Liposomal Phenylephrine Nanoparticles Enhance the Antitumor Activity of Intratumoral Chemotherapy in a Preclinical Model of Melanoma.

Intratumoral injection of anticancer agents has limited efficacy and is not routinely used for most cancers. In this study, we aimed to improve the efficacy of intratumoral chemotherapy using a novel approach comprising peri-tumoral injection of sustained-release liposomal nanoparticles containing phenylephrine, which is a potent vasoconstrictor. Using a preclinical model of melanoma, we have previously shown that systemically administered (intravenous) phenylephrine could transiently shunt blood flow to the tumor at the time of drug delivery, which in turn improved antitumor responses. This approach was called dynamic control of tumor-associated vessels. Herein, we used liposomal phenylephrine nanoparticles as a "local" dynamic control strategy for the B16 melanoma. Local dynamic control was shown to increase the retention and exposure time of tumors to intratumorally injected chemotherapy (melphalan). C57BL/6 mice bearing B16 tumors were treated with intratumoral melphalan and peri-tumoral injection of sustained-release liposomal phenylephrine nanoparticles (i.e., the local dynamic control protocol). These mice had statistically significantly improved antitumor responses compared to melphalan alone (p = 0.0011), whereby 58.3% obtained long-term complete clinical response. Our novel approach of local dynamic control demonstrated significantly enhanced antitumor efficacy and is the subject of future clinical trials being designed by our group.

Expression of c-erb-B2 oncoprotein as a neoantigen strategy to repurpose anti-neu antibody therapy in a model of melanoma.

In this study, we tested a novel approach of "repurposing" a biomarker typically associated with breast cancer for use in melanoma. HER2/neu is a well characterized biomarker in breast cancer for which effective anti-HER2/neu therapies are readily available. We constructed a lentivirus encoding c-erb-B2 (the animal homolog to HER2/neu). This was used to transfect B16 melanoma in vitro for use in an orthotopic preclinical mouse model, which resulted in expression of c-erb-B2 as a neoantigen target for anti-c-erb-B2 monoclonal antibody (7.16.4). The c-erb-B2-expressing melanoma was designated B16/neu. 7.16.4 produced statistically significant in vivo anti-tumor responses against B16/neu. This effect was mediated by NK-cell antibody-dependent cell-mediated cytotoxicity. To further model human melanoma (which expresses <5% HER2/neu), our c-erb-B2 encoding lentivirus was used to inoculate naïve (wild-type) B16 tumors in vivo, resulting in successful c-erb-B2 expression. When combined with 7.16.4, anti-tumor responses were again demonstrated where approximately 40% of mice treated with c-erb-B2 lentivirus and 7.16.4 achieved complete clinical response and long-term survival. For the first time, we demonstrated a novel strategy to repurpose c-erb-B2 as a neoantigen target for melanoma. Our findings are particularly significant in the contemporary setting where newer anti-HER2/neu antibody-drug candidates have shown increased efficacy.

Early Stage Breast Cancer: Does Histologic Subtype (Ductal vs. Lobular) Impact 5 Year Overall Survival?

Histology is an important predictor of the behavior of breast cancer. We aim to study the impact of histology on the overall survival (OS) of breast cancer patients. We studied 11,085 breast cancer patients diagnosed with T1-T2 tumors, clinically node-negative and non-metastatic, from 2004 to 2019 included in the National Cancer Database. Kaplan-Meier curves, log-rank tests and Cox regression models were used to study the impact of histology and other variables on OS. In our patient population, 8678 (78.28%) had ductal cancer (IDC), while 2407 (21.71%) had lobular cancer (ILC). ILC patients were significantly more likely to be older, Caucasian, have a lower grade at diagnosis and be hormone receptor-positive compared to IDC patients. There was no statistically significant difference in the 5-year OS of early stage ductal (16.8%) and lobular cancer patients (16.7%) (p = 0.200). Patients of Hispanic and African American origin had worse OS rates compared to non-Hispanic and Caucasian patients, respectively. For node-positive disease, HER2+ tumors and triple-negative tumors, chemotherapy had a positive influence on OS (HR 0.85, 95% CI 0.77-0.93, p = 0.0012). Histology did not have a significant impact on the 5-year OS of early stage breast cancer patients.

Role of Surgery in Metastatic Melanoma and Review of Melanoma Molecular Characteristics.

