High-risk Carcinoma Research Articles

Robot-Assisted Video Endoscopic Inguinal Lymph Node Dissection for Penile Cancer: An Indian Multicenter Experience.

Objective: To report outcomes of multicenter series of penile cancer patients undergoing robot-assisted video endoscopic inguinal lymph node dissection (RA-VEIL). Materials and Methods: In this retrospective analysis from 3 tertiary care centers in India, consecutive intermediate-/high-risk carcinoma penis (CaP) patients with nonpalpable inguinal lymphadenopathy and/or nonbulky (<3 cm) mobile inguinal lymphadenopathy undergoing RA-VEIL were included. Patients with matted/bulky (>3 cm) and fixed lymphadenopathy were excluded. Demographic, clinical, and intraoperative data were recorded. Perioperative complications were graded by the Clavien-Dindo classification (CDC). The International Society of Lymphology (ISL) {0-III} grading was used for the assessment of lymphedema. Incidence and pattern of recurrences were assessed on follow-up. Results: From January 1, 2011, to September 30, 2023, 115 patients (230 groins) underwent bilateral RA-VEIL for CaP. The median age of the cohort was 60 (50-69) years. Clinically palpable (either unilateral or bilateral) inguinal lymphadenopathy was seen in 54 patients (47%). The "per groin" median operative time was 120 (100-140) minutes with median lymph node yield of 12 (9-16). No complications were recorded in 87.8% groins operated, with major complications (CDC 3) seen in 2.6% groins. At a median follow-up of 13.5 months, 13 patients had documented recurrences and there were 10 cancer-related deaths. No port-site recurrences were observed. No/minimal lymphedema (ISL 0/I) was seen in 94% legs. Conclusion: RA-VEIL demonstrates safety and oncologic efficacy in penile cancer patients presenting with clinically nonpalpable and/or nonbulky inguinal lymphadenopathy, with favorable functional outcomes.

MRI-Guided Targeted and Systematic Prostate Biopsies as Prognostic Indicators for Prostate Cancer Treatment Decisions.

The standard procedure for the diagnosis of prostate carcinoma involves the collection of 10-12 systematic biopsies (SBx) from both lobes. MRI-guided targeted biopsies (TBx) from suspicious foci increase the detection rates of clinically significant (cs) PCa. We investigated the extent to which the results of the TBx predicted the tumor board treatment decisions. SBx and TBx were acquired from 150 patients. Risk stratifications and recommendations for interventional therapy (prostatectomy and radiotherapy) or active surveillance were established by interdisciplinary tumor boards. We analyzed how often TBx alone were enough to correctly classify the tumors as well as to indicate interventional therapy and how often the findings of SBx were crucial for therapy decisions. A total of 28/39 (72%) favorable risk tumors were detected in TBx, of which 11/26 (42%) very-low-risk tumors were not detected and 8/13 (62%) low-risk tumors were undergraded. A total of 36/44 (82%) intermediate-risk PCa were present in TBx, of which 4 (9%) were underdiagnosed as a favorable risk tumor. A total of 12/13 (92%) high-risk carcinomas were detected and correctly grouped in TBx. The majority of csPCa were identified by the sampling of TBx alone. The tumor size was underestimated in a proportion of ISUP grade 1 tumors. Systematic biopsy sampling is therefore indicated for the next AS follow-up in these cases.

Results for patients with muscle-invasive bladder cancer (MIBC) in the CheckMate 274 trial.

