Gabriel, Emmanuel

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.

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.

Abstract Background Metaplastic breast cancer (MBC) is a rare and aggressive subtype of breast cancer (BC) defined by presence of both epithelial and mesenchymal components. Most are triple negative but are often chemo-refractory and associated with poor survival outcomes compared to non-metaplastic triple negative BC. Advances in therapy have led to improvements in survival outcomes of patients (pts) with BC over the last decade. Our multicenter retrospective study aims to assess (1) progression free survival (PFS) and overall survival (OS) (2) factors predictive of survival outcomes in MBC pts Methods We performed a retrospective analysis of pts diagnosed with MBC from 1997-2021 at Mayo Clinic (Florida, Arizona and Rochester) under IRB approval. Kaplan-Meier method was used to estimate OS and PFS at 1, 3 and 5 years. Cox regression models were used to examine the association between risk factors and survival outcomes. All tests were two-sided with p value < 0.05 considered statistically significant Results We evaluated 158 pts with MBC. Median age and tumor size was 61 (range: 20-91) years and 2.8 (range: 0.5-21) cm, respectively, with 80% of pts being postmenopausal. At diagnosis, 14.6% of pts had clinical T3/T4 disease, 16.4% were clinically node-positive, and 6.3% (10 pts) had distant metastases (DM). Spindle cell histology was seen in 36 pts. Most MBC pts were triple-negative (68.3%), high grade (77.2%) and high Ki-67 (36/47; 76.5%). Of the 61 pts tested for germline mutation, 8 (13.1%) were positive, with BRCA1/2, PTEN, NBN, CHEK2, and BARD1 mutations. Most pts had lumpectomy (53.8%), followed by simple mastectomy (38.5), and modified radical mastectomy (7.7%). Majority of pts had sentinel lymph node biopsy (71.8%). Adjuvant radiation therapy was performed in 65.6% of pts. Pathologic complete response (pCR) was noted in 4/38 (10.5%) evaluable pts who received neoadjuvant chemotherapy (NACT). Residual cancer burden (RCB) scores of 2 and 3 were seen in 76.2% of evaluable pts. Median follow-up time was 2.2 years (range: 6 days-24.6 years). Overall, 1-, 3-, and 5-year OS was 93.3%, 81.7%, and 76.0%, while PFS was 80.8%, 67.9%, and 60.9%, respectively. The presence of DM at diagnosis [HR 38.55 (11.18, 132.93), p < 0.001] and spindle cell histology (SC) [HR 2.57 (1.19, 5.53), p = 0.02] predicted worse OS in multivariable analysis. Inferior PFS was predicted by DM [HR 18.84 (6.53, 54.35), p < 0.001], SC [HR 2.46 (1.25, 4.86), p = 0.009], and node-positivity at diagnosis [HR 3.65 (1.5, 8.89), p = 0.004]. The 5-year OS and PFS were 22.2% and 0% for DM pts versus 80.0% and 65.6% for non-DM pts. The 5-year OS and PFS were 71.5% and 54.7% for SC pts versus 81% and 66.6% for non-SC pts. 5-year OS and PFS for NACT pts was 67.3% and 52.6% for NACT pts versus 78.2% and 62.8% for non-NACT pts. Age at diagnosis, menopausal status, family history of BC, grade, stage, tumor size, hormone-receptor and HER2 status, and use of NACT were not found to be significantly associated with OS or PFS in multivariate analysis. Conclusion This study is one of the largest and most recent review of institutional experiences with MBC. Overall, OS at 5 years was improved compared to prior older studies of MBC but still remains very low for those with DM, representing an area of unmet clinical need. SC and DM correlated with worse outcomes for both PFS and OS. Additionally, node positivity at diagnosis was a predictor of worse PFS. In contrast, no association was seen between survival and tumor size, stage, hormone receptor-positivity, HER2 receptor-positivity. The low pCR rates following NACT in our study are consistent with reported literature. Further, use of NACT does not impact survival, suggesting pts with resectable disease should proceed with surgery first. Citation Format: Siven Chinniah, Raza Zarrar, Zhuo Li, Kostandinos Sideras, Alvaro Moreno-Aspitia, Saranya Chumsri, Rohit Rao, Sarah McLaughlin, James Jakub, Emmanuel Gabriel, Sanjay Bagaria, Laura Vallow, Santo Maimone, Pooja Advani. Clinical Factors associated with Survival Outcomes in Patients with Metaplastic Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-25.

