Extensive Tumor Invasion Research Articles

Development and Validation of CT-Based Clinical-Radiomics Nomogram for Early Stage Extranodal Nasal-Type NK/T Cell Lymphoma: A Multicenter Study

Most patients with extranodal nasal-type NK/T cell lymphoma (ENKTCL) had a localized disease with extensive primary tumor invasion at diagnosis (70-90%). Several clinical risk indexes, such as nomogram-revised risk index (NRI), international prognostic index (IPI), Korean Prognostic Index (KPI) and prognostic index of natural killer lymphoma (PINK), were used for ENKTCL patient stratification and providing information in clinical decision-making. However, they had low predictive power for early-stage patients with ENKTCL. This is the first study to construct a model with more predictive power through CT-based radiomics signature combined with traditional clinical risk indexes for overall survival (OS) of patients with early-stage ENKTCL. A total of 196 early stage ENKTCL patients were randomly assigned into the training (n = 147) and interval validation set (n = 49) in a 3:1 ratio. And 83 and 19 early stage ENKTCL patients from other two centers were used for external validation set (n = 62). All patients received radiotherapy after 2-3 cycles of chemotherapy. 1316 CT radiomic features before radiotherapy were extracted and selected to construct the radiomics signature (RS). A CT-based nomogram was established by integrating clinical indexes and radiomics signature in training set and was tested in two validation sets. With a median follow-up period of 59.9 months, 48 patients (24.1%) died. Compared with other prognostic index, NRI had better power to predict 5-year OS in the training cohort. The radiomics signature constructed by 11 selected radiomic features showed better prognostic performance than NRI for predicting 5-year OS in training set (C-index: 0.75 vs. 0.66), internal validation set (C-index: 0.71 vs. 0.62) and external validation set (C-index: 0.68 vs. 0.60). Patients were stratified into high- and low-risk groups by median radiomic signature. Patients in high-risk group had worse 5-year OS than patients in low-risk group (training set: 92% vs. 65%, P<0.001; internal validation set: 88% vs. 59%, P<0.05; external validation set 90% vs. 60%, P<0.05). The nomogram established by integrating radiomics signature with NRI showed optimal prognostic performance with C-index of 0.77 in training, 0.73 in internal and 0.71 in external validation set. Calibration curves showed good agreement. The clinical-radiomics nomogram integrating CT-based radiomics signature combined with traditional clinical risk index provided an excellent prognostic tool for OS, which could be helpful for personalized risk stratification and treatment in early stage ENKTCL patients.

A case of spontaneous ovarian malignant neoplasm rupture and life-threatening massive intra-abdominal bleeding

Although ovarian cancer is the second most common gynecological cancer, it is the most common gynecological malignancy that causes death. Approximately 75% of the patients are diagnosed at an advanced stage, and high-grade serous-type ovarian cancer is detected in most of these patients. The final pathology result in our case was high-grade serous ovarian carcinoma. Our patient, 39 years old, applied to our emergency department with complaints of inability to urinate for three days and new onset abdominal pain. We were consulted because of detection of an 11 cm solid mass and globe vesicle in the pelvic region detected on the computed tomography (CT) taken in the emergency department. The patient's initial hemoglobin value was 11.2 g/dL and the beta-human chorionic gonadotropin (ß-HCG) value was negative. During the follow-up, the patient’s hemoglobin values were 9.2 and then decreased to 8.6, 8.1, and 6.5 g/dL after which hypotensive shock developed in the patient. The patient was taken for an emergency laparotomy. Intra-operatively, 1500 mL of intra-abdominal hemorrhagic fluid and diffuse tumor fragments were observed. In the right adnexal area, approximately 11 cm of ruptured tumor tissue, which may originate from the ovary or uterus, was observed. It was observed that the Douglas pouch and uterine, internal iliac , and some parts of the external iliac arteries were extensively invaded by the tumor and active bleeding occurred. Total Abdominal Hysterectomy + Bilateral Salpingo-Oopherectomy (TAH+BSO) was performed on the patient. Additional surgical intervention could not be performed because the patient had extensive vascular tumor invasion, heavy bleeding, and was in hypotensive shock. Six anti-bleeding sponges were placed on intra-abdominal bleeding areas. In addition, packing was applied to the patient by placing four sterile compresses and soft drains inside the abdomen. Tranexamic acid was administered to the patient, and six units of red blood cell suspension and four units of fresh frozen plasma were transfused. The patient was transferred by ambulance to a higher institution, which is a gynecological oncology center, for follow-up, treatment, and complementary surgery. In this case, we aimed to draw attention to a rare case of ovarian malignancy rupture and hypotensive shock.