4585 Background: In the CheckMate 274 trial, disease-free survival (DFS) was significantly improved with nivolumab (NIVO) vs placebo (PBO) both in intent-to-treat (ITT) patients (pts) (hazard ratio [HR], 0.70; 98.22% confidence interval [CI], 0.55–0.90; P &lt; 0.001) and in pts with tumor programmed death ligand 1 (PD-L1) expression ≥ 1% (HR, 0.55; 98.72% CI, 0.35–0.85; P &lt; 0.001). We report results for the subgroup of pts with bladder cancer, the most predominant type of urothelial carcinoma. Methods: CheckMate 274 is a phase 3, randomized, double-blind trial of adjuvant NIVO vs PBO in high-risk muscle-invasive urothelial carcinoma (bladder, ureter, renal pelvis) after radical resection. Pts were randomized 1:1 to NIVO 240 mg intravenously every 2 weeks or PBO for ≤ 1 year of adjuvant treatment and stratified by nodal status, prior neoadjuvant cisplatin, and tumor PD-L1 expression. Pts had radical resection ± neoadjuvant chemotherapy and were at high risk of recurrence on final pathologic staging. Primary endpoints were DFS in ITT pts and in pts with PD-L1 ≥ 1%. Non–urothelial tract recurrence-free survival (NUTRFS) was a secondary endpoint, and distant metastasis-free survival (DMFS) was an exploratory endpoint. This exploratory analysis focused on the subgroup of pts with muscle-invasive bladder cancer (MIBC) after radical resection. Results: Of 709 randomized pts in the trial, 560 had MIBC (NIVO, n = 279; PBO, n = 281). With a minimum follow-up of 11.0 months, a DFS benefit was observed with NIVO vs PBO in these pts, regardless of tumor PD-L1 expression (Table). DFS probability at 12 months in all MIBC pts was 66% with NIVO and 45% with PBO. DFS was improved with NIVO vs PBO across subgroups according to age, sex, ECOG performance status, nodal status, and PD-L1 expression status. Improvement in NUTRFS and DMFS with NIVO vs PBO was also observed (Table). Grade 3–4 treatment-related adverse events occurred in 17% and 6% of pts in the NIVO and PBO arms, respectively. Conclusions: Improvement in DFS was observed with NIVO over PBO in pts with MIBC after radical resection regardless of tumor PD-L1 expression. The DFS benefit was observed in all prespecified subgroups. These results further support adjuvant NIVO as a standard-of-care treatment for pts with high-risk MIBC after radical resection ± neoadjuvant cisplatin-based chemotherapy. Clinical trial information: NCT02632409. [Table: see text]

Transanal Endoscopic Microsurgical Submucosal Dissection: An Efficient Treatment Option for Giant Superficial Neoplastic Lesions of the Rectum

Introduction: The resection of giant superficial neoplastic lesions of the rectum (>5 cm) is challenging even for experienced specialists. Endoscopic mucosal resection, endoscopic submucosal dissection (ESD), and transanal endoscopic microsurgery (TEM) have all been used for the treatment of such tumors. However, because of their individual disadvantages, the ideal technique for the treatment of these lesions has yet to be determined. Transanal endoscopic microsurgical submucosal dissection (TEM-ESD) is a recently developed hybrid technique that combines the advantages of conventional TEM and flexible ESD. The aim of our study was to assess the feasibility and outcomes of TEM-ESD for the resection of giant superficial rectal neoplasms. Methods: We retrospectively analyzed all cases of TEM-ESD performed in the Department of Surgery of the Municipal Hospital of Karlsruhe between 2010 and 2020 and isolated 43 patients with superficial rectal lesions >5 cm according to the postoperative histology report. The diagnostic, perioperative, histological, and follow-up data of the patients were analyzed in the form of a retrospective, observational cohort study. Results: We identified 43 cases matching our criteria, including 35 adenomas and 8 occult adenocarcinomas. The median size of the lesions was 75 mm and the median operating time was 81.5 min. En bloc resection was possible in all cases, and histologically complete en bloc resection was confirmed in 29 cases. Five patients presented with postoperative bleeding, 2 of which were treated conservatively, 2 were treated endoscopically, and 1 required revision surgery. The median follow-up period was 15 months. There was no recurrence among patients with adenomas, 1 recurrence of a low-risk carcinoma, and 1 recurrence after the resection of a high-risk carcinoma in a patient that refused further treatment. During the follow-up period, 3 patients developed a stenosis, which was treated endoscopically. Conclusions: TEM-ESD is a feasible and safe therapeutic option for the treatment of giant superficial rectal neoplasms.

Detection of High-Grade Prostate Cancer With a Super High B-value (4000 s/mm2) in Diffusion-Weighted Imaging Sequences by Magnetic Resonance Imaging

