Macroscopic Disease Research Articles

077 Identifying genetic factors that enable basal cell carcinoma to transition from microscopic to macroscopic disease

Basal cell carcinoma (BCC) is driven by constitutive activation of the Hedgehog (Hh) signaling pathway, most commonly through loss-of-function mutations in PTCH1. Using animal models, we demonstrate here that microscopic BCC-like tumors initiated by loss of Ptch1 or gain of Smo fail to progress and eventually enter into a dormant state. Because loss-of-function mutations in NOTCH1/2 and TRP53 are commonly detected in human BCC, we sought to determine if these genetic factors modulate tumor progression.

SY18-2 PARP inhibitors in epithelial ovarian cancer: actual positioning and future expectations

In high-grade serous or endometrioid ovarian cancers (HGOC), PARPi demonstrated benefit as maintenance therapy in relapsing BRCA-mutated and non-mutated tumors. Ovarian cancer is the leading cause of death among all gynaecological cancers in developed countries, with most patients presenting with advanced stage tumours, as defined by the spread of the disease outside the pelvis (FIGO stage III and IV). For advanced disease, complete resection of all macroscopic disease has been shown to be the single most important independent prognostic factor in advanced EOC and careful evaluation of patients prior to surgery is essential to defining the management plan.

Mucosal p-STAT1/3 correlates with histologic disease activity in Crohn’s disease and is responsive to filgotinib

ABSTRACT The validity and relevance of histologic disease activity in Crohn’s disease (CD) is unclear, owing to disconnects with endoscopic pathology. Here, we explore relationships between endoscopic, histologic, and molecular activity. This post hoc analysis of the Phase 2 FITZROY trial (NCT02048618) assessed baseline and week 10 (W10) inflammation across matched ileal and colonic segments in CD patients receiving filgotinib 200 mg (n = 42) vs placebo (n = 18). Macroscopic and microscopic disease were assessed by Simple Endoscopic Score for CD ulceration subscore (uSES-CD) and Global Histologic Activity Score activity subscore (aGHAS), respectively. Molecular activity was quantified by phosphorylated signal transducer and activator of transcription (pSTAT)1 and pSTAT3 in epithelium and nonepithelium. Segments were classified as “low” or “high” activity; correlations and concordance were calculated. Logistic regression identified W10 outcome predictors. Overall, 300 segments in 60 patients were assessed. Baseline uSES-CD and aGHAS correlations were 0.72 and 0.53 in colon and ileum, respectively. pSTAT levels had poor-to-moderate concordance with uSES-CD (κ range, 0.11–0.49) but moderate-to-good concordance with aGHAS (0.43–0.77). With filgotinib vs placebo, uSES-CD and aGHAS decreased in significantly more segments with high baseline uSES-CD and aGHAS, and significantly more segments with high baseline pSTAT improved at W10. pSTAT1 was more sensitive to change than uSES-CD and aGHAS. Low baseline pSTAT3 in colon nonepithelium predicted W10 low uSES-CD (P = .044). There was better concordance between histologic and molecular disease activity associated with higher sensitivity to change vs endoscopic severity in ileocolonic CD. Our results suggest histologic activity be included in the assessment of CD inflammatory burden.

Biomechanical and Microstructural Properties of Subchondral Bone From Three Metacarpophalangeal Joint Sites in Thoroughbred Racehorses.