We aimed to review the molecular characteristics of metastatic melanoma and the role of surgery in metastasectomy for metastatic melanoma. We performed a systematic literature search on PubMed to identify relevant studies focusing on several mutations, including NRAS, BRAF, NF1, MITF, PTEN, TP53, CDKN2A, TERT, TMB, EGFR, and c-KIT. This was performed in the context of metastatic melanoma and the role of metastasectomy in the metastatic melanoma population. A comprehensive review of these molecular characteristics is presented with a focus on their prognosis and role in surgical metastasectomy.

Time to treatment disparities in gastric cancer patients in the United States of America: a comprehensive retrospective analysis.

Introduction: Gastric cancer ranks as the 5th most prevalent cancer and the 4th leading cause of cancer-related deaths worldwide. Various treatment modalities, including surgical resection, chemotherapy, and radiotherapy, are available for gastric cancer patients. However, disparities related to age, sex, race, socioeconomic factors, insurance status, and demographic factors often lead to delayed time to treatment. Methods: In this retrospective study, conducted between 2004 and 2019, we utilized data from the National Cancer Database (NCDB) to investigate the factors contributing to disparities in the time to first treatment, surgery, chemotherapy, and radiotherapy among gastric cancer patients. Our analysis incorporated several variables, and statistical analysis was conducted to provide valuable insights into these disparities. Results: We observed notable disparities in the timing of treatment for various demographic groups, including age, sex, race, insurance status, geographic location, and facility type. These disparities include longer time to treatment in males (32.67 vs 30.75), Native Americans (35.10 vs 31.09 in Asians), low-income patients (32 vs 31.15), patients getting treatment in an academic setting (36.11 vs 29.61 in community setting), significantly longer time to chemotherapy in 70+ age group (51.13 vs 40.38 in <40 y age group), black race (55.81 vs 47.05 in whites), low income people (49.64 vs 46.74), significantly longer time to radiotherapy in females (101.61 vs 79.75), blacks and Asians (109.68 and 113.96 respectively vs 92.68 in Native Americans) etc. There are various other disparities in time to surgery, chemotherapy, and radiotherapy. Conclusions: Understanding these disparities is crucial in developing targeted strategies to improve timely access to appropriate treatments and enhance outcomes for gastric cancer patients. Future research with updated data and prospective study designs can provide a more comprehensive understanding of the factors influencing patient outcomes in gastric cancer.

Disparities in Time-to-treatment for Patients With Melanoma.

BACKGROUND/AIM: This study aimed to investigate the demographic and socioeconomic factors associated with disparities in the time-to-treatment for melanoma. PATIENTS AND METHODS: We conducted an analysis of patients with melanoma from 2004 to 2019 using the National Cancer Database. Time intervals from diagnosis to surgery, radiation, and chemotherapy were compared based on age, sex, race, and socioeconomic status. RESULTS: A total of 647,273 patients with melanoma were included. Overall, Hispanic patients had the longest times to surgery, radiation, and chemotherapy compared to non-Hispanic patients (surgery 38.52 vs. 31.90 days, radiation 130.12 vs. 99.67 days, chemotherapy 93.66 vs. 83.72 days, all p<0.01). Similarly, black patients and those who were uninsured had the longest times-to-treatment. CONCLUSION: We identified significant disparities in time-to-treatment, related to both race and socioeconomic factors. It is increasingly imperative to conduct further investigations into the root causes of these disparities to effectively address and rectify the inequities present in breast cancer care.

Inequities in Time to Treat Thyroid Cancer.

BACKGROUND/AIM: The purpose of this study was to determine socioeconomic and demographic factors which may contribute to inequities in time to treat thyroid cancer. PATIENTS AND METHODS: We used data from the National Cancer Database, 2004-2019, to conduct an analysis of thyroid cancer patients. All (434,083) patients with thyroid cancer, including papillary (395,598), follicular (23,494), medullary (7,638), and anaplastic (7,353) types were included. We compared the wait time from diagnosis to first treatment, surgery, radiotherapy, and chemotherapy for patients based on age, race, sex, location, and socioeconomic status (SES). RESULTS: A total of 434,083 patients with thyroid cancer were included. Hispanic patients had significantly longer wait times to all treatments compared to non-Hispanic patients (first treatment 33.44 vs. 20.45 days, surgery 40.06 vs. 26.49 days, radiotherapy 114.68 vs. 96.42 days, chemotherapy 92.70 vs. 58.71 days). Uninsured patients, patients at academic facilities, and patients in metropolitan areas also had the longest wait times to treatment. CONCLUSION: This study identified multiple disparities related to SES and demographics that correspond to delays in time to treatment. It is crucial that this topic is investigated further to help mitigate these incongruities in thyroid cancer care in the future.

