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.

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.

Treatment Contraindications Based on Comorbidity Status in Patients With Melanoma in the United States.

BACKGROUND/AIM: Melanoma incidence has increased in the United States over the past few decades, and disparities in patient treatment have been described. Although most patients with melanoma are good candidates for curative treatment, some are considered poor candidates for treatment because of comorbid conditions. We examined whether patient demographics influence treatment contraindication in melanoma. PATIENTS AND METHODS: The National Cancer Database (NCDB) was used to identify patients with melanoma from 2004 through 2015. Multivariate logistic regression was used to determine independent associations, adjusted for confounders. We excluded patients who did not receive treatment for reasons and patients with unknown treatment status. RESULTS: A total of 499,092 patients met the inclusion criteria. Of these, 525 (0.1%) had Treatment contraindicated because of comorbid conditions (TCBC) and 498,567 (99.9%) received treatment. Multivariate logistic regression showed higher odds of TCBC in patients with government insurance (OR=1.34, 95%CI=03-1.73; p=0.03) and patients without insurance (OR=2.75, 95%CI=1.76-4.29; p<0.001) than patients with private insurance. CONCLUSION: Demographic disparities affects treatment decision in oncological patients. Our study demonstrated a significantly higher likelihood of "nontreatment because of comorbid conditions" among melanoma patients with government insurance or without insurance. Greater efforts are needed to address inequalities in melanoma treatment in the United States.

Analysis of Differentiation Changes and Outcomes at Time of First Recurrence of Retroperitoneal Liposarcoma by Transatlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG).

BACKGROUND: Local recurrence following resection of retroperitoneal liposarcoma (RLPS) is common. Well-differentiated (WD) and dedifferentiated (DD) RLPS are distinct entities with differing outcomes. A few reports suggest that WDLPS can recur as DDLPS and that DDLPS can recur as WDLPS. This study evaluates whether this change in differentiation from the primary tumor to the first local recurrence impacts long-term outcomes. METHODS: Retrospective review from 22 sarcoma centers identified consecutive patients who underwent resection for a first locally recurrent RLPS from January 2002 to December 2011. Outcomes measured included overall survival, local recurrence, and distant metastasis. RESULTS: A total of 421 RPLS patients were identified. Of the 230 patients with primary DDLPS, 34 (15%) presented WDLPS upon recurrence (DD → WD); and of the 191 patients with primary WDLPS, 54 (28%) presented DDLPS upon recurrence (WD → DD). The 6-year overall survival probabilities (95% CI) for DD → DD, DD → WD, WD → WD, and WD → DD were 40% (32-48%), 73% (58-92%), 76% (68-85%), and 56% (43-73%) (p < 0.001), respectively. The 6-year second local recurrence incidence was 66% (59-73%), 63% (48-82%), 66% (57-76%), and 77% (66-90%), respectively. The 6-year distant metastasis incidence was 13% (9-19%), 3% (0.4-22%), 5% (2-11%), and 4% (1-16%), respectively. On multivariable analysis, DD → WD was associated with improved overall survival when compared with DD → DD (p < 0.001). Moreover, WD → DD was associated with a higher risk of LR (p = 0.025) CONCLUSION: A change in RLPS differentiation from primary tumor to first local recurrence appears to impact survival. These findings may be useful in counseling patients on their prognosis and subsequent management.

Morbidity and Outcomes After Distal Pancreatectomy for Primary Retroperitoneal Sarcoma: An Analysis by the Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group.

BACKGROUND: Multi-visceral resection often is used in the treatment of retroperitoneal sarcoma (RPS). The morbidity after distal pancreatectomy for primary pancreatic cancer is well-documented, but the outcomes after distal pancreatectomy for primary RPS are not. This study aimed to evaluate morbidity and oncologic outcomes after distal pancreatectomy for primary RPS. METHODS: In this study, 26 sarcoma centers that are members of the Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG) retrospectively identified consecutive patients who underwent distal pancreatectomy for primary RPS from 2008 to 2017. The outcomes measured were 90-day severe complications (Clavien-Dindo ≥ 3), postoperative pancreatic fistula (POPF) rate, and oncologic outcomes. RESULTS: Between 2008 and 2017, 280 patients underwent distal pancreatectomy for primary RPS. The median tumor size was 25 cm, and the median number of organs resected, including the pancreas, was three. In 96% of the operations, R0/R1 resection was achieved. The 90-day severe complication rate was 40 %. The grades B and C POPF complication rates were respectively 19% and 5% and not associated with worse overall survival. Administration of preoperative radiation and factors to mitigate POPF did not have an impact on the risk for the development of a POPF. The RPS invaded the pancreas in 38% of the patients, and local recurrence was doubled for the patients who had a microscopic, positive pancreas margin (hazard ratio, 2.0; p = 0.042). CONCLUSION: Distal pancreatectomy for primary RPS has acceptable morbidity and oncologic outcomes and is a reasonable approach to facilitate complete tumor resection.