Fatigue-induced subchondral bone (SCB) injury is common in racehorses. Understanding how subchondral microstructure and microdamage influence mechanical properties is important for developing injury prevention strategies. Mechanical properties of the disto-palmar third metacarpal condyle (MCIII) correlate poorly with microstructure, and it is unknown whether the properties of other sites within the metacarpophalangeal (fetlock) joint are similarly complex. We aimed to investigate the mechanical and structural properties of equine SCB from specimens with minimal evidence of macroscopic disease. Three sites within the metacarpophalangeal joint were examined: the disto-palmar MCIII, disto-dorsal MCIII, and proximal sesamoid bone. Two regions of interest within the SCB were compared, a 2 mm superficial and an underlying 2 mm deep layer. Cartilage-bone specimens underwent micro-computed tomography, then cyclic compression for 100 cycles at 2 Hz. Disto-dorsal MCIII specimens were loaded to 30 MPa (n = 10), while disto-palmar MCIII (n = 10) and proximal sesamoid (n = 10) specimens were loaded to 40 MPa. Digital image correlation determined local strains. Specimens were stained with lead-uranyl acetate for volumetric microdamage quantification. The dorsal MCIII SCB had lower bone volume fraction (BVTV), bone mineral density (BMD), and stiffness compared to the palmar MCIII and sesamoid bone (p < 0.05). Superficial SCB had higher BVTV and lower BMD than deeper SCB (p < 0.05), except at the palmar MCIII site where there was no difference in BVTV between depths (p = 0.419). At all sites, the deep bone was stiffer (p < 0.001), although the superficial to deep gradient was smaller in the dorsal MCIII. Hysteresis (energy loss) was greater superficially in palmar MCIII and sesamoid (p < 0.001), but not dorsal MCIII specimens (p = 0.118). The stiffness increased with cyclic loading in total cartilage-bone specimens (p < 0.001), but not in superficial and deep layers of the bone, whereas hysteresis decreased with the cycle for all sites and layers (p < 0.001). Superficial equine SCB is uniformly less stiff than deeper bone despite non-uniform differences in bone density and damage levels. The more compliant superficial layer has an important role in energy dissipation, but whether this is a specific adaptation or a result of microdamage accumulation is not clear.

Abstract 2248: Environmental factors associated with residual disease after ovarian cancer primary cytoreduction surgery

Abstract Background: Ovarian cancer is the deadliest gynecologic cancer. Standard treatments for advanced stage high-grade serous ovarian cancer, the most common type, include (1) primary cytoreductive surgery (PCS) followed by adjuvant chemotherapy or (2) neoadjuvant chemotherapy (NACT) with interval debulking surgery. Patients in whom PCS is unlikely to yield optimal cytoreduction to no visible residual disease (R0) or who have medical contraindications to PCS are recommended to undergo NACT. Previous studies on associations between environmental factors and risk of any macroscopic residual disease have yielded inconsistent results. We aimed to (1) comprehensively examine the associations between demographic, lifestyle and reproductive factors and risk of residual disease after PCS; and (2) develop and internally validate a risk prediction model based on these factors. Methods: We used pooled data on 3,492 women who had PCS following a diagnosis with advanced stage high-grade serous ovarian, fallopian tube or primary peritoneal cancers from the Ovarian Cancer Association Consortium. Fifteen exposures of interest included age at diagnosis, menopausal status, race/ethnicity, education level, first-degree family history of ovarian cancer, endometriosis, smoking, body mass index, parity, incomplete pregnancy, tubal ligation, use of combined oral contraceptives, depot-medroxyprogesterone acetate, estrogen (ET), and combined estrogen-progestin therapy. We fit logistic regression models to examine each exposure-residual disease association in 80% of the data (n=2,794; random selection of participants). We developed a risk prediction model including the factors with p-values ≤0.2. Area under the receiver operating characteristic curve (AUC) was used to assess the model’s discrimination in the remaining 20% of the data (n=698). Results: Of the 3,492 participants, 2,003 (57%) had residual disease following PCS. Older age at diagnosis was associated with an increased risk of residual disease (OR=1.07 per five years, 95% CI 1.03-1.11). In contrast, a family history of ovarian cancer (OR=0.63, 95% CI 0.42-0.95) or ET use for 5+ years (OR=0.61, 95% CI 0.39-0.96) were associated with achieving R0. These above factors were included in the risk prediction model as were race/ethnicity, personal history of endometriosis, and smoking, whose p-values ≤0.2. The model showed modest performance in the validation set (AUC=0.64). Conclusions: Younger age at diagnosis, family history of ovarian cancer, and long-term ET use were associated with achieving R0 following PCS. Future studies incorporating genetic and clinical factors to improve the risk prediction for residual disease following PCS are warranted. Citation Format: Minh Tung Phung, Andrew Berchuck, Ellen L. Goode, Marc T. Goodman, Gillian E. Hanley, Jean Richardson, Bronwyn Grout, Anne Chase, Cindy McKinnon Deurloo, Beth Y. Karlan, Toon Van Gorp, Keitaro Matsuo, Karen McLean, Malcolm C. Pike, Joellen M. Schildkraut, Kathryn L. Terry, Anna DeFazio, Penelope M. Webb, Paul D. P. Pharoah, Susan J. Ramus, Celeste Leigh Pearce. Environmental factors associated with residual disease after ovarian cancer primary cytoreduction surgery [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 2248.