Sociodemographic Barriers to the Timely Treatment of Pancreatic Cancer.

BACKGROUND/AIM: Pancreatic cancer has a high mortality rate and timely treatment is imperative for favorable patient outcomes. This retrospective study aimed to identify disparities in time to treatment for pancreatic cancer based on sociodemographic factors. PATIENTS AND METHODS: The study used the National Cancer Database from 2004 to 2019. A total of 423,482 patients with pancreatic cancer were included in the study. Time to first treatment, surgery, radiation, and chemotherapy were analyzed in the context of age, sex, race, Hispanic origin, insurance status, income, facility type, geographic setting, grade, stage, and Charlson-Deyo Comorbidity score (CDC). RESULTS: All sociodemographic factors included were found to be significantly associated with disparities for time to treatment in at least one of the categories studied. Minorities, treatment at academic facilities, and patients with a high CDC score had consistently longer times to all treatment classifications. CONCLUSION: The analyzed sociodemographic factors affected time to pancreatic cancer treatment. Disparities in time to treatment for pancreatic cancer must be studied and understood to ameliorate the impact this cancer has on society and assure the best possible care for all communities.

Disparities in Time to Treatment for Skin Cancer.

BACKGROUND/AIM: Skin cancer is the most common cancer worldwide. This study aimed to identify factors contributing to the disparities in skin cancer treatment. PATIENTS AND METHODS: Data from The National Cancer Database (NCDB) spanning 2004 to 2019 were utilized. Variables including age, sex, race, Hispanic origin, Charlson-Deyo Comorbidity (CDC) score, geographic location, insurance status, income, grade and stage of cancer, and type of treatment facility impacting the time to treatment, surgery, radiation, and chemotherapy were analyzed. RESULTS: Trends of longer time to treatment were seen with older age, non-Hispanic white, uninsured, those with a higher CDC score, and treated at academic facilities. Additionally, annual income and clinicopathology of cancer were also significantly associated with time to treatment. CONCLUSION: Our findings contribute to the expanding body of evidence pointing to the influence of socioeconomic and demographic factors in treatment disparities across diverse patient populations.

Clinical manifestations and expression of CD18 to guide the diagnosis of leukocyte adhesion deficiency type 1: Mexico experience.

BACKGROUND: Leukocyte adhesion deficiency type 1 (LAD-1) is an inborn error of immunity characterized by a defect in leukocyte trafficking. METHODS: Patients with clinical suspicion of LAD-1 were referred to our institution. Complete blood count and flow cytometric analysis, to identify the expression of CD18, CD11b, and the lymphocyte population phenotyping, were performed, and statistical analysis was completed. RESULTS: We report clinical manifestations and immunological findings of six Mexican patients diagnosed with LAD-1. The diagnosis was based on typical clinical presentation, combined with laboratory demonstration of leukocytosis, and significant reduction or near absence of CD18 and its associated molecules CD11a, CD11b, and CD11c on leukocytes. We found atypical manifestations, not described in other countries, such as early-onset autoimmunity or infections caused by certain microorganisms. CONCLUSIONS: Patients with LAD-1 may present with atypical manifestations, making flow cytometry an indispensable tool to confirm the diagnosis. We present the first report of LAD-1 patients in a Latin American country.

Progenitor-like exhausted SPRY1+CD8+ T cells potentiate responsiveness to neoadjuvant PD-1 blockade in esophageal squamous cell carcinoma.

Neoadjuvant immune checkpoint blockade (ICB) demonstrates promise in operable esophageal squamous cell carcinoma (ESCC), but lacks available efficacy biomarkers. Here, we perform single-cell RNA-sequencing of tumors from patients with ESCC undergoing neoadjuvant ICB, revealing a subset of exhausted CD8+ T cells expressing SPRY1 (CD8+ Tex-SPRY1) that displays a progenitor exhausted T cell (Tpex) phenotype and correlates with complete response to ICB. We validate CD8+ Tex-SPRY1 cells as an ICB-specific predictor of improved response and survival using independent ICB-/non-ICB cohorts and demonstrate that expression of SPRY1 in CD8+ T cells enforces Tpex phenotype and enhances ICB efficacy. Additionally, CD8+ Tex-SPRY1 cells contribute to proinflammatory phenotype of macrophages and functional state of B cells, which thereby promotes antitumor immunity by enhancing CD8+ T cell effector functions. Overall, our findings unravel progenitor-like CD8+ Tex-SPRY1 cells' role in effective responses to ICB for ESCC and inform mechanistic biomarkers for future individualized immunotherapy.