Introduction: High-grade adenocarcinoma of the prostate tends to have denser glandular structures and a prominent desmoplastic reaction, which could be detected by magnetic resonance imaging (MRI) with a super-high b-value in diffusion-weighted imaging (DWI) sequence, to differentiate it from low-grade carcinomas.Objective: To evaluate the diagnostic validity of the diffusion sequence with values ​​of b4000 s/mm2 for the diagnosis of high-grade prostate cancer (Gleason score ≥ 7).Materials and methods: It is a retrospective analytical study of male patients who have undergone a prostate biopsy and count with a prostate MRI with a DWI sequence of a super-high b-value (4000 s/mm2).Results: The sensitivity of the diffusion sequence with b4000 s/mm2 values ​​to classify as positive for prostate cancer was 57.14% as compared to biopsy. The specificity of the diffusion sequence with b4000 s/mm2 values ​​classifying patients with prostate carcinoma as negative was 84.62%. The probability that the diffusion sequence with b4000 s/mm2 values ​​classifies patients with prostate cancer was 80%. The probability that the diffusion sequence with b4000 s/mm2 values ​​does not classify patients with prostate cancer was 64.71%. The proportion of patients adequately classified with prostate cancer using the diffusion sequence with b4000 s/mm2 values ​​was 70.37%.Conclusions: The study shows that using the diffusion sequence with values of b4000 s/mm2 is an optimal value that serves as a tool to be able to decant those high-risk carcinomas with those of low risk; however, it is not a definitive method of diagnosis that could replace the performance of a biopsy. Since the study sample was limited, these results cannot be interpreted as reliable for diagnosing high-grade prostate cancer and should encourage future studies on a larger scale population to obtain significant evidence for a non-invasive diagnostic tool with a better cost-benefit for the patient.

Comparison of patients with high-risk nonmetastatic clear cell renal carcinoma in adjuvant therapy trials versus nonclinical trial patients.

361 Background: Characteristics of patients with high risk for recurrence non-metastatic renal cell carcinoma (nmRCC) participating in adjuvant therapy clinical trials post-nephrectomy have not been well described. We evaluated high risk nmRCC patients in the CKCis database to explore differences between trial and non-trial patients. Methods: Adult patients undergoing partial or radical nephrectomy for clear cell nmRCC between January 1, 2011 and March 31, 2021 were included. CKCis is a prospective cohort of patients from 14 Canadian academic institutions. Patients with high risk nmRCC (using modified UCLA Integrated Staging System) were included. Demographic, clinical, and survival statistics were analyzed for all patients and comparatively for the trial and non-trial groups. Results: 1459 patients, including 63 in adjuvant trials, were evaluated. 71% were male, 91% had pT3N0M0 disease. Disease characteristics including tumor size, stage, grade, location, necrosis, and margin status were similar between groups. Trial patients were younger (mean age 58.1 vs. 63.6; p &lt; 0.0001) and had lower Charlson Comorbidity Index scores (median 4 [3,6) vs. 5 [4,6] p &lt; 0.001). Estimated overall survival (OS) at 5 years was 80.8% (95% CI, 65,90) for trial patients and 74.8% (95% CI, 71,78.2) for non-trial patients. Recurrence-free survival at 5 years for trial patients was 48.6% (95% CI, 34,61.7) and 39.2% (95% CI, 35.2,43.1) for non-trial patients. Conclusions: Patients in adjuvant trials were younger and healthier at baseline than the average high risk nmRCC CKCis patient. Trial patients appear to have had longer time to recurrence and longer survival compared to non-trial patients, although not reaching statistical significance. Selection bias is common in clinical trials and evaluation of real-world population-based evidence of patients receiving adjuvant therapy will be important to ensure phase 3 trial results have external validity.

Analysis of disease-free survival in CheckMate 274 by PD-L1 combined positive score and tumor proportion score.