36P Factors associated with platinum resistance in ovarian cancer patients receiving neoadjuvant chemotherapy

36P Factors associated with platinum resistance in ovarian cancer patients receiving neoadjuvant chemotherapy

Phase III study with atezolizumab versus placebo in patients with malignant pleural mesothelioma after pleurectomy/decortication (AtezoMeso study).

TPS8591 Background: Surgery for malignant pleural mesothelioma (MPM) is indicated mainly in multimodal approaches and in clinical trial settings. Different studies have shown significantly lower complication rates, lower peri-operative morbidity and mortality with pleural/decortication (P/D), with similar overall survival rates. The biology of mesothelioma shows significant heterogeneity. Surgical tumor reduction may create a host environment more amenable to immunotherapy by reducing the ratio of tumor cells versus antitumor effector T lymphocytes, reducing the quantities of intratumor and/or systemic immunosuppressive cells, and ablating tumor-derived paracrine factors that promote local recruitment of immunosuppressive cells. Encouraging clinical data emerging in the field of tumor immunotherapy have demonstrated that therapies focused on enhancing T-cell responses against cancer can result in a significant survival benefit. The AtezoMeso Study evaluates the introduction of atezolizumab-ATEZO in MPM, patients (pts) after P/D and platinum/pemetrexed perioperative therapy. Methods: This is a double-blind, placebo controlled, phase III trial, in 20 Italian centers. Main inclusion criteria are P/D without macroscopic residual and ECOG-PS 0-1. Pts who underwent to P/D without macroscopic residual disease and have received at least 4 cycles of perioperative therapy with cisplatin/carboplatin and pemetrexed, will be randomized (2:1) to receive ATEZO or placebo. Therapy will be administered at dose of 1,200 mg iv, every 21 days, for 12 months or until recurrence, unacceptable toxicity or patient/physician decision. Randomization will be done through a centralized system, using histology (epithelioid vs nonepithelioid) and stage (I vs &gt; I) as stratification factors. Pts will be radiologically evaluated after surgical before starting therapy and then every 12 weeks for 24 months or until recurrence. Quality of life (QoL) will be evaluated with the EQ-5D questionnaire administered at baseline and every 12 weeks. Tissue tumor samples will be centrally analyzed to determinate the genomic profile using FoundationOne CDx platform. The primary endpoint is the evaluation of the atezolizumab efficacy in terms of disease free survival (DFS). Secondary endpoints include the safety and efficacy in terms of overall survivall and QoL. Assuming a median DFS equal to 9 months in placebo arm, an accrual time of 24 months and a follow-up time of 24 months, a sample size of 162 pts will allow to detect true hazard ratios of 0.62 with power 0.8, at a confidence level of 95%. At February 14th, 2022, 3 pts have been enrolled. Clinical trial information: 2020-003762-39; GOIRC-02-2019.

Low-Grade Serous Ovarian Carcinoma: a Retrospective Study from a Tertiary Cancer Institute.

The aim of this study was to evaluate the clinico-pathological behaviour and treatment patterns of low-grade serous carcinomas (LGSC) of ovary treated at a regional cancer centre. A retrospective analysis was done for the histopathology-proven cases of low-grade serous ovarian carcinoma, treated at a tertiary cancer institute between January, 2010, and September, 2019. There were 28 patients identified from the medical records with low-grade serous ovarian carcinoma. Median age of the patients was 43years [22-79years]. Average BMI was 22.3 ± 4.0kg/m2 [range 15.2-31.2]. Twenty-one (75%) were parous and 7 (25%) were non-parous women. Median CA125 level was 188IU/ml [range 6-14,187IU/ml]. Ten (35.7%) patients had primary surgery elsewhere and 8 (80%) out of these patients had to undergo repeat staging. Fertility sparing surgery (FSS) was offered to 4 (14.3%) patients. Five (17.8%) patients had received neoadjuvant chemotherapy for advanced disease and poor performance status. Almost 82.2% (23) of the patients had no macroscopic residual disease at the primary surgery. According to International Federation of Obstetrics and Gynaecologists (FIGO) stage for ovarian carcinoma, there were 7 (25%), 6 (21.4%), 13 (46.4%), and 2 (7.1%) patients in the stages I, II, III, and IV respectively. Post-operative adjuvant chemotherapy was offered to 7 (25%), hormonal therapy (anastrozole/tamoxifen) to 7 (25%), and rest of 14 (50%) patients were under surveillance. Median follow-up time for the study group was 36months. Overall survival (OS) and disease-free survival (DFS) at 2years was 96.4% and 89.1%, respectively. Low-grade serous carcinomas of ovary differ biologically from high-grade serous ovarian carcinoma. Surgery is the cornerstone of the treatment. Further research is needed to understand the behaviour of these tumours for effective treatment strategies in future.