A narrative review of prognostic indices in the evaluation of gastrointestinal cancers.

Background and Objective: Accurate cancer prognostication allows for conscious decision-making. There is a need for precise indices, along with predictive biomarkers, which aid cancer prognostication. We sought to conduct an overview of the current state of prognostic indices and biomarkers in the evaluation of gastrointestinal (GI) cancers, specifically esophageal, colon and rectal. Methods: We conducted a comprehensive review of articles in the PubMed database between September 2001 and February 2022. Only articles written in English were included. We reviewed retrospective analyses and prospective observational studies. Key Content and Findings: Nomograms are well-described tools that provide estimates of specific cancer-related events, such as overall survival (OS). They are also useful in unroofing specific patient-related variables, which may be associated with cancer survival. Certain prognostic indices have been tested against each other with the goal of discerning superiority. Finally, specific biomarkers have emerged as promising prognostic indicators. Conclusions: Nomograms play a significant role in the prognostication of GI cancer. The identification of specific biomarkers in cancer prognostication is evolving. As we embark on the era of precision medicine, further investigation of reliable prognostic indices and biomarkers is needed.

Overall Survival Following Neoadjuvant Chemotherapy Versus Adjuvant Chemotherapy in Clinically Node Negative T1 Triple Negative Breast Cancer.

BACKGROUND: The purpose of this study was to compare the overall survival (OS) of upfront surgery followed by adjuvant chemotherapy (ACT) versus neoadjuvant chemotherapy (NACT) followed by surgery in patients with clinical T1 clinically node negative triple negative breast cancer (TNBC). PATIENTS AND METHODS: We retrospectively reviewed 48,329 women with cT1N0 TNBC from 2006 to 2016 in the National Cancer Database (NCDB). Patients were categorized into five pathologic subgroups based on ACT versus NACT and definitive pathologic stage after surgery: ACT with unchanged stage (pT0-1N0), ACT with pathologic upstage (any nodal disease, > pT1N0), NACT with pCR (ypT0-isN0), NACT with stable disease (SD) (ypT1N0), and NACT with progressive disease (PD) (any nodal disease, > ypT1N0). The primary outcome was 5 year OS. RESULTS: Patients with TNBC who underwent upfront surgery followed by ACT had better OS compared with those who received NACT (p < 0.001). The hazard ratio (HR) for death for NACT compared with ACT was 1.42 (95% CI 1.26-1.59, p < 0.001) on multivariate analysis. Patients who underwent upfront surgery followed by ACT and whose pathological stage was unchanged from clinical stage had similar outcomes compared with those who received NACT and attained pCR with 5 year OS of 92.7% versus 93.3% (p = 0.34). Patients with clinical T1cN0 tumors who underwent NACT with pCR had better outcomes compared with those who underwent ACT with unchanged stages. (p = 0.025). CONCLUSIONS: For cT1N0 TNBC patients, OS of upfront surgery followed by ACT was not inferior to those who underwent NACT. Neoadjuvant chemotherapy was associated with better outcomes in cT1c patients who attained pCR.

Human intravital microscopy in the study of sarcomas: an early trial of feasibility.

Sarcomas comprise a vast and heterogenous group of rare tumors. Because of their diversity, it is challenging to study sarcomas as a whole with regard to their biological and molecular characteristics. This diverse set of tumors may also possess differences related to their tumor-associated vasculature, which in turn may impact the ability to deliver systemic therapies (e.g., chemotherapy, targeted therapies, and immunotherapy). Consequently, response to systemic treatment may also be variable as these depend on the ability of the therapy to reach the tumor target via the tumor-associated vasculature. There is a paucity of data regarding sarcoma-related tumor vessels, likely in part to the rarity and heterogeneity of this cancer as well as the previously limited ability to image tumor-associated vessels in real time. Our group has previously utilized confocal fluorescent imaging technology to observe and characterize tumor-associated vessels in real time during surgical resection of tumors, including cutaneous melanoma and carcinomatosis implants derived from gastrointestinal, gynecological, or primary peritoneal (e.g., mesothelioma) tumors. Our prior studies have demonstrated the feasibility of real-time, human intravital microscopy in the study of these tumor types, leading to early but important new data regarding tumor vessel characteristics and their potential implications on drug delivery and efficacy. In this brief report, we present our latest descriptive findings in a cohort of patients with sarcoma who underwent surgical resection and real-time, intravital microscopy of their tumors. Overall, intravital imaging was feasible during the surgical resection of large sarcomas. Clinical trial registrations: ClinicalTrials.gov, identifier NCT03517852; ClinicalTrials.gov, identifier NCT03823144.