PSUN329 Non-islet Cell Tumor Hypoglycemia Secondary to Advanced Hepatocellular Carcinoma in a 29-Year-Old Male

Abstract Summary: Non-islet cell tumor hypoglycemia (NICTH) is a rare, but serious complication that can be seen in most all tumors. It is typically mediated by high levels of an incompletely processed form of insulin-growth factor 2 ("big IGF-2") that is produced by the tumor. We describe a case of a 29-year-old male with history of chronic hepatitis B and advanced stage hepatocellular carcinoma (HCC) who had failed prior chemotherapies. The patient was admitted to the hospital for a liver biopsy, following which he developed severe hypoglycemia, refractory to high dose, continuous dextrose infusion. Evaluation was remarkable for low levels of insulin, proinsulin, C-peptide, and IGF-1, normal cortisol, and an IGF-2: IGF-1 ratio of 8, suggestive of NICTH due to IGF-2, although the patient's hypoglycemia may additionally have been due to worsening, and strikingly extensive tumor invasion of the liver. This patient was unfortunately not considered a surgical candidate; hypoglycemia was ultimately controlled with initiation of high dose corticosteroids and total parenteral nutrition with high amounts of dextrose. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m.

Impact of surgery on survival outcomes for Bismuth type IV Klatskin tumors

BackgroundBismuth–Corlette type IV Klatskin tumors have conventionally been considered unresectable. This retrospective study aimed to demonstrate the survival improvement of patients with type IV Klatskin tumors when resected and suggest possible radiological features for R0 resectability. MethodsData on type IV Klatskin tumors diagnosed between 2008 and 2019 were reviewed retrospectively. Patients with distant metastasis, concomitant other cancers at the initial state, extensive vascular invasions, poor liver function, and poor general condition were excluded. The survival outcomes of patients and radiologic parameters of bile duct tumors were compared between the curative resection (R0, 1 resection) and non-resection groups. ResultsThe demographic findings of patients with curative resection (n = 48) and non-resection (n = 111) were comparable. Both were potentially resectable in the initial state. The postoperative morbidity was 22.9% and the 90-day mortality 4.2%. There was a significant difference in the median survival among the curative-intended resection, palliative treatment, and supportive care groups (35, 16, and 12 months, respectively; P < 0.001). DiscussionIn patients with type IV Klatskin tumor without extensive tumor invasion into adjacent tissues, including major vessels, surgical resection can be considered for better survival. Clinical registration numberIRB No. 2009–100-1157

Tumor growth, angiogenesis, and invasion as clinical hallmarks of glioblastoma: A case report

The clinical hallmarks of tumor growth, angiogenesis, and invasion were identified in a patient with isocitrate dehydrogenase-1 wild-type glioblastoma at initial diagnosis and management issues were examined. The head magnetic resonance imaging (MRI) showed multiple solid and cystic contrast enhancements in the rostral portion of the tumor located within the left motor gyrus and the adjacent brain. Extensive tumor invasion was noted along the left corticospinal tract extending into the cerebral peduncle and pons. After an open craniotomy for tissue biopsy, the patient underwent external beam radiotherapy and concomitant temozolomide, and his motor deficit was stabilized with concurrent bevacizumab infusion while dexamethasone was weaned off. After two cycles of adjuvant temozolomide, the patient experienced worsening motor deficit in the right hand. A repeat gadolinium-enhanced head MRI revealed increased fluid-attenuated inversion recovery hyperintensity in the left cerebral peduncle indicating tumor progression. This case illustrates the extensive invasion from a glioblastoma that cannot be adequately quantified or effectively treated. A wider margin of radiation may be needed to cover microscopic and infiltrative tumor cells. The early use of bevacizumab can also reverse neurological deficits and obviate the long-term use of dexamethasone and insulin in this patient. This study was approved by the Institutional Review Board at Dana Farber Cancer Institute #12-519 onMay 5, 2020.