Understanding Molecular Heterogeneity in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is the 5th most common cause of cancer‐related death in the United States with an estimated 32,000 annual deaths. Roughly 30% of HCC cases demonstrate mutations in the CTNNB1 oncogene that encodes a form of the ꞵ‐catenin protein that cannot be degraded. Recently, we developed a mouse model of HCC that genetically represents ~9‐12% of all human HCCs. Here, we combine hydrodynamic tail vein injections with the Sleeping Beauty Transposase – a non‐viral method of expressing genes of interest. Our model uses a clinically observed mutant of ꞵ‐catenin‐(T41A) that is co‐expressed with a mutant form of the nuclear factor erythroid 2–related factor 2 (Nrf2‐G31A) in the livers of wild‐type mice (B+N). This system results in microscopic HCC within 3 weeks and evident macroscopic disease by 7 weeks after induction.ꞵ‐catenin activation can be identified by the expression of its downstream target gene Glutamine Synthetase (GS) in the liver. Patient HCCs with ꞵ‐catenin mutations strongly correlate with GS expression. The evolution and function of GS in b‐catenin‐mutated HCC, remains unclear. Also, there is a gap in the knowledge whether elevated GS expression correlates with HCC biology, which were all subjects of the current study. B+N mouse model of HCC was examined temporally for development of HCC along with GS expression. B+N mice develop HCCs with heterogeneous GS expression in the form of GS‐high and GS‐low to GS‐negative foci. We next asked whether GS expression is associated with cell proliferation or death in the B+N model. We stained tissues for TUNEL and PCNA to mark cell apoptosis and proliferation, respectively in 7‐ and 9.5 weeks post‐injection livers, which were then correlated to GS staining of HCC nodules. While we found no correlation between apoptosis and GS, we found nodules with lower GS expression to have higher proliferation and vice versa. Finally, we asked if eliminating GS expression from B+N HCCs will impact tumor burden. Five weeks after B+N tumor induction in GS‐floxed mice, these animals were injected with AAV8‐TBG‐Cre virus to delete Glul,and mice were harvested after 2‐ or 4.5‐weeks. We found B+N mice with Glul deletion show increased liver weight to body weight ratio, a measurement of HCC burden, compared to controls. The livers of these mice were enriched for GS‐negative tumors. Together, our data suggests that HCC nodules with lower GS expression may outperform GS‐positive foci, and thus are more aggressive compared to the nodules with higher GS expression, which may be more differentiated. The mechanisms of GS heterogeneity and elucidation of its functional significance may help select the most effective targeted therapies for HCC patients with ꞵ‐catenin mutations.

Basal cell carcinomas acquire secondary mutations to overcome dormancy and progress from microscopic to macroscopic disease.

SUMMARYBasal cell carcinomas (BCCs) frequently possess immense mutational burdens; however, the functional significance of most of these mutations remains unclear. Here, we report that loss of Ptch1, the most common mutation that activates upstream Hedgehog (Hh) signaling, initiates the formation of nascent BCC-like tumors that eventually enter into a dormant state. However, rare tumors that overcome dormancy acquire the ability to hyperactivate downstream Hh signaling through a variety of mechanisms, including amplification of Gli1/2 and upregulation of Mycn. Furthermore, we demonstrate that MYCN overexpression promotes the progression of tumors induced by loss of Ptch1. These findings suggest that canonical mutations that activate upstream Hh signaling are necessary, but not sufficient, for BCC to fully progress. Rather, tumors likely acquire secondary mutations that further hyperactivate downstream Hh signaling in order to escape dormancy and enter a trajectory of uncontrolled expansion.

The Road to Dissemination: The Concept of Oligometastases and the Barriers for Widespread Disease.

