immunohistochemistry for androgen receptor, HER-2 and ALK. For Part 2, patients with no targeted therapies available were eligible to receive selinexor 60 mg given twice weekly every 28 days. The primary endpoint was objective response rate. Secondary endpoints included progression-free survival (PFS) and prevalence of druggable alterations across SGT. RESULTS: One hundred patients were enrolled in GEMS-001 and underwent genomic and immunohistochemistry profiling. A total of 21 patients who lacked available matched therapies were treated with selinexor. SGT subtypes (WHO classification) included adenoid cystic carcinoma (n = 10), salivary duct carcinoma (n = 3), acinic cell carcinoma (n = 2), myoepithelial carcinoma (n = 2), carcinoma ex pleomorphic adenoma (n = 2) and other (n = 2). Of 18 evaluable patients, stable disease (SD) was observed in 17 patients (94%) (SD ≥6 months in 7 patients (39%)). However, no objective responses were observed. The median PFS was 4.9 months (95% confidence interval, 3.4-10). The most common treatment-related Grade 1-2 adverse events were nausea [17 patients (81%)], fatigue [16 patients (76%)], and dysgeusia [12 patients (57%)]. Most common treatment-related Grade 3-4 adverse events were hyponatremia [3 patients (14%)], neutrophil count decrease [3 patients (14%)] and cataracts [2 patients (10%)]. No treatment-related deaths were observed. CONCLUSIONS: Although tumor reduction was observed across participants, single agent selinexor anti-tumor activity was limited.

Differences in Colorectal Cancer Survival Based on Primary Tumor Location: Retrospective Study from a Single Institution.

Objective: The location of the primary tumor in colorectal cancer (CRC) could be a prognostic factor related to survival. However, its usefulness has not been sufficiently analyzed. The results in patients with tumors in initial stages are very limited, and there are descriptive parameters of survival that have not been analyzed in detail. In this study, the relationship between primary tumor location and survival in CRC patients was analyzed. Materials And Methods: This was a retrospective observational study. All patients treated consecutively for CRC between January 2005 and December 2019 in the same hospital center were included. Overall survival (OS), cancer-related survival (CRS), time to recurrence (TTR), relapse-free survival (RFS) and postrecurrence survival (PRS) were analyzed, and the results were classified by tumor stage. The results were compared among patients with right colon (RS), left colon (LS) and rectal tumors. Results: In the entire cohort, patients with RS tumors had lower OS and lower CRS at 60 months after diagnosis than did patients with LS or rectal tumors. In the regression analysis, the localization of the primary tumor was an independent prognostic indicator for OS and CRS. Analysis by tumor stage showed that patients with RS stage III tumors had lower OS and lower CRS at 60 months than did patients with LS and rectal tumors (42%, 59% and 53%, respectively, p = 0.006; and 48%, 63% and 57%, respectively, p = 0.025). Additionally, patients with RS Stage IV tumors had lower OS and lower CRS at 36 months than did patients with LS and rectal tumors (9%, 24%, 24%, respectively, p < 0.001; and 10%, 24% and 24%, respectively, p < 0.001). No differences were found in TTR and RFS among patients with stage I and II RS, LS, and rectal tumors. In contrast, patients with stage RS III tumors had significantly poorer PRS (9% for RS tumors, 13% for LS tumors, and 22% for rectal tumors) (p < 0.001). Conclusion: The location of the primary tumor in patients with CRC is related to survival. The effect of laterality is more marked in patients with stage III and IV tumors. Patients with RS tumors had lower OS and CRS due to the lower survival of patients with stage IV RS tumors and lower PRS for patients with stage III tumors.

Safety, Immunologic, and Clinical Activity of Durvalumab in Combination with Olaparib or Cediranib in Advanced Leiomyosarcoma: Results of the DAPPER Clinical Trial.

PURPOSE: Non-inflamed (cold) tumors such as leiomyosarcoma do not benefit from immune checkpoint blockade (ICB) monotherapy. Combining ICB with angiogenesis or PARP inhibitors may increase tumor immunogenicity by altering the immune cell composition of the tumor microenvironment (TME). The DAPPER phase II study evaluated the safety, immunologic, and clinical activity of ICB-based combinations in pretreated patients with leiomyosarcoma. PATIENTS AND METHODS: Patients were randomized to receive durvalumab 1,500 mg IV every 4 weeks with either olaparib 300 mg twice a day orally (Arm A) or cediranib 20 mg every day orally 5 days/week (Arm B) until unacceptable toxicity or disease progression. Paired tumor biopsies, serial radiologic assessments and stool collections were performed. Primary endpoints were safety and immune cell changes in the TME. Objective responses and survival were correlated with transcriptomic, radiomic, and microbiome parameters. RESULTS: Among 30 heavily pretreated patients (15 on each arm), grade ≥ 3 toxicity occurred in 3 (20%) and 2 (13%) on Arms A and B, respectively. On Arm A, 1 patient achieved partial response (PR) with increase in CD8 T cells and macrophages in the TME during treatment, while 4 had stable disease (SD) ≥ 6 months. No patients on Arm B achieved PR or SD ≥ 6 months. Transcriptome analysis showed that baseline M1-macrophage and B-cell activity were associated with overall survival. CONCLUSIONS: Durvalumab plus olaparib increased immune cell infiltration of TME with clinical benefit in some patients with leiomyosarcoma. Baseline M1-macrophage and B-cell activity may identify patients with leiomyosarcoma with favorable outcomes on immunotherapy and should be further evaluated.

A pan-cancer clinical platform to predict immunotherapy outcomes and prioritize immuno-oncology combinations in early-phase trials.

BACKGROUND: Immunotherapy is effective, but current biomarkers for patient selection have proven modest sensitivity. Here, we developed VIGex, an optimized gene signature based on the expression level of 12 genes involved in immune response with RNA sequencing. METHODS: We implemented VIGex using the nCounter platform (Nanostring) on a large clinical cohort encompassing 909 tumor samples across 45 tumor types. VIGex was developed as a continuous variable, with cutoffs selected to detect three main categories (hot, intermediate-cold and cold) based on the different inflammatory status of the tumor microenvironment. FINDINGS: Hot tumors had the highest VIGex scores and exhibited an increased abundance of tumor-infiltrating lymphocytes as compared with the intermediate-cold and cold. VIGex scores varied depending on tumor origin and anatomic site of metastases, with liver metastases showing an immunosuppressive tumor microenvironment. The predictive power of VIGex-Hot was observed in a cohort of 98 refractory solid tumor from patients treated in early-phase immunotherapy trials and its clinical performance was confirmed through an extensive metanalysis across 13 clinically annotated gene expression datasets from 877 patients treated with immunotherapy agents. Last, we generated a pan-cancer biomarker platform that integrates VIGex categories with the expression levels of immunotherapy targets under development in early-phase clinical trials. CONCLUSIONS: Our results support the clinical utility of VIGex as a tool to aid clinicians for patient selection and personalized immunotherapy interventions. FUNDING: BBVA Foundation; 202-2021 Division of Medical Oncology and Hematology Fellowship award; Princess Margaret Cancer Center.