Geographic and Demographic Disparities in Colorectal Cancer: A National Cancer Database Analysis.

BACKGROUND AND OBJECTIVES: Area of residence may adversely affect survival and outcomes in many cancers. The objective of this study was to evaluate the impact of geographical and demographic disparities on survival of patients with colorectal cancer. MATERIALS AND METHODS: Data were obtained from the National Cancer Database (NCDB) colon, rectosigmoid, and rectal datasets. Patients were categorized by area of residence, namely, metropolitan (MA), urban (UA), or rural (RA). Sociodemographic and tumor-related data were collected and analyzed to evaluate variables affecting overall survival (OS). RESULTS: In total, 973,139 patients between 2004 and 2013 were included in the study, of which 83%, 15%, and 2% were MA, UA, and RA residents, respectively. RA and UA patients were mostly white male with low income and no comorbidities. In univariate analysis, OS was worse for RA (hazard ratio [HR] 1.10) and UA (HR 1.06) colorectal cancer patients than that for MA colorectal cancer patients. In multivariate analysis revealed significant association between OS and geographic residence, with worse OS for RA (HR 1.02, p = 0.04) and UA (HR 1.01, p = 0.003) patients. Black (HR 1.14) and Native American (HR 1.17) patients had worse outcomes, while Asians (HR 0.8), women (HR 0.88), and patients with higher income had improved OS (HR 0.88). CONCLUSION: The differences in the OS for RA and UA patients with colorectal cancer were significantly driven by economic disparity. Area of residence represents an important factor independently limiting access to care, particularly in geographically isolated individuals.

Abscopal Effect Following Cryoablation in a Patient with Metastatic Breast Cancer.

While breast cancer is a common disease with many available treatment options, many patients still have limited responses, especially those with metastatic breast cancer. Surgery of the primary tumor or metastatic sites is often not part of the treatment regimen for patients with metastatic breast cancer. Cryoablation is a relatively non-invasive procedure that is being investigated for patients with breast cancer. Patients with metastatic breast cancer who are not surgical candidates may derive benefit from cryoablation through the abscopal effect. In this case report, we present a patient with stage IV breast cancer who was treated with cryoablation of the primary breast tumor and showed evidence of an abscopal effect in regional and distant metastases.

How Well Does Non-mass Enhancement Correlate With DCIS/Invasive Cancer?

INTRODUCTION: Contiguous non-mass enhancement (NME) often coexists with a solid tumor component on MRI, but it can be challenging to predict whether NME represents invasive breast cancer, ductal carcinoma in situ (DCIS), benign disease, or biopsy site reaction. The purpose of this study was to determine the association between the size/extent of NME and the presence of invasive cancer and/or DCIS on final pathology. METHODS: This was a single institution retrospective analysis of a prospectively maintained breast cancer registry (2010-2020). Female patients who underwent surgical resection were included if they had a diagnosis of invasive breast cancer (with or without DCIS) and had an MRI showing both a solid mass and contiguous NME. The size of NME on MRI was compared with the size of invasive cancer and/or DCIS on the final pathology. RESULTS: From a total of 3443 patients, 225 patients were included. 86.2% had invasive ductal carcinoma (IDC), and 12.0% had invasive lobular carcinoma 76.9% were ER+, 16.4% were HER2+, and 13.3% were triple negative breast cancer (TNBC). 18.7% received neoadjuvant chemotherapy (NCT) of whom 31% achieved a complete radiographic/pathologic response. Pearson correlation coefficients (r) between the size of NME and invasive cancer/DCIS showed a strong and positive correlation of MRI NME with DCIS on pathology in patients without NCT. Subgroup analysis showed the strongest correlations for NME and DCIS among non-white (r = .70) and HER2 + patients (r = .74) who did not receive NCT. CONCLUSIONS: Strong correlations between NME and DCIS were found for HER2 + disease and non-white patients, but only modest correlations were found for other patient/disease characteristics. These correlations may impact decisions in surgical approach.