491 Background: CheckMate 274 demonstrated a significant improvement in disease-free survival (DFS) with nivolumab (NIVO) versus placebo (PBO) both in the intent-to-treat population (hazard ratio [HR], 0.70; 98.22% confidence interval [CI], 0.55–0.90; P &lt; 0.001) and in patients (pts) with tumor programmed death ligand 1 (PD-L1) expression ≥ 1% assessed by the tumor proportion score (TPS) (HR, 0.55; 98.72% CI, 0.35–0.85; P &lt; 0.001). An exploratory subgroup analysis showed a trend toward a DFS benefit with NIVO in pts with TPS &lt; 1% (0.82; 95% CI, 0.63–1.06). To further characterize the relationship between PD-L1 expression and NIVO efficacy, we report an analysis of DFS based on PD-L1 expression in both tumor and immune cells using the combined positive score (CPS). Methods: CheckMate 274 is a phase 3, randomized, double-blind, multicenter trial of NIVO versus PBO in pts with high-risk muscle-invasive urothelial carcinoma after radical surgery. Pts were randomized 1:1 to NIVO 240 mg or PBO every 2 weeks intravenously for 1 year of adjuvant treatment. The primary endpoints of the study are DFS in the intent-to-treat population and in pts with TPS ≥ 1%. The Dako PD-L1 IHC 28-8 pharmDx assay was used to evaluate TPS. CPS was determined retrospectively from previously stained immunohistochemistry slides using the CPS algorithm. CPS was calculated as the number of both PD-L1 positive tumor and immune cells divided by the number of viable tumor cells in the evaluable tumor area, multiplied by 100; TPS was similarly calculated with the number of PD-L1 positive tumor cells as the numerator. This analysis only included pts with both quantifiable CPS and TPS. Results: Of the 629 pts with quantifiable TPS and CPS, 249 (40%) had TPS ≥ 1% (NIVO, n = 124; PBO, n = 125), 380 (60%) had TPS &lt; 1% (NIVO, n = 191; PBO, n = 189), 557 (89%) had CPS ≥ 1 (NIVO, n = 281; PBO, n = 276), and 72 (11%) had CPS &lt; 1 (NIVO, n = 34; PBO, n = 38). Within TPS &lt; 1% pts, 81% (n = 309) had CPS ≥ 1. The number of pts and the DFS outcomes in pts with TPS ≥ 1% and CPS ≥ 1 are shown in the Table. In pts with TPS &lt; 1% who also had CPS ≥ 1, median DFS (95% CI) was 19.2 (15.6–33.4) months with NIVO versus 10.1 (8.2–19.4) months with PBO. The HR for NIVO versus PBO in these pts was 0.73 (95% CI, 0.54–0.99). Conclusions: This exploratory analysis of PD-L1 expression by CPS showed a higher proportion of pts with CPS ≥ 1 than TPS ≥ 1%, and that most pts with TPS &lt; 1% had CPS ≥ 1. In the CPS ≥ 1 subgroup, median DFS with NIVO was more than double that with placebo. These results support the conclusion that pts with TPS &lt; 1% also benefit from adjuvant NIVO. Clinical trial information: NCT02632409. [Table: see text]

Abstract P1-05-01: The tumor immune microenvironment and HER2 landscape of high-risk ductal carcinoma in situ: The DEFENSE study

Abstract Introduction: Ductal carcinoma in situ (DCIS) of the breast is a premalignant lesion representing a spectrum of biology from indolent to aggressive. A minority of women present with clinically high-risk features associated with poor outcome. Yet even in patients with biologically aggressive DCIS, the risk of breast cancer mortality is only 3.3% compared to 30-40% in patients with biologically aggressive invasive cancer of the same size.1 We hypothesize that the tumor immune microenvironment could play a proactive role in preventing invasion in high grade clinically high-risk DCIS and that HER2 status, including specific HER2 isoform expression and post-translational modification of HER2, could impact progression. Methods: DCIS: Elaboration of Factors from Enlarged lesions that Nevertheless remain Stage 0 Entities (DEFENSE) is a study of high-risk DCIS, defined as having at least two of the following characteristics: large (&amp;gt;5cm), high grade, hormone receptor-negative status and/or HER2+ status. Slides obtained from FFPE tissue blocks were stained with fluorescence-based multiplex immunohistochemistry (mIHC) panels and imaged to characterize immune infiltrate within the ducts and the stromal compartments. mIHC was also used to detect extracellular and intracellular domains of HER2 with imaging analysis performed to identify HER2 isoforms of HER2+ specimens. Isoforms were characterized as 1) full-length/extracellular domain (ECD) intact, 2) pure/complete loss of ECD (p95 isoform), 3) subclonal populations of both full-length ECD and p95 and 4) gradient/representing partial loss of ECD per cell (reflecting post-translational cleavage). Clinical characteristics were correlated with molecular profile, tumor immune infiltrates, and HER2 isoform. Finally, expression profiling with a 44k array was conducted by Agendia, and MammaPrint and BluePrint results were generated. Results: Of 92 total patients, median age is 46 years. The average DCIS lesion size is 8.2cm, and 33% are hormone receptor negative (HR-). Based upon initial analysis, mIHC demonstrates significant heterogeneity in immune infiltrate populations of pathologically identical DCIS specimens and within regions of the same specimen. High-grade HR- disease has highly reactive stroma, characterized by dense CD3+, CD34+, and CD68+ infiltrate within the stromal compartment. HER2 testing of the first 51 cases demonstrates a high rate of positivity of 67% (34/51). Of those tested for HER2 isoform expression (n=21), none had homogeneous intact full-length HER2. Six (29%) demonstrate the pure p95 isoform, 3 (14%) demonstrate the subclonal isoform, and 12 (57%) demonstrate a gradient HER2 isoform phenotype. Preliminary data from expression profiling shows that the HER2+ cases are also HER2 intrinsic sub-type by BluePrint. Across all of the high-risk DCIS cases, all were scored as MammaPrint high risk, either Luminal B or HER2-type, with only 1 basal and no Luminal A. Additional analyses are ongoing, including completion of testing for the whole data set as well whole exome DNA sequencing and SMART-3SEQ RNA sequencing. Conclusions: Clinically high-risk and pathologically homogenous DCIS lesions demonstrate significant immune infiltrate heterogeneity. Nearly 70% of these large clinically high-risk DCIS lesions are HER2+ with HER2 isoforms most commonly representing either partial or complete loss of the HER2 ECD. This is significantly higher than what is reported for invasive HER2+ breast cancer. A comparison to size and molecularly matched invasive cancers, including from the I-SPY 2 trial, is underway in an effort to elucidate how molecularly aggressive lesions remain in situ despite their large size.

