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.

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.

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.

Effect of low-level creatinine clearance on short-term postoperative complications in patients with colorectal cancer.

Background: Renal function is closely related to cancer prognosis. Since preoperative renal insufficiency has been identified as a risk factor for postoperative complications, this study aimed to investigate the effect of preoperative creatinine clearance rate (CrCl) on short-term prognosis of patients undergoing colorectal surgery. Methods: A retrospective analysis was conducted of the electronic health records of 526 adult patients who underwent elective colorectal cancer (CRC) surgery from September 2014 to February 2019 at the First Affiliated Hospital of Wenzhou Medical University. Cases were divided into two groups according to CrCl level and clinical variables were compared. Risk factors associated with postoperative complications were evaluated through univariate and multivariate logistic regression analyses. Results: A total of 526 patients met the inclusion criteria. The overall rate of postoperative complications was 28.14%. Overall, the incidence of postoperative complications was significantly higher in the low CrCl patients. A low-level CrCl, multi-organ combined resection, and Charlson comorbidity index (CCI) were independent risk factors for short-term complications in patients with CRC. However, a low CrCl was identified as an independent risk factor for short-term postoperative complications in elderly, but not young patients in a subgroup analysis. Conclusions: Preoperative low-level CrCl, multi-organ combined resection, and CCI were significant risk factors of postoperative complications in CRC patients. Preoperative low-level CrCl and multi-organ combined resection has a poor prognostic impact for elderly patients with CRC. These findings should have important implications for health care decision-making among patients with CRC who are at higher risk for post-operative complications.

Circulating tumor DNA for breast cancer: Review of active clinical trials.

BACKGROUND: The new diagnostic concept of liquid biopsy is based on the analysis of circulating tumor cells (CTCs) and cell-free DNA (ctDNA). In addition to providing a more comprehensive view of the tumor characteristics including molecular variations, ctDNA analysis through liquid biopsies may also allow for a non-invasive, rapid, and cost-effective identification of biomarkers for tumor detection and monitoring of tumor progression. OBJECTIVE: In this review, we summarize key active clinical trial studies involving utilization of ctDNA derived from liquid biopsy in the early and metastatic breast cancer setting. With this, we also provide a brief overview of the potential future implementations of the LB technology and outlining how ctDNA analysis needs to be standardized through the performance of similar clinical studies. METHODS: A review was conducted on Clinicaltrials.gov to identify active trials related to use of circulating tumor DNA (ctDNA) for breast cancer. Search terms included "breast cancer," "liquid biopsy," and "ctDNA." CONCLUSION: While LB is gaining traction in many cancer settings, its use in BC is still early and warrants more investigation in breast cancer diagnostic and treatment settings, including early detection of disease recurrence.

Liquid biopsies for colorectal cancer: a narrative review of ongoing clinical trials and the current use of this technology at a comprehensive cancer center.

Objective: In this review, we summarize ongoing clinical trials involving liquid biopsies (LB) for colorectal cancer (CRC), outlining the current landscape and the future implementation of this technology. We also describe the current use of LB in CRC treatment at our institution, the Mayo Clinic Enterprise. Background: The use of LB in CRC treatment merits close attention. Their role is being evaluated in the screening, non-intervention, intervention, and surveillance settings through many active trials. This, coupled with the technique's rapid integration into clinical practice, creates constant evolution of care. Methods: Review of ClinicalTrials.gov was performed identifying relevant and active trials involving LB for CRC. "Colorectal cancer" plus other terms including "liquid biopsies" and "ctDNA" were used as search terms, identifying 35 active trials. Conclusions: LB use for the CRC is actively being investigated and requires close attention. Based on current evidence, Mayo Clinic Enterprise currently uses LB in the non-interventional, interventional and surveillance setting, but not for screening. Results of these trials may further establish the use of LB in the management of CRC.

Outcomes of patients with invasive mucinous and tubular carcinomas of the breast.