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).

Clinicopathologic Characteristics and Prognosis of Invasive Papillary Carcinoma of the Breast.

BACKGROUND: Invasive papillary carcinoma (IPC) of the breast is thought to carry a more favorable prognosis than invasive ductal carcinoma (IDC). The aim of this study is to investigate the clinicopathological characteristics between IPC and IDC and their prognosis using a large nationwide data set. METHODS: Female patients diagnosed with malignant IPC and IDC between 2005 and 2014 were analyzed. Patients with incomplete survival data, stage 0/IV, unknown stage, or recurrent disease were excluded. Five-year overall survival was compared between IPC and IDC. RESULTS: Among 308,426 patients, 1147 had IPC and 307,279 had IDC. IPC presented more in older postmenopausal women, black Americans, and people who had government insurance. IPC had larger tumor size, lower-grade, and earlier-stage disease, less node-positive disease, higher hormone positivity, and lower human epidermal growth factor receptor 2 amplification. Adjuvant radiation and chemotherapy rates were lower in IPC than those in IDC. IPC had a similar 5-year overall survival as compared with IDC overall (86.8% versus 88.7%) (P = 0.06). Age, pathologic stage, and radiation treatment were shown to be independent prognostic factors of IPC. CONCLUSIONS: IPC has a similar prognosis as IDC, suggesting that these patients should follow the same treatment protocols.

Postoperative Morbidity After Resection of Recurrent Retroperitoneal Sarcoma: A Report from the Transatlantic Australasian RPS Working Group (TARPSWG).

BACKGROUND: This study aimed to evaluate perioperative morbidity after surgery for first locally recurrent (LR1) retroperitoneal sarcoma (RPS). Data concerning the safety of resecting recurrent RPS are lacking. METHODS: Data were collected on all patients undergoing resection of RPS-LR1 at 22 Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG) centers from 2002 to 2011. Uni- and multivariable logistic models were fitted to study the association between major (Clavien-Dindo grade ≥ 3) complications and patient/surgery characteristics as well as outcome. The resected organ score, a method of standardizing the number of organs resected, as previously described by the TARPSWG, was used. RESULTS: The 681 patients in this study had a median age of 59 years, and 51.8% were female. The most common histologic subtype was de-differentiated liposarcoma (43%), the median resected organ score was 1, and 83.3% of the patients achieved an R0 or R1 resection. Major complications occurred for 16% of the patients, and the 90-day mortality rate was 0.4%. In the multivariable analysis, a transfusion requirement was found to be a significant predictor of major complications (p < 0.001) and worse overall survival (OS) (p = 0.010). However, having a major complication was not associated with a worse OS or a higher incidence of local recurrence or distant metastasis. CONCLUSIONS: A surgical approach to recurrent RPS is relatively safe and comparable with primary RPS in terms of complications and postoperative mortality when performed at specialized sarcoma centers. Because alternative effective therapies still are lacking, when indicated, resection of a recurrent RPS is a reasonable option. Every effort should be made to minimize the need for blood transfusions.

Amelanotic melanoma of the head and neck: analysis of tumor characteristics from the National Cancer Database.

BACKGROUND: Amelanotic melanoma is an extremely rare subtype of cutaneous melanoma. The tumor characteristics are still not well understood, especially for those located in the head and neck. METHODS: Tumor characteristics of patients diagnosed with amelanotic melanoma of the head and neck (AMHN) from January 1, 2004, to December 31, 2015, were analyzed by querying the National Cancer Database. Characteristics of AMHN were subsequently compared with common malignant melanoma of the head and neck (CMMHN). RESULTS: Three hundred and sixty-eight patients were diagnosed with AMHN, and 69,267 were diagnosed with CMMHN. Of those with AMHN, 128 (34.8%) had melanoma located on the scalp and neck, and 172 (46.7%) were diagnosed with an early disease stage (i.e., 0, I, or II). When compared with CMMHN, patients with AMHN were more likely to be diagnosed after 80 years of age (25.3% vs. 18.2%; odds ratio [OR], 3.28; 95% CI, 1.09-9.84; P = 0.03), when Breslow depth was between 2.01 and 4.00 mm (28.5% vs. 6.5%; OR, 1.92; 95% CI, 1.15-3.19; P = 0.01), when ulceration was present (36.7% vs. 9.0%; OR, 1.99; 95% CI, 1.34-2.97; P = 0.001), and when mitotic count was 1 or more/mm2 (40.5% vs. 12.8%; OR; 2.53; 95% CI, 1.09-5.89; P = 0.03). No statistical difference was found for sex, specific location, stage, or lymph node involvement. CONCLUSION: Our study determined that AMHN is associated with older age, increased Breslow depth, presence of ulceration, and greater mitotic count when compared with CMMHN.