Impact of external beam pelvic radiotherapy of endometrial carcinoma: A focus on chronic digestive toxicity

PurposeThe standard treatment for endometrial cancer is surgery, although depending on the risk factors, adjuvant radiation therapy may also be given. It is proposed for high-risk carcinomas for which an improvement in progression-free survival though not overall survival has been shown. However, despite the development of radiotherapy treatments with intensity modulation and image guidance, adjuvant radiation therapy remains toxic to the digestive system. We aimed to investigate the incidence of digestive toxicity and the presence of any predictive factors. Materials and methodsData were retrospectively collected from patients treated with adjuvant radiotherapy for endometrial carcinoma at the Institut de cancérologie de Lorraine and centre hospitalier Émile-Durkheim between January 2010 and October 2016 and analyzed to identify factors associated with chronic digestive toxicity. ResultsOne hundred and thirty-nine patients received a total dose of 50Gy fractionated into 25 sessions, five per week for five weeks. The median follow-up after irradiation completion was 38 months. The incidence of gastrointestinal and rectal toxicity in all patients treated with pelvic irradiation for endometrial carcinoma was 11.1% (95% confidence interval [95%CI]: 5.4–19%) for grade 3–4 and 25.6% (95%CI: 17.0–34.9%) for grade 2–4. No factor was found to be significantly predictive of chronic digestive toxicity. At five years, the overall survival was 74.3%, (95%CI: 65.3–81.4%), progression-free survival was 69.6% (95%CI: 60.1–77.3%) and incidence of pelvic recurrence was 7.9% (95%CI: 3.8–13.9%). ConclusionOur results confirmed that pelvic radiotherapy can induce a relatively high rate of digestive toxicity but failed to identify relevant factors able to predict it.

Transanal endoscopic microsurgical submucosal dissection (TEM-ESD): A novel approach to the local treatment of early rectal cancer

BackgroundComplete local resection is currently the treatment of choice for low-risk early rectal cancer; however, the ideal resection technique for such tumours is still debated. Transanal endoscopic microsurgical submucosal dissection (TEM-ESD) is a new technique which combines the ergonomic advantages of transanal endoscopic microsurgery (TEM) with the minimally invasive approach of endoscopic submucosal dissection (ESD). The aim of our study was to assess the feasibility, safety, and long-term outcomes of TEM-ESD in treating early rectal cancer. Materials and methodsWe retrospectively analysed all cases of rectal adenocarcinomas treated with TEM-ESD in Karlsruhe Municipal Hospital between 2012 and 2019, as well as the perioperative and follow-up data of the patients. ResultsWe identified 40 cases (19 low-risk and 21 high-risk carcinomas) matching our criteria. The median size of the lesions was 3.8 cm and the median operating time 48.5 min. En bloc resection was possible in all cases, while histologically complete resection was confirmed in 18 of 19 low-risk tumours and in 30 out of all lesions. The resection was curative in 19 cases. No scarring of the mesorectum was reported during the completion of total mesorectal excision for high-risk tumours. There was only 1 case of local recurrence among patients treated with curative intent, with an overall survival rate of 100% and a disease-free survival rate of 96% at both 2 and 5 years for these patients. ConclusionTEM-ESD is a safe and feasible therapeutic option for resecting early rectal cancer, offering very good long-term outcomes.

Robot-Assisted Radical Nephroureterectomy.