Invasive tubular carcinoma (ITC) and invasive mucinous carcinoma (IMC) of the breast are rare histologic subtypes of breast cancer associated with favorable prognoses. The aim of our study was to investigate the outcomes for these rare subtypes using the National Cancer Database. Female patients diagnosed with ITC or IMC between 2005 and 2014 were analyzed. The primary outcome was overall survival (OS), and we analyzed its association with adjuvant therapy. 2735 patients with ITC and 5602 patients with IMC were identified. ITC presented in younger patients (57 vs. 67 years), had smaller tumors (size <1 cm, 63.1% vs. 25.4%), earlier stage, and less node-positive disease (5% vs. 8.6%), compared with IMC. Older age, government insurance, lower income, treatment in a community cancer program, large tumor size, positive nodal status, and without endocrine therapy were associated with worse OS with either subtype on multivariate analysis. No OS benefit was found for node-positive ITC that received adjuvant chemotherapy compared with those who did not. (5-year OS of 96.0% vs. 91.3%, p = 0.17).OS was improved for IMC that received adjuvant chemotherapy (10-year OS: 82.5% vs. 60.1%, p = 0.008) and endocrine therapy (10-year OS: 86.6% vs. 81.2%, p < 0.001). We concluded that ITC has favorable clinicopathological characteristics and prognosis, even with node-positive disease. ITC and IMC may need to be evaluated independently when administering adjuvant treatment plans.

Skin cancer in non-white liver transplant recipients: Mayo Clinic experience.

BACKGROUND: Limited data are available on the development of skin cancer and the associated risk factors for non-White liver transplant (LT) recipients. The aim of this study is to determine the incidence of newly diagnosed skin cancer postoperatively and to identify the risk factors for the development of skin cancer in non-White LT recipients. METHODS: We conducted an initial retrospective chart review of non-White LT patients who received a transplant at our center between January 1, 2011, and December 31, 2013. RESULTS: Of the 96 patients in the study cohort, 32% were Black, 17% were Asian, 15% were White Hispanic, and 10% were Black Hispanic. One patient had a history of nonmelanoma skin cancer before transplant. No skin cancers were diagnosed during follow-up (median, 1.3 years; range, 17 days to 8.6 years). CONCLUSION: Our center's experience is consistent with the literature and suggests that the incidence of newly diagnosed skin cancer in non-White liver transplant recipients is low. Longer follow-up may provide additional insights into the specific risk factors for the posttransplant development of skin cancer.

A pilot trial of intravital microscopy in the study of the tumor vasculature of patients with peritoneal carcinomatosis.

Aberrancies in the tumor microvasculature limit the systemic delivery of anticancer agents, which impedes tumor response. Using human intravital microscopy (HIVM), we hypothesized that HIVM would be feasible in patients with peritoneal carcinomatosis (PC). During cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for PC, HIVM was performed in both tumor and non-tumor areas. The primary outcome was HIVM feasibility to measure vessel characteristics. We secondarily evaluated associations between HIVM vessel characteristics and oncologic outcomes (RECIST response to neoadjuvant therapy and disease-specific survival). Thirty patients with PC were enrolled. Nineteen patients (63.3%) received neoadjuvant therapy. HIVM was feasible in all patients. Compared to non-tumor (control) areas, PC areas had a lower density of functional vessels, higher proportion of non-functional vessels, smaller lumenal diameters, and lower blood flow velocity. Qualitative differences in these vessel characteristics were observed among patients who had partial response, stable disease, or progressive disease after receiving neoadjuvant therapy. However, no statistically significant relationships were found between HIVM vessel characteristics and oncologic outcomes. These novel findings comprise the first-in-human, real-time evidence of the microscopic differences between normal and tumor-associated vessels and form the basis for our larger, ongoing clinical trial appropriately powered to determine the clinical utility of HIVM (NCT03823144).

Comparative Analysis of Acral Melanoma in Chinese and Caucasian Patients.

BACKGROUND: Acral melanoma (AM) is a rare subtype of melanoma, which is one of the least common in Caucasian patients but is a common subtype of melanoma in Chinese patients. It is unclear if prognosis differs between Chinese and Caucasian patients diagnosed with AM. The aim of our study is to investigate patient characteristics and survival differences between Chinese and Caucasian AM patients. METHODS: Two large institutional melanoma databases from Fudan University Shanghai Cancer Center (FUSCC) and Mayo Clinic enterprise were retrospectively reviewed from 2009 to 2015. Clinicopathologic and survival data were collected and analyzed between the two groups. The primary outcome was disease-specific survival (DSS) and was calculated using the Kaplan Meier (KM) method. RESULTS: The Chinese group presented with more advanced disease compared with Caucasians: thicker Breslow depth (median 3.0 mm vs. 1.2 mm, p=0.003), more ulcerated disease (66.1% vs. 29%; p < 0.001), and advanced stages (stage II/III 84.3% vs. 37.1%; p < 0.001). No significant difference was identified in terms of age at diagnosis, location, histologic subtypes, or node positive rate. The 5-year DSS rate was 68.4% and 73% (p=0.56) in Chinese and Caucasians AM patients, respectively. Male gender, Breslow thickness, ulceration, and positive sentinel lymph nodes were independent poor prognostic factors on multivariate analysis. CONCLUSIONS: There appears to be no difference in stage-stratified survival between Chinese and Caucasians, supporting the implementation of clinical trials for AM that could include both Chinese and Caucasian patients.