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.

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.

Introduction: Nearly half of the adult population in the United States has been diagnosed with hypertension. Adrenal hormonal hypersecretion is a leading cause of secondary hypertension. Adrenal vein sampling (AVS) may assist in differentiating between unilateral and bilateral adrenal hormonal hypersecretion to identify patients who are candidates for adrenalectomy. We reviewed the use of AVS at our institution along with associated outcomes after adrenalectomy. Materials and Methods: A retrospective chart review was conducted of patients with a diagnosis of primary hyperaldosteronism (PA) or adrenocorticotropic hormone-independent Cushing syndrome (AICS) and who underwent adrenalectomy between January 1, 2010, and December 1, 2021. Patient data of baseline characteristics, preoperative workup, including AVS, and postoperative outcomes were collected and analyzed. Results: Seventy-one patients were identified in the study period (48 PA and 23 AICS). Computed tomography scan identified unilateral adrenal nodules in 52 patients (29 left; and 23 right), bilateral nodules in 13 patients, and no nodules in 6 patients. AVS was performed in 45 patients with PA (93%) and 5 patients with AICS (21%). After surgery, the number of PA patients with hypokalemia or requiring potassium supplementation significantly decreased after adrenalectomy (before surgery: 33 [68.7%]; and after surgery: 5 [10.4%], P < .01). The number of medications required for hypertension in AICS patients also significantly decreased. No major adverse events were noted. Conclusions : Our long-term experience demonstrates the ongoing use of AVS during workup of patients with primary hyperaldosteronism and for select patients with adrenocorticotropic hormone-independent Cushing syndrome. However, a low level of discordance between imaging and AVS findings in PA patients suggests that there may be a subset of patients in whom preoperative AVS is not necessary.

Abstract INTRODUCTION: HER2/neu is a potent biomarker for which anti-HER2/neu antibodies offer significant responses. However, many cancers, such as melanoma, have less than 5% expression of HER2/neu. The purpose of this study was to determine whether induced expression of erbb2 (mouse HER2/neu analogue) could function as a neoantigen target for anti-erbb2 antibody. METHODS: RT-PCR was used to construct a rat erbb2-encoding vector using the live, non-replicating lentivirus pLenti6.3. erbb2-encoding pLenti6.3 was transfected in vitro into the B16 mouse melanoma cell line, which has less than 5% endogenous expression of erbb2. The generated erbb2+ B16 cell line was designated B16/neu. Anti-erbb2 antibody (7.16.4) was used to treat C57Bl/6 male and female mice bearing B16/neu (200 ug intraperitoneally three times per week for 3 weeks). To confirm activity of 7.16.4, this antibody (100 ug per T75 flask) was co-cultured with B16/neu in vitro, and cell growth/confluence was measured. RESULTS: The novel B16/neu cell line expressed approximately 50% erbb2 in vitro on flow cytometry analysis, compared to 2% errb2 expression in naïve B16. Erbb2/neu expression was confirmed on fluorescent Western blot. Anti-erbb2 antibody (7.16.4) slowed the growth of B16/neu in vitro, confirming the suppressive effects of 7.16.4. In B16/neu-bearing mice, 7.16.4 resulted in effective control of tumor growth and a complete tumor response rate of 35.7%, (5/14 mice) compared to placebo controls (p &lt; 0.01). Interestingly, B16/neu tumors demonstrated slower growth kinetics compared to naïve B16 tumors (p = 0.013), suggesting immune recognition of erbb2 in naïve C57Bl/6 mice as a neoantigen target. No adverse reactions were observed with 7.16.4. In vivo inoculation of erbb2-encoding pLenti6.3 in naïve B16 tumors and treatment of in vivo transfected B16/neu tumors with 7.16.4 comprise ongoing experiments. CONCLUSIONS: erbb2 expression on B16 melanoma was successfully achieved using a novel erbb2-encoding lentivirus. Induced erbb2 served as a neoantigen target for anti-erbb2 antibody. This preclinical study provides translational evidence that induced HER2/neu expression may be utilized to repurpose anti-HER2 antibodies for human malignancies that do not normally express high levels of HER2/neu. Citation Format: Emmanuel M. Gabriel, Brian Necela, Deborah Bahr, Jamie Kaplan, Kristopher Attwood, Keith Knutson. Repurposing erbb2 (HER2/neu) as a neoantigen target for neu-negative tumors using a novel erbb2-encoding lentivirus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5371.