First proposed by Kimball and Ferris in 1933 for the treatment of papillary tumors in the upper urinary tract, radical nephroureterectomy (RNU) with bladder cuff excision remains the gold standard for management of high-risk upper tract urothelial carcinoma involving the proximal ureter and/or pelvicaliceal system. Over three decades since the first description of laparoscopic RNU, minimally invasive approaches to RNU have continued to evolve and become increasingly utilized. More recently, robot-assisted RNU (RARNU) has increasingly become a viable approach. Specifically, RARNU affords a reduction in perioperative morbidity and improved convalescence as a minimally invasive approach, all while adhering to traditional open surgical principles and providing surgeons with improved technical ergonomics and streamlined operating room logistics, particularly with the advent of the da Vinci Xi platform. In this study, we describe our approach to transperitoneal RARNU, including indications, operating room setup, step-by-step surgical technique, and perioperative care.

Modulation of the immune microenvironment of high-risk ductal carcinoma in situ by intralesional pembrolizumab injection

Ductal carcinoma in situ (DCIS) is a risk factor for the subsequent development of invasive breast cancer. High-risk features include age <45 years, size >5 cm, high-grade, palpable mass, hormone receptor negativity, and HER2 positivity. We have previously shown that immune infiltrates are positively associated with these high-risk features, suggesting that manipulating the immune microenvironment in high-risk DCIS could potentially alter disease progression. Patients with high-risk DCIS were enrolled in this 3 × 3 phase 1 dose-escalation pilot study of 2, 4, and 8 mg intralesional injections of the PD-1 immune checkpoint inhibitor, pembrolizumab. Study participants received two intralesional injections, three weeks apart, prior to surgery. Tissue from pre-treatment biopsies and post-treatment surgical resections was analyzed using multiplex immunofluorescence (mIF) staining for various immune cell populations. The intralesional injections were easily administered and well-tolerated. mIF analyses demonstrated significant increases in total T cell and CD8+ T cell percentages in most patients after receiving pembrolizumab, even at the 2 mg dose. T cell expansion was confined primarily to the stroma rather than within DCIS-containing ducts. Neither cleaved caspase 3 (CC3) staining, a marker for apoptosis, nor DCIS volume (as measured by MRI) changed significantly following treatment. Intralesional injection of pembrolizumab is safe and feasible in patients with DCIS. Nearly all patients experienced robust total and CD8+ T cell responses. However, we did not observe evidence of cell death or tumor volume decrease by MRI, suggesting that additional strategies may be needed to elicit stronger anti-tumor immunity.

Nivolumab Nearly Doubles DFS in High-Risk Urothelial Carcinoma

Nivolumab Nearly Doubles DFS in High-Risk Urothelial Carcinoma

Multi-modal imaging of high-risk ductal carcinoma in situ of the breast using C2Am: a targeted cell death imaging agent

BackgroundDuctal carcinoma in situ (DCIS) is a non-invasive form of early breast cancer, with a poorly understood natural history of invasive transformation. Necrosis is a well-recognized adverse prognostic feature of DCIS, and non-invasive detection of its presence and spatial extent could provide information not obtainable by biopsy. We describe here imaging of the distribution and extent of comedo-type necrosis in a model of human DCIS using C2Am, an imaging agent that binds to the phosphatidylserine exposed by necrotic cells.MethodsWe used an established xenograft model of human DCIS that mimics the histopathological features of the disease. Planar near-infrared and optoacoustic imaging, using fluorescently labeled C2Am, were used to image non-invasively the presence and extent of lesion necrosis.ResultsC2Am showed specific and sensitive binding to necrotic areas in DCIS tissue, detectable both in vivo and ex vivo. The imaging signal generated in vivo using near-infrared (NIR) fluorescence imaging was up to 6-fold higher in DCIS lesions than in surrounding fat pad or skin tissue. There was a correlation between the C2Am NIR fluorescence (Pearson R = 0.783, P = 0.0125) and optoacoustic signals (R > 0.875, P < 0.022) in the DCIS lesions in vivo and the corresponding levels of cell death detected histologically.ConclusionsC2Am is a targeted multi-modal imaging agent that could complement current anatomical imaging methods for detecting DCIS. Imaging the presence and spatial extent of necrosis may give better prognostic information than that obtained by biopsy alone.