Dynamic control of tumor vasculature improves antitumor responses in a regional model of melanoma.

Despite advances in therapy for melanoma, heterogeneous responses with limited durability represent a major gap in treatment outcomes. The purpose of this study was to determine whether alteration in tumor blood flow could augment drug delivery and improve antitumor responses in a regional model of melanoma. This approach to altering tumor blood flow was termed "dynamic control." Dynamic control of tumor vessels in C57BL/6 mice bearing B16 melanoma was performed using volume expansion (saline bolus) followed by phenylephrine. Intravital microscopy (IVM) was used to observe changes directly in real time. Our approach restored blood flow in non-functional tumor vessels. It also resulted in increased chemotherapy (melphalan) activity, as measured by formation of DNA adducts. The combination of dynamic control and melphalan resulted in superior outcomes compared to melphalan alone (median time to event 40.0 vs 25.0 days, respectively, p = 0.041). Moreover, 25% (3/12) of the mice treated with the combination approach showed complete tumor response. Importantly, dynamic control plus melphalan did not result in increased adverse events. In summary, we showed that dynamic control was feasible, directly observable, and augmented antitumor responses in a regional model of melanoma. Early clinical trials to determine the translational feasibility of dynamic control are ongoing.

Completion lymph node dissection in patients with sentinel lymph node positive cutaneous head and neck melanoma.

BACKGROUND: Relatively few cutaneous head and neck melanoma (CHNM) patients with were included in the multicenter selective lymphadenectomy trial II (MSLT-II). Our objective was to investigate whether immediate completion lymph node dissection completion of lymph node dissection (CLND) was associated with survival benefit for sentinel lymph node (SLN) positive CHNM using the National Cancer Database. METHODS: SLN positive patients with CHNM from 2012 to 2014 were retrospectively analyzed. Patients were divided into two groups: those who underwent SLN biopsy (SLNB) only versus those who underwent SLNB followed by CLND (SLNB + CLND). The primary outcome was 5-year overall survival (OS). RESULTS: Among 530 SLNB + patients, 342 patients underwent SLNB followed by CLND (SLNB + CLND). The SLNB only group had fewer positive SLN, less advanced pathologic stage, and a lower rate of adjuvant immunotherapy. There was no significant difference in 5-year OS between the two groups (51.0% vs 67%; P = .56). After adjusting for pathologic stage, there remained no difference in 5-year OS among patients with stage IIIA (63.0% vs. 73.6%, P = 0.22) or IIIB/IIIC disease (39.1% vs 57.8%; P = .52). Conclusions Using a large nationwide database, CLND was not shown to be associated with improved OS for patients with SLNB positive CHNM, validating the results of MSLT-II.

Residual Tumor on Wide Excisional Margins After Treatment of Invasive Melanoma.

BACKGROUND/AIM: The surgical management of invasive melanoma has been debated for many years and recommended excisional margins have been established. We aimed to describe the factors and survival related to the presence of residual tumor in patients with invasive melanoma lymph nodes negative. PATIENTS AND METHODS: We performed a retrospective study by querying the National Cancer Database from 2004 to 2015. Associations were tested using a multivariate analysis. Overall survival was compared using the Kaplan-Meier method. RESULTS: A total of 26,440 patients met the inclusion criteria. For Breslow depth groups ≤1 mm and >2 mm, older age and location in the head and neck were factors associated to residual tumor in margins (p<0.05), whereas only location in the head and neck was associated to residual tumor for patients with Breslow depth between 1.01-2.00 mm (p<0.05). CONCLUSION: Knowledge of the factors associated with the residual tumor will help establish a patient-centered management and decrease the recurrence of disease.

A novel anesthesiologist-led multidisciplinary model for evaluating high-risk surgical patients at a comprehensive cancer center.