Simple SummaryOligometastatic disease is an intermediate state of metastatic dissemination with a limited number of metastatic sites and extent of disease. Tumor cells need multiple capabilities in order to migrate, survive and evolve to macroscopic metastases. These capabilities are acquired by evolutionary mechanisms and are associated with several clinical factors and biomarkers. Better understanding of these properties and biomarkers may help to select patients that can benefit from local ablative therapies, which have shown to be a promising approach in recent clinical evidence.Over the last years, the oligometastatic disease state has gained more and more interest, and randomized trials are now suggesting an added value of stereotactic radiotherapy on all macroscopic disease in oligometastatic patients; but what barriers could impede widespread disease in some patients? In this review, we first discuss the concept of oligometastatic disease and some examples of clinical evidence. We then explore the route to dissemination: the hurdles a tumoral clone has to overtake before it can produce efficient and widespread dissemination. The spectrum theory argues that the range of metastatic patterns encountered in the clinic is the consequence of gradually obtained metastatic abilities of the tumor cells. Tumor clones can obtain these capabilities by Darwinian evolution, hence early in their genetic progression tumors might produce only a limited number of metastases. We illustrate selective dissemination by discussing organ tropism, the preference of different cancer (sub)types to metastasize to certain organs. Finally we discuss biomarkers that may help to distinguish the oligometastatic state.

When we open and close: Postoperative outcomes after aborted primary cytoreduction for ovarian cancer

ObjectiveLittle data exists to adequately counsel patients on the postsurgical morbidity and outcomes of an aborted primary debulking (AD) for advance stage epithelial ovarian cancer. Our objectives were to examine the 30-day morbidity of AD, percentage of patients who subsequently undergo neoadjuvant chemotherapy (NACT) and interval cytoreductive surgery (ICS), residual disease at ICS, and predictors for complications after AD. MethodsThis was a single-institution retrospective analysis of patients who underwent AD for ovarian cancer from 01/2008 to 12/2020 using ICD-10 diagnoses and procedure codes. Patient demographics, perioperative metrics, and residual disease at ICS were collected. Thirty-day postoperative complications were graded by the Common Terminology Criteria for Adverse Events. Fisher’s exact tests compared categorical and Wilcoxon rank-sum tests compared continuous variables. Logistic regression provided unadjusted odds ratios to identify predictors for post-AD complications. ResultsForty-eight patients underwent AD, and 43 were included for analysis. All had at least stage IIIC high grade serous ovarian cancer. All patients subsequently underwent ICS, with 21 (48.8%) achieving no residual macroscopic disease and 21 (48.8%) to ≤ 1 cm of macroscopic disease. After AD, 16 (37.2%) experienced at least one G ≥ 3 event within the first 30 days. The most common complication was gastrointestinal complications. Preoperative albumin was the only significant predictor for G ≥ 3 complication after AD. ConclusionsApproximately one-third of patients will experience at least one G ≥ 3 complications after AD. Complications may be anticipated by low preoperative albumin. Patients can be counseled that, after AD, proceeding to subsequent NACT and ICS and achieving optimal debulking is common.

The Role of Urologist in Ovarian Cancer Debulking Surgery

Although spread of advanced ovarian cancer (OC) into the urinary tract was considered a contraindication for surgery until the last decade, advancement of oncological centers tries to perform these radical surgeries. Urologist plays a significant role during these surgeries in order to obtain an optimal cytoreductive surgery (CRS). The aim of debulking surgeries is to achieve radical resection of involved organs by eliminating macroscopic disease. If urinary organs are involved, patients’ survival depends on tumor resection with free postoperative margins and without residual disease and the incidence of postoperative obstruction. Preoperative evaluation of the extent of tumor into the urinary tract or dilation of the renal tract caused by ovarian spread is considered challenging. First, urologists should aim to the decompression of the lower urinary tract by placing either ureteral stents or nephrostomy tubes. After initial decompression of ureteral obstruction, urinary surgeries should follow aiming to initial identification of ureters and reconstruction of ureteral lesions. Optimal CRS in cases of OC invading the urinary bladder can be achieved either by radical or by bladder-sparing surgical procedures. Furthermore, urologists should aim to the surgical management, pre- and postoperative evaluation of patients with advanced OC involving the kidney. Due to restricted knowledge on this topic, there are no current guidelines concerning the surgical approach of urinary organs during debulking surgeries for OC, while surgical treatment of these patients should follow guidelines for the management of advanced OC invading other types of organs.