Flavonoids Synergistically Enhance the Anti-Glioblastoma Effects of Chemotherapeutic Drugs.

Flavonoids are polyphenolic plant secondary metabolites with pleiotropic biological properties, including anti-cancer activities. These natural compounds have potential utility in glioblastoma (GBM), a malignant central nervous system tumor derived from astrocytes. Conventional GBM treatment modalities such as chemotherapy, radiation therapy, and surgical tumor resection are beneficial but limited by extensive tumor invasion and drug/radiation resistance. Therefore, dietary flavonoids—with demonstrated anti-GBM properties in preclinical research—are potential alternative therapies. This review explores the synergistic enhancement of the anti-GBM effects of conventional chemotherapeutic drugs by flavonoids. Primary studies published between 2011 and 2021 on flavonoid–chemotherapeutic synergy in GBM were obtained from PubMed. These studies demonstrate that flavonoids such as chrysin, epigallocatechin-3-gallate (EGCG), formononetin, hispidulin, icariin, quercetin, rutin, and silibinin synergistically enhance the effects of canonical chemotherapeutics. These beneficial effects are mediated by the modulation of intracellular signaling mechanisms related to apoptosis, proliferation, autophagy, motility, and chemoresistance. In this light, flavonoids hold promise in improving current therapeutic strategies and ultimately overcoming GBM drug resistance. However, despite positive preclinical results, further investigations are necessary before the commencement of clinical trials. Key considerations include the bioavailability, blood–brain barrier (BBB) permeability, and safety of flavonoids; optimal dosages of flavonoids and chemotherapeutics; drug delivery platforms; and the potential for adverse interactions.

Small cell carcinoma presenting as a biatrial mass with obstructive physiology: a case report

BackgroundSmall cell carcinoma is a highly aggressive and often fatal cancer that most commonly arises in the lung, although it can occasionally arise from other sites, such as the gastrointestinal tract, prostate or cervix. Cardiac involvement, however, is extremely uncommon and therefore has been poorly documented in the literature.Case presentationWe describe a rare case of a 31-year-old male with small cell carcinoma presenting as a massive, 15-cm cardiac tumor invading the bilateral atria, interatrial septum, and pericardium without an apparent primary malignancy on PET CT and cardiac MRI. With extensive tissue necrosis, traditional methods of obtaining a right atrial endomyocardial biopsy via internal jugular venous access failed and a diagnosis was made via endoscopic ultrasound guided transesophageal fine needle aspiration of the left atrial mass. Due to the extensive tumor invasion, the patient was not a suitable candidate for surgical resection, debulking, or heart transplant. The patient was treated with etoposide, carboplatin, atezolizumab, and radiation therapy with initial monitoring in the intensive care unit due to concern that tumor lysis may cause rapid cardiac decompensation. Unfortunately, 4 months after chemoradiation therapy, the malignancy progressed and the patient passed away 6 months after the initial diagnosis.ConclusionWe describe a rare occurrence of small cell carcinoma presenting as a massive cardiac tumor without apparent primary malignancy. This case demonstrates useful alternative diagnostic strategies and treatment considerations for patients presenting with a rare cardiac mass.