Abstract INTRODUCTION: Intratumoral phenylephrine (α1 vasoconstrictor) combined with chemotherapy has been used for cutaneous malignancies with modest local response. The purpose of this study was to improve the efficacy of intratumoral melphalan using sustained-release, liposomal nanoparticles containing phenylephrine in a mouse model of melanoma. METHODS: A modified ethanol injection method was used to develop the liposomal phenylephrine nanoparticles. These were injected peri-tumorally to generate a local vasoconstrictive effect intended to “entrap” intratumorally injected melphalan. Drug exposure/dwell time was measured with fluorescent imaging. Mice bearing B16 (subclone F10) melanoma tumors were treated with intratumoral melphalan (20 ug/50 ul) with or without peri-tumoral liposomal phenylephrine (10 ug/50-100 ul x 4-5 injections around the tumor periphery) twice weekly x 3 weeks. RESULTS: UV-Absorbance spectroscopy confirmed encapsulation of phenylephrine within the liposomal nanoparticles with an expected absorbance of 275 nm. The modified ethanol injection method produced liposomal phenylephrine encapsulation of approximately 25%. Peri-tumoral, liposomal phenylephrine caused vasoconstriction of normal surrounding vessels with an approximate 10% decrease in vessel diameter. Our liposomal phenylephrine nanoparticles also led to increased retention of intratumorally injected fluorescently-labeled (FITC) liposomes 24-48 hours after inoculation, using both melanoma (B16) and breast (TUBO/4T1) cell lines orthotopically grown within mice (C57Bl/6 and BALB/c, respectively). The combination of intratumoral melphalan with peri-tumoral phenylephrine resulted in more effective control of tumor growth and a complete tumor response rate of 44.4%, compared to phenylephrine/melphalan only controls (p &lt; 0.01, n=18 per group). However, there was significant adverse reaction with the combination therapy, resulting in ulceration of the injection/tumor site. Ulcers healed about 14 days after completion of treatment. Immunohistochemistry demonstrated increased infiltration of CD11b+ cells into the tumors, suggesting an immune-mediated response in addition to direct chemotoxicity. CONCLUSIONS: Liposomal nanoparticles containing phenylephrine increased retention/dwell time of intratumorally administered melphalan and resulted in superior anti-tumor response. Our preclinical model holds innovative, translational promise for the clinical advancement of intralesional therapies in cutaneous/subcutaneous malignancies. Citation Format: Emmanuel M. Gabriel, Vijay Madamsetty, Deborah Bahr, Jamie Kaplan, Kristopher Attwood, Sanjay Bagaria, Keith Knutson, Debabrata Mukhopadhyay. Novel approach to intra- and peri-tumoral delivery of sustained-release chemotherapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5071.

The management of cancer has always relied heavily on the imaging modalities used to detect and monitor it. While many of these modalities have been around for decades, the technology surrounding them is always improving, and much has been discovered in recent years about the nature of tumors because of this. There have been several areas that have aided those discoveries. The use of artificial intelligence has already helped immensely in the quality of images taken but has not yet been widely implemented in clinical settings. Molecular imaging has proven to be useful in diagnosing different types of cancers based on the specificity of the probes/contrast agents used. Intravital imaging has already uncovered new information regarding the heterogeneity of the tumor vasculature. These three areas have provided a lot of useful information for the diagnosis and treatment of cancer, but further research and development in human trials is necessary to allow these techniques to fully utilize the information obtained thus far.