Primary mesenteric sarcomas: Collaborative experience from the Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG).

BACKGROUND: Primary mesenteric soft tissue sarcomas (STS) are rare and limited evidence is available to inform management. Surgical resection is challenging due to the proximity of vital structures and a need to preserve enteric function. OBJECTIVES: To determine the overall survival (OS) and recurrence-free survival (RFS) for patients undergoing primary resection for mesenteric STS. METHODS: The Trans-Atlantic Australasian Retroperitoneal Sarcoma Working Group (TARPSWG) is an intercontinental collaborative comprising specialist sarcoma centers. Data were collected retrospectively for all patients with mesenteric STS undergoing primary resection between 2000 and 2019. RESULTS: Fifty-six cases from 15 institutions were included. The spectrum of pathology was similar to the retroperitoneum, although of a higher grade. R0/R1 resection was achieved in 87%. Median OS was 56 months. OS was significantly shorter in higher-grade tumors (p = .018) and extensive resection (p < .001). No significant association between OS and resection margin or tumor size was detected. Rates of local recurrence (LR) and distant metastases (DM) at 5 years were 60% and 41%, respectively. Liver metastases were common (60%), reflecting portal drainage of the mesentery. CONCLUSION: Primary mesenteric sarcoma is rare, with a modest survival rate. LR and DM are frequent events. Liver metastases are common, highlighting the need for surveillance imaging.

Intravital Microscopy (IVM) in Human Solid Tumors: Novel Protocol to Examine Tumor-Associated Vessels.

BACKGROUND: Intravital microscopy (IVM) allows the real-time, direct visualization of microscopic blood vessels. This pilot clinical trial will elucidate the physical and functional characteristics of vessels associated with solid tumors. OBJECTIVE: The main objective of this study is to determine the feasibility of performing IVM in patients with solid tumors during the standard course of surgical resection. IVM will also be performed when vasopressors or fluid boluses are administered during the standard course of the operation. METHODS: This is an open-label, nonrandomized, single-center, pilot study of IVM observation in subjects with solid tumors undergoing surgical resection. RESULTS: This study was active on January 1, 2019 (NCT03823144) and funded by the Mayo Clinic Florida Cancer Focused Research Team Award. As of September 27, 2020, we had enrolled 20 patients. Accrual period is expected to end by December 31, 2021. CONCLUSIONS: This trial will support the development of interventions to improve patient treatment by extending the application of IVM to the tumor microenvironment. IVM observations during volume and pressor management at the time of surgery may aid in the development of strategies to augment responses to systemic treatments. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/15677.

Identification of stage I/IIA melanoma patients at high risk for disease relapse using a clinicopathologic and gene expression model.

PURPOSE: Patients with stage I/IIA cutaneous melanoma (CM) are currently not eligible for adjuvant therapies despite uncertainty in relapse risk. Here, we studied the ability of a recently developed model which combines clinicopathologic and gene expression variables (CP-GEP) to identify stage I/IIA melanoma patients who have a high risk for disease relapse. PATIENTS AND METHODS: Archival specimens from a cohort of 837 consecutive primary CMs were used for assessing the prognostic performance of CP-GEP. The CP-GEP model combines Breslow thickness and patient age, with the expression of eight genes in the primary tumour. Our specific patient group, represented by 580 stage I/IIA patients, was stratified based on their risk of relapse: CP-GEP High Risk and CP-GEP Low Risk. The main clinical end-point of this study was five-year relapse-free survival (RFS). RESULTS: Within the stage I/IIA melanoma group, CP-GEP identified a high-risk patient group (47% of total stage I/IIA patients) which had a considerably worse five-year RFS than the low-risk patient group; 74% (95% confidence interval [CI]: 67%-80%) versus 89% (95% CI: 84%-93%); hazard ratio [HR] = 2.98 (95% CI: 1.78-4.98); P < 0.0001. Of patients in the high-risk group, those who relapsed were most likely to do so within the first 3 years. CONCLUSION: The CP-GEP model can be used to identify stage I/IIA patients who have a high risk for disease relapse. These patients may benefit from adjuvant therapy.

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.