Incidence and prognostic significance of inguinal lymph node metastasis in women with newly diagnosed epithelial ovarian cancer

Objective(s)To assess incidence and oncologic outcomes in women with advanced epithelial ovarian cancer (EOC) with inguinal lymph node metastasis (ILNM) at diagnosis. MethodsAn IRB-approved, retrospective single-institution cohort study was performed in women with stage III/IV EOC from 2009 to 2017. Patients with inguinal lymphadenopathy (defined as >1 cm in short axis) clinically or radiographically were identified. The impact of ILNM on progression-free survival (PFS) and overall survival (OS) were assessed. ResultsOf the 562 women with advanced EOC, 18 (3.2%) had ILNM at diagnosis, accounting for 25.7% of all patients with stage IVB disease (n = 70). Five patients (27.7%) had a known genetic predisposition for EOC, including BRCA1 (11.1%, n = 2), BRCA2 (11.1%, n = 2) and BRIP1 (5.6%, n = 1). The majority of patients underwent optimal primary cytoreductive surgery (CRS), including debulking of inguinal nodal metastasis (83.3%, n = 15), with 50% (n = 9) having no gross residual disease after surgery. There was no difference in PFS (19.9 vs. 19.9 vs. 17.2 months, p = 0.84) or OS (137.2 vs. 52.9 vs. 67.6 months, p = 0.29) in women with stage III/IV with ILNM, stage III/IV without ILNM, and stage IVB disease without ILNM, respectively. Progression-free survival was improved in women with ILNM who underwent an optimal resection to no macroscopic disease vs. non-optimal resection (27.4 vs. 14.3 months, p = 0.019). Median overall survival at the time of analysis did not reach statistical significance (137.2 vs. 57.3 months, p = 0.24). Conclusion(s)In this retrospective cohort study, 3.2% of women with advanced EOC presented with ILNM at diagnosis. Although ILNM did not portend worse clinical outcomes compared to all Stage III/IV and Stage IVB patients, respectively, resection to no gross residual disease was associated with improved PFS.

The surgical outcomes and perioperative complications of bowel resection as part of debulking surgery of advanced ovarian cancer patients

BackgroundTo review the utilization of bowel resection in ovarian cancer surgery in our institution.MethodsAll ovarian cancer patients who received bowel resection between 2006/01 and 2018/12 were identified. Postoperative morbidities were assessed according to the Clavien–Dindo classification (CDC).ResultsThere were 182 patients in the anastomosis group and 100 patients in the ostomy group, yielding a total of 282 patients. The median age was 57 years, and most patients had high-grade serous histology (88.7%). Forty-nine (17.3%) patients received neoadjuvant chemotherapy. During the operation, 78.7% of patients had ascites, and the median volume was 800 mL. Extensive bowel resection (at least two-segment) and upper abdominal operation were performed in 29 (10.2%) and 69 (24.4%) patients, respectively. The rectosigmoid colon was the most commonly resected (83.8%) followed by right hemicolectomy (5.9%) and small bowel resection (2.8%). No macroscopic residual disease was observed in 42.9% of the patients, whereas 87.9% had residual disease ≤ 1 cm. Among the entire cohort, 23.0% (65/282) experienced different complications. Severe complications (CDC 3–5) accounted for 9.2% of complications and were mostly categorized as pleural effusion requiring drainage (3.5%) followed by wound dehiscence requiring delayed repair in the operating room (1.8%). Nine patients experienced anastomotic leakage (AL): one in the ostomy group with extensive bowel resection and eight in the anastomosis group. The overall AL rate was 4.2% (9/212) per anastomosis.ConclusionsThe execution of bowel resection as part of debulking surgery in patients with newly diagnosed ovarian cancer resulted in a severe morbidity rate of 9.2%.

Cell-free human papillomavirus DNA kinetics after surgery for human papillomavirus-associated oropharyngeal cancer.