Efficacy of Lung Autotransplantation for Central Non-small Cell Lung Cancer

背景与目的全肺切除术和袖状切除术是治疗中央型非小细胞肺癌的常规术式, 但存在肺功能差不能耐受全肺切除或因为肿瘤广泛侵犯支气管和肺动脉而不能进行袖状切除的情况。本研究旨在探讨自体肺移植治疗中央型非小细胞肺癌的可行性。方法回顾性分析2016年12月-2018年12月3例行自体肺移植的中央型非小细胞肺癌患者的诊疗资料。1例双袖状切除左肺上叶, 吻合支气管, 因肺动脉切除过长, 肺动脉吻合口张力大, 遂切断下肺静脉, 将下肺上移后再吻合肺动脉, 最后将下肺静脉与上肺静脉残端吻合。2例行左全肺切除, 体外切除左肺上叶, 将修剪、灌洗后的左肺下叶重置胸腔, 依次吻合支气管、肺动脉、肺静脉。结果平均手术时间333 min, 平均血流阻断65 min, 平均出血量450 mL, 平均住院日18.7 d; 围手术期出现痰栓堵塞支气管1例, 经支纤镜吸痰后好转; 平均随访时间20个月, 癌症死亡1例, 术后吻合口复发及脑转移1例, 4R淋巴结转移1例(经化疗后病情稳定), 无复发生存1例。结论对于肿瘤侵犯广泛, 不能进行袖状切除或无法耐受全肺切除的中央型非小细胞肺癌患者, 自体肺移植可在彻底切除肿瘤基础上最大限度保留肺功能, 提高术后生存质量。

Hypercalcemia of Malignancy in a Case of Peripheral Nerve Sheath Tumor: Elucidating the Roles of Simultaneous Mechanisms

Hypercalcemia of malignancy (HCM) is caused by 1 of 5 known mechanisms including systemic release of ectopic parathyroid hormone (PTH)-related protein (PTHrP), calcitriol, PTH, cytokines, or destruction of bone by osteolytic metastases. We report the first case of 2 simultaneous mechanisms for HCM in a patient with a peripheral nerve sheath tumor (PNST). PubMed and Google Scholar searches were performed using "hypercalcemia of malignancy" as the search term. A 26-year-old woman with neurofibromatosis presented with worsening left hip pain. Magnetic resonance imaging showed a large left paraspinal mass, subtotal resection of which confirmed PNST. Despite chemo-radiation therapy, the tumor progressed over 16 months, requiring tumor debulking and L3-4 lumbar laminectomy. The patient developed progressive bilateral lower extremity weakness due to direct tumor invasion of the lumbosacral vertebrae with concurrent hypercalcemia. Ionized calcium was 1.47 mmol/dL (reference range is 0.95 to 1.32 mmol/dL), PTH was <4.0 pg/mL (reference range is 8 to 85 pg/mL), 25-hydroxyvitamin D was 14 ng/mL, calcitriol was <8.0 pg/mL (reference range is 18 to 78 pg/mL), PTHrP was 40 pg/mL(reference range is 14 to 27 pg/mL), urinary calcium was <2.0 mg/24 hours, serum C-telopeptide was 1,008 pg/mL (reference range is 64 to 640 pg/mL), and bone-specific alkaline phosphatase was 15.7 μg/L (reference range is 4.7 to 17.8 μg/L). Her serum magnesium, phosphorus, and creatinine levels were normal. Intravenous zoledronic acid and hydration resulted in a normal ionized calcium. Additional imaging revealed extensive tumor invasion of L3-S1 vertebrae. Due to her poor response to all cancer therapies, the patient was discharged to home hospice services. HCM due to PTHrP and osteolytic metastases has not been independently reported to our knowledge in association with malignant PNST as in our patient. The therapeutic importance of characterizing the mechanism of HCM is further discussed in detail.

Differential gene expression in growth factors, epithelial mesenchymal transition and chemotaxis in the diffuse type compared with the intestinal type of gastric cancer.

Gastric cancer (GC) is a highly heterogeneous disease and one of the major causes of cancer-related mortality worldwide. Diffuse-type gastric adenocarcinoma (or poorly cohesive- with independent cells) is characterized by aggressive behavior (rapid invasion, chemoresistance and peritoneal metastasis), as compared with intestinal-subtype adenocarcinoma. Diffuse subtype GC additionally has a substantially increasing incidence rate in Europe and the USA, and was often associated with younger age. Our objective was to analyze the expression and clinical significance of genes involved in several signaling pathways in diffuse-type GC. Tumors samples and non-malignant gastric tissues were obtained from patients with GC (diffuse-type and intestinal-subtype adenocarcinoma). The expression of 33 genes coding for proteins involved in four categories, growth factors and receptors, epithelial-mesenchymal transition, cell proliferation and migration, and angiogenesis was determined by reverse transcription-quantitative polymerase chain reaction. The expression of 22 genes was significantly upregulated in diffuse-type GC and two were downregulated (including CDH1) compared with normal tissues. Among these genes, acompared with intestinal-subtype adenocarcinoma, diffuse-type GC revealed elevated levels of IGF1 and IGF1R, FGF7 and FGFR1, ZEB2, CXCR4, CXCL12 and RHOA, and decreased levels of CDH1, MMP9 and MKI67. The expression of selected genes was compared with other genes and according to clinical parameters. Furthermore, TGF-β expression was significantly increased in linitis, a sub-population of diffusely infiltrating type associated with extensive fibrosis and tumor invasion. Our study identified new target genes (IGF1, FGF7, CXCR4, TG-β and ZEB2) whose expression is associated with aggressive phenotype of diffuse-type GC.