Abstract PS18-14: Elucidating the biology of high-risk ductal carcinoma in situ (DCIS) through genomics and immunohistochemical profiling of the tumor microenvironment: The DEFENSE study

Abstract Introduction: Ductal carcinoma in situ (DCIS) of the breast is a premalignant lesion representing a spectrum of biology and risk. While many patients with DCIS undergo surgical resection with no survival benefit given the indolent nature of their disease, others do possess biologically aggressive DCIS that has the potential to evolve into invasive cancer if left untreated. Yet even among those patients with biologically aggressive DCIS, their risk of dying from metastatic breast cancer is only 3.3% compared to 30-40% among patients with biologically aggressive invasive cancer.1 The DEFENSE study, supported with funding from the NCI Molecular Characterization of Screen-Detected Lesions (MCL) consortium, was designed to identify molecular, immunological, and stromal-related factors that allow DCIS to develop high-risk features without ever becoming invasive breast cancer. Methods: The overall objective of the DEFENSE study is to compare 100 patients with invasive high-risk breast cancer enrolled on the I-SPY2 trial matched based upon age and tumor molecular profile (Mammaprint) to 100 patients with high-risk DCIS, defined as having at least two of the following characteristics: large (&amp;gt;5cm), high-grade, hormone receptor-negative status and/or HER2-positive status. Tumors obtained from each of these patients are divided into 22 sequential sections with regions of pathologic interest identified prior to undergoing whole exome DNA sequencing, SMART-3SEQ RNA sequencing, multiplex immunofluoresence (mIF) for immune cell infiltrates, and stromal profiling by IHC. Each profiling modality is performed by a different institution included in the MCL consortium (UCSF, UCD, UCSD, Stanford, and UVM). In order to evaluate the logistic and financial feasibility of our multi-institution protocol prior to expanding to our proposed full-scale study, we are conducting a pilot study of 11 high-risk DCIS specimens. Results: The 11 pilot specimens have been successfully sent and received by each institution. H&amp;E images from the sectioned specimens have been uploaded to the NASA Jet Propulsion Lab (JPL) cloud-based platform and shared for pathologic annotation among institutions. mIF of the pilot cohort has been completed, but interpretation of associations between tumor subtype and immune cell infiltrate is limited by the small sample size. Whole exome DNA sequencing, SMART-3SEQ RNA sequencing, and stromal profiling of the pilot cohort are each ongoing. We anticipate being able to provide full results from each profiling modality performed from the pilot cohort, as well as results from an expanded cohort of 40 additional specimens, by December 2020. Conclusions: We have successfully shown that a multi-institution collaboration can effectively share pathologic data and conduct data analyses using a variety of tumor profiling modalities. We anticipate that data from our expanded cohort will allow us to differentiate the underlying biology of high-risk DCIS from invasive breast cancer, identifying mechanistic opportunities for future intervention.

Skin Myasis Associated with High-Risk Epidermoid Carcinoma in a Possible Lung Metastasis Patient.

Skin Myasis Associated with High-Risk Epidermoid Carcinoma in a Possible Lung Metastasis Patient.

Combined immune checkpoint inhibition for high-risk urothelial carcinoma.

Combined immune checkpoint inhibition for high-risk urothelial carcinoma.

Adjuvant chemotherapy after radical nephroureterectomy improves the survival outcome of high-risk upper tract urothelial carcinoma patients with cardiovascular comorbidity