New ultrasensitive methods for detecting residual disease after surgery are needed in human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV+OPSCC). To determine whether the clearance kinetics of circulating tumor human papillomavirus DNA (ctHPVDNA) is associated with postoperative disease status, a prospective observational study was conducted in 33 patients with HPV+OPSCC undergoing surgery. Blood was collected before surgery, postoperative days 1 (POD 1), 7, and 30 and with follow-up. A subcohort of 12 patients underwent frequent blood collections in the first 24hours after surgery to define early clearance kinetics. Plasma was run on custom droplet digital polymerase chain reaction (ddPCR) assays for HPV genotypes 16, 18, 33, 35, and 45. In patients without pathologic risk factors for recurrence who were observed after surgery, ctHPVDNA rapidly decreased to <1copy/mL by POD 1 (n=8/8). In patients with risk factors for macroscopic residual disease, ctHPVDNA was markedly elevated on POD 1 (>350copies/mL) and remained elevated until adjuvant treatment (n=3/3). Patients with intermediate POD 1 ctHPVDNA levels (1.2-58.4 copies/mL) all possessed pathologic risk factors for microscopic residual disease (n=9/9). POD 1 ctHPVDNA levels were higher in patients with known adverse pathologic risk factors such as extranodal extension >1mm (P=.0481) and with increasing lymph nodes involved (P=.0453) and were further associated with adjuvant treatment received (P=.0076). One of 33 patients had a recurrence that was detected by ctHPVDNA 2months earlier than clinical detection. POD 1 ctHPVDNA levels are associated with the risk of residual disease in patients with HPV+OPSCC undergoing curative intent surgery and thus could be used as a personalized biomarker for selecting adjuvant treatment in the future. Human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV+OPSCC) is increasing at epidemic proportions and is commonly treated with surgery. This report describes results from a study examining the clearance kinetics of circulating tumor HPV DNA (circulating tumor human papillomavirus DNA [ctHPVDNA]) following surgical treatment of HPV+OPSCC. We found that ctHPVDNA levels 1day after surgery are associated with the risk of residual disease in patients with HPV+OPSCC and thus could be used as a personalized biomarker for selecting adjuvant treatment in the future. These findings are the first to demonstrate the potential utility of ctHPVDNA in patients with HPV+OPSCC undergoing surgery.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis.

Peritoneal carcinomatosis (PC) is a common presentation of several gastrointestinal and gynecological malignancies. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) is a treatment regimen recently introduced in Pakistan for PC. The goal of cytoreductive surgery is complete removal of macroscopic disease. HIPEC is administered following surgery, with the aim of eliminating disease at a microscopic level. In this study, 11 patients, who underwent CRS+HIPEC at the Shifa International Hospital, Islamabad, Pakistan, were selected. Disease severity was classified using PCI score. There were 54.5% women and 45.5% men with mean age of 48.5 ± 12.5 years. The mean PCI score was 20.3 ± 3.4. The mean time from diagnosis was 12.7 ± 11.6 months. A complete tumor resection (CC-0) was achieved in 10 (90.9%) patients, while the rest were CC-1. The duration of HIPEC circulation was 90 minutes in every patient. Postoperative morbidity was observed in 2 (18.2%) patients. No 30-day perioperative mortality was seen. It was concluded that with effective patient selection, surgical skills and center experience, CRS+HIPEC can have low perioperative morbidity and mortality, and complete cytoreduction leads to prolonged overall survival. Key Words: Peritoneal carcinomatosis, Cytoreductive surgery, Hyperthermic intraperitoneal chemotherapy.

Review of Regional Therapies for Gastric Cancer with Peritoneal Metastases.