1628P - Preoperative hypofractionated radiotherapy (RT) combined with chemotherapy in primary marginally resectable high grade soft tissue sarcomas (STS) of extremities or trunk wall: Interim analysis of prospective phase II clinical trial

Background: The management of marginally resectable STS is challenging. The study aim is to assess the efficacy and safety of preoperative hypofractionated RT combined with chemotherapy in primary locally advanced STS. Methods: Single-arm clinical trial enrolls patients for one cycle of doxorubicin and ifosfamide (AI) chemotherapy followed by 5x5 Gy RT, and 2 cycles of AI in 7-8 weeks gap between RT end and surgery. Tumor response was assessed in DWI-MR imaging and pathologically by EORTC STBSG criteria. The primary endpoint is rate of limb-sparing surgeries and R0 resections. Results: 24 patients(pts) met eligibility criteria: 21 finished the whole planned protocol treatment. 3 pts underwent extremity amputation, two after 1st AI cycle due to poor tolerance, one due to extensive tumor invasion without possibility of vessels reconstruction. One toxic death occurred outside our center related to severe bone marrow suppression with septic shock after 2nd AI cycle. Early tolerance of chemotherapy was acceptable. Grade 3+ CTCAE4.03 toxicity developed in 11pts. AI dose was reduced in 8pts who completed therapy (4pts in 2 cycles; 4pts in 1 cycle). Early RT tolerance was satisfactory. EORTC grade 1 radiation dermatitis developed in 13pts and grade 2 in 2pts. Postoperative wound complications occurred in 6pts, including 2 severe wound dehiscence with hospitalization. Very good pathological response (<1% of stainable tumor cells; grade A/B) was reported in 5pts, good pathological response (<50% tumor cells; grade C/D) - in 12pts. Conclusions: Preoperative AI chemotherapy combined with hypofractionated RT is a feasible method of the management of marginally resectable STS providing a good pathological responses and acceptable treatment toxicity. Legal entity responsible for the study: Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland. Funding: Maria Sklodowska-Curie Institute - Oncology Center, Warsaw, Poland. Disclosure: T. Switaj: Honoraria for lectures: Novartis, Roche, MSD, BMS. A.M. Czarnecka: Honoraria for lectures: Novartis, MSD, BMS. P.L. Rutkowski: Honoraria: Bristol-Myers Squibb, Roche, Novartis, Merck, Sharp & Dohme, GlaxoSmithKline; Paid consulting role: Bristol-Myers Squibb, Roche, Merck, Sharp & Dohme, Blueprint Medicines, Amgen; Speakers’ bureau: Novartis, Pfizer, Merck, Sharp & Dohme; Institutional research funding: Bristol-Myers Squibb, Novartis; Travel expenses: Novartis. All other authors have declared no conflicts of interest.

Synchronous multiple primary gallbladder and gastric malignancies: Report of two cases and review of the literature

Multiple primary malignancies (MPM) are rare. In particular, synchronous gallbladder and gastric malignancies are extremely rare, are associated with a concealed onset and atypical symptoms, and are highly likely to be overlooked or misdiagnosed. The clinical data of two patients with synchronous gallbladder and gastric malignancies are herein reported and integrated with the relevant literature to retrospectively analyze and summarize the pathogenesis and clinical characteristics of MPM. Case 1 was a male 46-year-old patient who underwent laparoscopic cholecystectomy, and succumbed to extensive tumor metastasis 2 months after the operation. Case 2 was an 80-year-old female patient who was treated with distal gastrectomy for gastric cancer, cholecystectomy, gastrojejunostomy and dissection of 5 suprapyloric, 6 subpyloric, 7 left gastric and 8 common hepatic artery lymph nodes, and succumbed to multiple organ failure induced by extensive tumor invasion within 1 week after the operation. Clinical physicians must pay closer attention to early symptoms of MPM in order to make an accurate diagnosis, perform timely radical surgical treatment and achieve favorable therapeutic outcomes, in terms of significantly increasing long-term patient survival rates.