This prospective randomized comparative trial study aimed to evaluate the therapeutic outcomes of radical nephroureterectomy and adjuvant chemotherapy (ACT) used in combination in high risk upper tract urothelial carcinoma (UTUC) patients with cardiovascular comorbidity. Based on the inclusion criteria of high-risk UTUC in EAU guidelines (updated in 2014), all eligible patients treated in our hospital from January 2014 to March 2018 were included, and cases with late disease, renal dysfunction, severe cardiopulmonary disease or other malignant tumors were excluded. The cases were randomized into two groups based on treatment regimen. Multivariate analyses were performed to analyze the influencing factors of survival outcome in the enrolled patients. The Cox proportional-hazards model and the Kaplan–Meier method were employed to assess progression free survival (PFS), overall survival (OS) and cancer specific survival (CSS). In addition, the potential adverse effects of chemotherapy were actively monitored. A total of 176 high-risk UTUC individuals with cardiovascular comorbidity were enrolled and evaluated in this study. Median follow-up durations were 30 months (range 6–54) in the RNU (n = 82) group and 36 months (range 6–54) in the RNU + ACT (n = 94) group. Multivariable analysis indicated that peri-operative cardiovascular events risk grade was independent prognostic factor for OS. Tumor size was independent prognostic factor for PFS and CSS. BMI and lymphovacular invasion were significant predictors of PFS. Clinical stage, lymph node involvement, and tumor grade were significant predictors of PFS, OS and CSS in these patients. Especially, chemotherapy was helpful in improving PFS [P < 0.001, HR = 6.327 (5.115–7.793)], OS [P = 0.013, HR = 2.336 (1.956–2.883)] and CSS [P = 0.008, HR = 3.073 (2.533–3.738)]. Kaplan–Meier analysis demonstrated that the oncologic outcomes of RNU treated high-risk UTUC patients were improved much significantly by ACT, including PFS [P = 0.0033, HR = 3.78 (3.13–4.55)], OS [P = 0.0397, HR = 1.39 (1.01–1.75)] and CSS [P = 0.0255, HR = 1.26 (1.07–1.45)]. Further analysis of the lymph node positive subgroup showed that the median time of oncologic events was enhanced in RNU + ACT treated individuals in comparison with the RNU group, including PFS (11.4 months vs. 31.9 months, P = 0.0018), OS (26.8 months vs. 36.3 months, P = 0.0255) and CSS (28.2 months vs. 39.3 months, P = 0.0197). In the T3/4 cohort, significantly increased median PFS (13.9 months vs. 36.3 months, P = 0.0217), OS (20.6 months vs. 32.2 months, P = 0.0183) and CSS (21.9 months vs. 38.4 months, P = 0.0226) were obtained in the combination group. Additionally, no severe adverse events (over grade 4) associated with chemotherapy were detected in the RNU + ACT group. In conclusion, ACT after radical surgery has statistically significant therapeutic effects on PFS, OS and CSS in high-risk UTUC patients with cardiovascular comorbidity.

Does the Incorporation of Chemotherapy to Adjuvant Radiation Skew the Influence of Treatment Package Time in High-risk Oral Cavity Carcinoma? A Multi-institutional Collaborative Study

Does the Incorporation of Chemotherapy to Adjuvant Radiation Skew the Influence of Treatment Package Time in High-risk Oral Cavity Carcinoma? A Multi-institutional Collaborative Study

Abstract 5440: Understanding the biology of high-risk ductal carcinoma in situ (DCIS) through genomics and the tumor immune microenvironment: The DEFENSE study

Abstract Introduction: Ductal carcinoma in situ (DCIS) of the breast is a premalignant lesion representing a spectrum of biology and risk. While many patients with DCIS undergo surgical resection with no survival benefit given the indolent nature of their disease, others do possess biologically aggressive DCIS that has the potential to evolve into invasive cancer if left untreated. Yet even among those patients with biologically aggressive DCIS, their risk of dying from metastatic breast cancer is only 3.3% compared to 30-40% among patients with biologically aggressive invasive cancer.1 We are interested in identifying molecular and tumor immune microenvironment factors that allow DCIS to develop high-risk features without ever becoming invasive breast cancer. Methods: We are conducting a retrospective pilot study (DEFENSE) of 10 patients with invasive high-risk breast cancer enrolled on the I-SPY2 trial matched based upon age and tumor molecular profile to 10 patients with high-risk DCIS, defined as having at least two of the following characteristics: large (&amp;gt;5cm), high-grade, hormone receptor-negative status and/or HER2-positive status. Tumors obtained from each of these patients will be divided into 22 sequential sections with regions of pathologic interest identified prior to undergoing whole exome DNA sequencing, SMART-3SEQ RNA sequencing, multiplex immunohistochemistry (mIHC) using three immune panels, and stromal profiling. Each profiling modality will be performed by a different institution included in the NIH Molecular Characterization of Screen-Detected Lesions (MCL) consortium. This pilot study will inform our decision to expand our study to a full-scale review of 200 patients (100 DCIS, 100 invasive cancer) among our institutions. Results: We have thus far demonstrated the feasibility of our pilot study with 10 blocks in total sent to and received by each institution. Whole exome DNA sequencing, SMART-3SEQ, mIHC, and stromal profiling work has begun and will be available for presentation, and we plan to make pathology, clinical and genomic data available through the MCL's collaborative partnership with the NASA Jet Propulsion Lab (JPL) cloud-based platform. Conclusions: We have successfully shown that a multi-institution collaborative can effectively share pathologic data and conduct data analyses using a variety of tumor profiling modalities. We anticipate that our data will allow us to differentiate the underlying biology of high-risk DCIS from invasive breast cancer, identifying mechanistic opportunities for future intervention.