Simple SummaryGastric cancer is usually diagnosed at late stages and is associated with poor five-year survival rates. Metastasis to the peritoneal cavity is common and leads to even worse outcomes. Currently, the mainstay of treatment for metastatic gastric cancer is systemic chemotherapy or supportive care. These recommendations remain despite evidence that suggests systemic therapy has poor penetration into the abdominal cavity, limiting efficacy against peritoneal disease. Newer treatments have been developed to address this problem, specifically regional therapies aimed at delivering chemotherapy directly into the peritoneal cavity to eradicate tumor cells. These novel therapies include hyperthermic intraperitoneal chemotherapy, normothermic intraperitoneal chemotherapy, and pressurized intraperitoneal aerosolized chemotherapy. Regional therapies may also be combined with surgery to remove both macroscopic and microscopic disease. Although more clinical trials are needed to evaluate its efficacy, early studies have shown promising outcomes with intraperitoneal chemotherapy.Gastric cancer carries a poor prognosis and is a leading cause of cancer-related mortality worldwide. Patients with gastric cancer who develop peritoneal metastases have an even more dismal prognosis, with median survival time measured in months. Since studies have demonstrated that systemic chemotherapy has poor penetration into the peritoneum, multimodal treatment with intraperitoneal chemotherapy has been proposed for the treatment of peritoneal metastases and has become the foundation for newer therapeutic techniques and clinical trials. These include heated intraperitoneal chemotherapy (HIPEC) with cytoreductive surgery (CRS), which involves the application of heated chemotherapy into the abdomen with or without tumor debulking surgery; normothermic intraperitoneal chemotherapy (NIPEC), in which non-heated chemotherapy can be delivered into the abdomen via a peritoneal port allowing for repeat dosing; and pressurized intraperitoneal aerosolized chemotherapy (PIPAC), a newer technique of pressurized and aerosolized chemotherapy delivered into the abdomen during laparoscopy. Early results with intraperitoneal chemotherapy have shown promise in increasing disease-free and overall survival in select patients. Additionally, there may be a palliative effect of these regional therapies. In this review, we explore and summarize these different intraperitoneal chemotherapy treatment regimens for gastric cancer with peritoneal metastases.

P710 Evaluation of helminth extracellular vesicles as a novel therapeutic for inflammatory bowel disease in murine models of colitis

Abstract Background With the increasing complexity of inflammatory bowel disease (IBD) new therapies are clearly required. Recent evidence is coming to light demonstrating beneficial effects of helminth proteins. We aim to assess the prophylactic and therapeutic effects of extracellular vesicles (EVs) from the nematode N. brasiliensis, which serves as a model organism for human hookworm infections, in an acute and chronic model of colitis. Methods Prophylactic and therapeutic effects of EVs were assessed in an acute model of colitis by the administration of 20µg intraperitoneally (i.p) of Nb EVs or grape EVs. Mice were sacrificed after 5 days. The therapeutic effects of Nb EVs were also assessed in a chronic model of colitis. Here, Rag1 knockout mice were treated twice weekly for three weeks with 20µg of either Nb EV, grape EV or aIL-12. Outcomes assessed for both experiments included weight loss, clinical disease, as well as macroscopic and histologic disease scores. Groups were statistically compared for significant differences. Results The prophylactic administration of Nb EVs significantly reduced weight loss, clinical disease, and histologic pathology compared to grape EV-treated negative controls. Therapeutic administration of Nb EVs significantly reduced weight loss and histologic pathology in the colon. Conclusion The current study provides important evidence that the anti-inflammatory effects of helminth EVs can be harnessed to prevent and reverse inflammation in an acute and chronic mouse model of colitis. With further characterization of helminth EVs, these compounds have the potential to generate much needed new anti-inflammatory therapies for IBD.

Characteristics of long-term survival in advanced stage ovarian cancer: a nationwide cohort in the Netherlands

Objective: Despite optimal treatment with debulking surgery and chemotherapy, the majority of patients with advanced stage epithelial ovarian cancer (EOC) die within five years. Survival beyond eight years is rare and the mechanisms that lead to such favorable outcomes are incompletely understood. We aimed to identify characteristics associated with long-term survival (LTS) in a population-based cohort of patients with advanced stage EOC. Methods: Patients with advanced stage (FIGO IIB-IV) EOC diagnosed between 2008 and 2012 were identified from the Netherlands Cancer Registry. LTS was defined as survival for more than eight years after diagnosis, based on 20% survival within this cohort. Patient, tumor, and treatment characteristics were analyzed using multivariable logistic regression to find predictors for LTS. Results: We identified 2744 eligible patients of whom 571 were long-term survivors (survival longer than eight years). Younger age, lower tumor stage, low-grade histology, FIGO IV based on extra-abdominal lymph node compared to pleural metastasis, primary debulking surgery vs neo-adjuvant chemotherapy followed by interval debulking surgery, residual disease less than one cm or no macroscopic disease, and ascites less than 100 mL were associated with LTS. Furthermore, less than six chemotherapy cycles compared to six, and carboplatin plus paclitaxel combined with other chemotherapy agents compared to carboplatin plus paclitaxel, were associated with a lower odds of LTS. Conclusion: Characteristics of the tumor, patient and treatment play a substantial role in respect to the prognosis of advanced stage EOC, and can assist in the prediction of LTS.