Current Drug Targets for Thymic Neoplasms.

Thymic neoplasms are rare malignant tumors, and the mainstay of treatment for patients with thymic tumors is surgical resection. Chemotherapy is necessary for patients with extensive tumor invasion or metastasis who are unable to undergo complete radical excision. However, only two-thirds of these patients respond to chemotherapy. For those patients who are resistant to chemotherapy, targeted therapy has been proposed as a beneficial alternative. Many genes implicated in tumorigenesis and metastasis have been demonstrated to be therapeutic targets in thymic malignancies. Currently, a number of case reports and small clinical trials have reported that a few inhibitors, such as sorafenib and sunitinib, are effective for the treatment of thymoma. This review describes the current potential drug targets and their roles in the development of thymic malignancy. Drugs that are used for the targeted therapy of thymoma and the results of related clinical trials are addressed. Furthermore, we provide an overview of the screening of specific patients who are suitable for targeted therapy and the efficacy of targeted therapy in patients with refractory or recurrent thymic tumors.

Sclerosing mucoepidermoid carcinoma with eosinophilia of the thyroid: more aggressive than previously reported.

Sclerosing mucoepidermoid carcinoma with eosinophilia (SMECE) of the thyroid is a rare traditionally "low-grade" tumor that predominantly occurs in women. Approximately 50 cases have been reported in the literature. It arises in a background of Hashimoto thyroiditis and is characterized by nests of epidermoid and mucin-secreting cells located within an eosinophil-rich sclerotic stroma. Herein, we outline the clinicopathological and immunohistochemical characteristics of 6 cases of thyroid SMECE. All tumors were detected in women (age, 36-89 years; average, 59 years), and all patients underwent total thyroidectomies. Clinicopathological findings included extensive tumor invasion into the adjacent soft tissues, trachea, pharynx, and esophagus. Of 6 specimens, 5 had positive surgical margins. Cervical lymph node metastases were seen in 4, and distant metastases were in 3 patients. Immunohistochemically, all tumors were positive for CK19, galectin 3, and p63 and negative for calcitonin, calponin, S-100, and smooth muscle actin. Interestingly, 2 tumors also showed faint focal staining for thyroglobulin, and 2 others had focal positivity for thyroid transcription factor 1. Together, galectin 3 and CK19 expression supported the malignancy of these lesions, and p63 expression raised the possibility that these tumors originated from the ultimobranchial body. In summary, SMECE tumors in our series exhibit a clear female predominance with aggressive behavior and appear to arise from pluripotent solid cell nests. A correct diagnosis is crucial to providing SMECE patients with the appropriate treatment options, and we recommend a closer follow-up schedule than previously considered.

Epigenetic reprogramming reverses the malignant epigenotype of the MMP/TIMP axis genes in tumor cells

Cancer progression is characterized by extensive tumor invasion into the surrounding extracellular matrix (ECM) and migration to metastatic sites. The increased proteolytic degradation of the ECM during tumor invasion is directly dependent on the activity of matrix metalloproteinases (MMPs), counter-balanced by tissue inhibitors of matrix metalloproteinases (TIMPs). In this study, we found that unbalanced expression of MMP/TIMP axis genes in tumors was correlated with aberrant epigenotypes in the various gene promoters. The malignant epigenotypes could be therapeutically corrected by a simple defined factor-mediated reprogramming approach. Correction of the abnormal epigenotypes by nuclear remodeling leads to a rebalance in the gene expression profile, an alteration in tumor cell morphology, attenuation of tumor cell migration and invasion in vitro, and reduced tumorigenicity in nude mice. We further identified the downregulation of the MKK-p38 MAPK signal pathway as an important underlying mechanism for reduced tumorigenicity in this epigenetic reprogramming model. These data demonstrate that the malignant phenotypes seen in cancer can be corrected by a nuclear remodeling mechanism, thus highlighting a novel non-chemotherapeutic, non-radiotherapeutic approach for the treatment of cancer.