The objective of this retrospective analysis was to describe the development and implementation of an anesthesiologist-led multidisciplinary committee to evaluate high-risk surgical patients in order to improve surgical appropriateness. The study was conducted in an anesthesia preoperative evaluation clinic at an academic comprehensive cancer center. One hundred sixty-seven high-risk surgical patients with cancer-related diagnoses were evaluated and discussed at a High-Risk Committee (HRC) meeting to determine surgical appropriateness and optimize perioperative care. The HRC is an anesthesiologist-led model for multidisciplinary review of high-risk patients developed at Roswell Park Comprehensive Cancer Center. The group of high-risk patients in which surgery was not performed had, on average, a greater percentage of hypertension, smoking history, dyspnea, heart failure, chronic obstructive pulmonary disease, diabetes, renal failure, and sleep apnea than the group in whom surgery was performed. Only one of 107 high-risk patients who had surgery died within the first 30 days after surgery. A smaller percentage of patients died in the group that had surgery versus the group in which surgery was canceled. For all patients discussed by the HRC, the mortality was less than 2% within the first 30 days after the HRC.

Is metastasectomy a worthy option?-the role of surgery in metastatic colon cancer to liver and lungs.

BACKGROUND: The role of surgery and metastasectomy is controversial in the treatment of stage IV colon cancer (CC). The aim of this study was to investigate the relationship between primary tumor resection (PTR) with metastasectomy and survival in patients diagnosed with metastatic CC. METHODS: The National Cancer Data Base (NCDB) was retrospectively queried for patients diagnosed with colon adenocarcinoma from 2004 to 2013. Patient demographics, clinical characteristics, and short-term outcomes were collected. Groups were generated based on if surgery was performed and, if so, was metastasectomy involved. Associations between groups were evaluated using Kruskal-Wallis and Pearson Chi-square tests. Overall survival (OS) was summarized using standard Kaplan-Meier methods. The association between surgical group and OS was evaluated using the log-rank test. RESULTS: Of 31,172 patients, 13,214 (42.4%) had surgery while 17,958 (57.6%) did not. Among these, 81.3% of patients had liver metastases only, while 18.7% of patients had both liver and lung metastases. Median OS was 15.1 months (95% CI: 14.8 to 15.5 months) for the entire cohort. However, median OS was significantly better for those who had surgery (either PTR alone or PTR with metastasectomy) compared to those who did not (21.8 vs. 7.5 months, P<0.001). Patients who received PTR with metastasectomy had worse median OS (20.5 vs. 21.8 months, P=0.035) compared to those who only received PTR (P=0.211). CONCLUSIONS: PTR in select patients diagnosed with metastatic CC provides a remarkable improvement to survival rate. The role of metastasectomy remains controversial as no difference in survival outcomes exists between patients who received it and who did not.

Intraoperative fluid restriction in hyperthermic intraperitoneal chemotherapy.

BACKGROUND: Multiple studies highlight the importance of liberal fluid administration in cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC). Over-resuscitation can delay recovery and wound healing. We report an intraoperative protocol that restricts fluid administration and minimizes morbidity. MATERIALS AND METHODS: Retrospective analysis of 35 patients that underwent CRS-HIPEC for curative intent under fluid restriction protocol from June 2015 to July 2017 was performed. Protocol consists of continuous infusion of vasopressin 0.02 units/h and maintaining urine output at 0.5 mL/kg/h via crystalloid and colloid. Endpoint was Clavien-Dindo ≥3 events within 30 d of CRS-HIPEC. RESULTS: Median age was 56 y; 71% were female. Malignancies treated: appendix (49%), colon (31%), and other (20%). Median peritoneal cancer index was 15, complete cytoreduction was achieved in 91% of patients. Median time for return of bowel function was 5 d, median length of hospital stay was 7 d. There were 28 bowel anastomoses. Median intraoperative crystalloid, colloid, and packed red blood cells were (1900, 1500, and 700 mL), respectively. Clavien-Dindo grade 3-4 events occurred in five patients. There were no deaths 30 d after surgery. CONCLUSIONS: A fluid restriction protocol appears to be safe and feasible in the setting of CRS-HIPEC for curative intent.

Intravital microscopy in the study of the tumor microenvironment: from bench to human application.

Intravital microscopy (IVM) is a dynamic imaging modality that allows for the real time observation of biologic processes in vivo, including angiogenesis and immune cell interactions. In the setting of preclinical cancer models, IVM has facilitated an understanding of the tumor associated vasculature and the role of effector immune cells in the tumor microenvironment. Novel approaches to apply IVM to human malignancies have thus far focused on cancer diagnosis and tumor vessel characterization, but have the potential to provide advances in the field of personalized medicine by identifying individual patients who may respond to systemically delivered chemotherapeutic drugs or immunotherapeutic agents. In this review, we highlight the role that IVM has had in investigating tumor vasculature and the tumor microenvironment in preclinical studies and discuss its current and future applications to directly observe human tumors.