MO‐D‐141‐06: Multiscale PET/Cerenkov Image‐Guided Surgery: Demonstration in An Invasive Mouse Tumor Model

Purpose: Real‐time biological imaging is being investigated to delineate positive tumor margins which during oncological surgery. We investigated the ability of Cerenkov optical emission from Fluorodeoxyglucose (FDG) to resect neoplastic tissue, as guided by Positron Emission Tomography (PET). This technique was demonstrated in a TRAMP mouse model, where prostate cancer that had invaded beyond the capsule of the prostate was identified intra‐operatively. Methods: Studies were performed in vivo in a tumor mouse model. PET imaging was performed with a Siemens Inveon scanner; Cerenkov images were collected with a commercial optical imaging system (Perkin‐Elmer). A transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse model was used to investigate the feasibility of imaging local invasion of the cancer beyond the prostate capsule. Four mice with ∼1cm prostate tumors with questionable invasion as determined by T2‐W MRI were injected with ∼1 mCi of FDG. The injection was followed by PET/CT after 75 minutes, and subsequent sacrifice; surgery commenced immediately after. PET/CT was used to identify tissues pre‐operatively. Resected tissues were analyzed with histology to identify tissues that contained tumor cells for correlation to Cerenkov imaging. Results: All four TRAMP mice exhibited extensive tumor invasion in the prostate with subsequent invasion into the seminal vesicles. No tumor tissue was identified in the other tissues, as confirmed by pathology. Cerenkov imaging was able to significantly differentiate between tissues involved with tumor and those with no tumor (P&lt;0.01). Conclusion: The multiscale strategy, where PET helped to guide surgical resection of Cerenkov‐enhancing tissues, proved to significantly delineate tumor from non‐tumor tissue. This study demonstrates a potentially powerful technique to surgical resection of tumors. We acknowledge the NCI R01 CA128908, NIH ICMIC P50CA114747, DOD Breast Cancer Fellowship W81XWH‐10‐1‐0506, and the Center for Biomedical Imaging at Stanford (CBIS).

Direct visualization of changes of lymphatic function and drainage pathways in lymph node metastasis of B16F10 melanoma using near-infrared fluorescence imaging

The lymphatic system provides an initial route for cancer cell dissemination in many cancers including melanoma. However, it is largely unknown how the lymphatic system changes during tumor progression due in part to the lack of imaging techniques currently available. In this study, we non-invasively imaged changes of lymphatic function and drainage patterns using near-infrared fluorescence (NIRF) imaging. Dynamic NIRF imaging following intradermal injection of indocyanine green (ICG) was conducted in C57BL/6 mice prior to inoculation of B16F10 murine melanoma cells to the dorsal aspect of the left hindpaw for baseline data or directly to the popliteal lymph node (PLN) and until 21 days post-implantation (p.i.). A series of acquired fluorescent images were quantified to measure lymphatic contractile function. Computed tomography (CT) was also performed to measure the volume of tumor-draining lymph nodes (LNs). We observed significant reduction of lymphatic contractility from 7 days p.i. until 21 days p.i.. Altered lymphatic drainage patterns were also detected at 21 days p.i. in mice with tumor in the paw and at 11 days p.i. in mice with tumor in the PLN, due to lymphatic obstruction of normal lymphatic drainages caused by extensive tumor invasion of draining LNs. Since lymphatic function and architecture were progressively altered during tumor growth and metastasis, non-invasive NIRF imaging may provide a new method to stage disease. In addition, this novel technique can be used as a diagnostic method to non-invasively assess lymphatic response as mechanism of therapeutic action.

Abstract A43: Direct visualization of changes of lymphatic function and drainage pathways in lymph node metastasis of B16F10 melanoma using near-infrared fluorescence imaging

Abstract The lymphatic system provides an initial route for cancer cell dissemination in many cancers including melanoma. However, it is largely unknown how the lymphatic system changes during tumor progression, due in part to the lack of imaging techniques available. In this study, we non-invasively imaged changes of lymphatic function and drainage patterns using dynamic near-infrared fluorescence (NIRF) imaging. Dynamic NIRF imaging following intradermal injection of indocyanine green (ICG) was conducted in C57BL/6 mice prior to inoculation of B16F10 murine melanoma cells to the dorsal foot for baseline data and until 21 days post-implant (p.i.). A series of acquired fluorescent images were quantified to measure lymphatic contractile function. Computed tomography (CT) was also performed to measure the volume of tumor-draining lymph nodes (LNs). In addition, intravital color images using a stereomicroscope were acquired after a skin incision. Then, the PLNs and inguinal LNs (ILNs) were harvested for ex vivo NIRF and intravital color imaging. We observed significant reduction of lymphatic contractility from 7 days p.i. until 21 days p.i.. Altered lymphatic drainage patterns were detected at 21 days p.i., due to lymphatic obstruction of normal lymphatic drainages caused by extensive tumor invasion of draining LNs. Magnified fluorescent images of tumor-draining lymphatic vessels showed numerous fluorescent lymphatic vessels at day 21 p.i. as compared to well-defined fluorescent vessels from a baseline image. Our CT data showed enlarged tumor-draining PLNs at 21 days p.i. and intravital images confirmed the PLN harbored melanoma cells. Overlay of white light and fluorescent images of dissected LNs showed strong ICG fluorescence in the ILN and to less extent in the PLN on the tumor bearing side, indicating significantly reduced lymph flow to the PLN due to blockage of normal lymph flow by tumor in the PLN. Since lymphatic function and architecture were progressively altered during tumor growth and metastasis, non-invasive NIRF imaging may provide a new method to stage disease. In addition, this novel technique can be used as a diagnostic method to non-invasively assess lymphatic response as mechanism of therapeutic action. Citation Format: Sunkuk Kwon, Germaine Agollah, Grace Wu, Sevick Sevick-Muraca. Direct visualization of changes of lymphatic function and drainage pathways in lymph node metastasis of B16F10 melanoma using near-infrared fluorescence imaging. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A43.

Prostate cancer with Paneth cell-like neuroendocrine differentiation and extensive perineural invasion: Coincidence or causal relationship?

The case of a 74-year-old man is reported who suffered from a locally advanced prostate cancer treated by neoadjuvant hormonal ablation, followed by prostatectomy. Histological examination of the prostatectomy specimen disclosed an adenocarcinoma with partial, Paneth-like, neuroendocrine differentiation. Extensive perineural tumor invasion was found with a total of 921 perineural tumor foci. Neuroendocrine differentiation of tumor cells was accentuated in perineural locations and was associated with an elevated expression of N-CAM and vimentin, and a reduced expression of E-Cadherin and Ki-67. We hypothesize that neuroendocrine differentiation may promote perineural invasion of prostate cancer cells by a “catherin-switch” and by mechanisms involving epithelial-mesenchymal transition.

Functional significance of VEGF-a in human ovarian carcinoma: Role in vasculogenic mimicry

Ovarian cancer is a silent killer, and shows early extensive tumor invasion and peritoneal metastasis. The microcirculation of most tumors includes cooperation of pre-existing vessels, intussusceptive microvascular growth, postnatal vasculogenesis, glomeruloid angiogenesis, and vasculogenic mimicry (VM). VM is critical for a tumor blood supply and is asscociated with aggressive features and metastasis. Our studies highlight the plasticity of aggressive human ovarian carcinoma cells and call into question the underlying significance of their ability to form VM in vitro induced by VEGF-a. These studies also show their clinicalpathological features of the cancers with human Paraffin-embedded tumor tissue samples. Results show that the process: VEGF-a→EphA2→MMPs→VM is the main pathway for VM formation and VEGF-a appears to play an important role in the formation of VM based on our in vitro assays and clinical immunohistochemical analyses. VM-targeting strategies for ovarian cancer include anti-VEGF-a treatment, knocking down the EphA2 gene and using antibodies against human MMPs if the tumor is VM positive. This strategy may be of significant value in laying the foundation for a more explicit anti-tumor angiogenesis therapy.