scholarly journals A new oncolyticVacciniavirusaugments antitumor immune responses to prevent tumor recurrence and metastasis after surgery

2020 ◽  
Vol 8 (1) ◽  
pp. e000415 ◽  
Author(s):  
Jahangir Ahmed ◽  
Louisa S Chard ◽  
Ming Yuan ◽  
Jiwei Wang ◽  
Anwen Howells ◽  
...  
Keyword(s):  
Tumor Recurrence ◽  
Residual Disease ◽  
Neoadjuvant Treatment ◽  
Residual Tumor ◽  
Oncolytic Viruses ◽  
Postoperative Survival ◽  
Interleukin 12 ◽  
Patients With Cancer ◽  
Post Surgery ◽  
Attractive Option

BackgroundLocal recurrence and remote metastasis are major challenges to overcome in order to improve the survival of patients with cancer after surgery. Oncolytic viruses are a particularly attractive option for prevention of postsurgical disease as they offer a non-toxic treatment option that can directly target residual tumor deposits and beneficially modulate the systemic immune environment that is suppressed post surgery and allows residual disease escape from control. Here, we report that a novelVaccinia virus(VV), VVΔTKΔN1L (with deletion of both thymidine kinase (TK) and N1L genes) armed with interleukin 12 (IL-12), can prolong postoperative survival when used as a neoadjuvant treatment in different murine and hamster surgical models of cancer.MethodsA tumor-targeted replicating VV with deletion of TK gene and N1L gene (VVΔTKΔN1L) was created. This virus was armed rationally with IL-12. The effect of VVΔTKΔN1L and VVΔTKΔN1L-IL12 on modulation of the tumor microenvironment and induction of tumor-specific immunity as well the feasibility and safety as a neoadjuvant agent for preventing recurrence and metastasis after surgery were assessed in several clinically relevant models.ResultsVVΔTKΔN1L can significantly prolong postoperative survival when used as a neoadjuvant treatment in three different surgery-induced metastatic models of cancer. Efficacy was critically dependent on elevation of circulating natural killer cells that was achieved by virus-induced cytokine production from cells infected with N1L-deleted, but not N1L-intact VV. This effect was further enhanced by arming VVΔTKΔN1L with IL-12, a potent antitumor cytokine. Five daily treatments with VVΔTKΔN1L-IL12 before surgery dramatically improved postsurgical survival. VVΔTKΔN1L armed with human IL-12 completely prevented tumor recurrence in surgical models of head and neck cancer in Syrian hamsters.ConclusionsThese data provide a proof of concept for translation of the regime into clinical trials. VVΔTKΔN1L-IL12 is a promising agent for use as an adjuvant to surgical treatment of solid tumors.

Neoadjuvant chemotherapy with metronomic doxorubicin, cyclophosphamide, and capecitabine in patients with locally advanced (LA) triple-negative breast cancer (TNBC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e12027-e12027
Author(s):  
Mona Frolova ◽  
Marina Skrypnikova ◽  
Ekaterina Ignatova ◽  
Alexander Petrovsky ◽  
Marina Stenina ◽  
...  
Keyword(s):  
Neoadjuvant Chemotherapy ◽  
Cumulative Dose ◽  
Residual Disease ◽  
Locally Advanced ◽  
Pilot Trial ◽  
Survival Rates ◽  
Neoadjuvant Treatment ◽  
Residual Tumor ◽  
Complete Regression ◽  
Grade 3

e12027 Background: TNBC is associated with aggressive behavior and poor prognosis. It has been shown that patients (pts) with TNBC with pathological complete regression (pCR) after neoadjuvant chemotherapy have a higher survival. Rates of pCR with standard antracycline- and taxanebased chemotherapy regimens don’t exceed 20-27%. Dose-dense and metronomic schedules may be more effective in these highly proliferative tumors. We performed a prospective pilot trial to evaluate efficacy of metronomic schedule of doxorubicin, cyclophosphamide and capecitabine in pts with LA TNBC. Methods: Pts with LA TNBC (cT2-4N1-3M0) were treated with doxorubicin 25 mg/m2 iv weekly, cyclophosphamide 50 mg po daily and capecitabine 1500 mg po daily for planned 16-19 weeks followed by surgery. Pathological response was evaluated according to the Chevallier classification. Results: Twenty pts was included in the study in 2009-2010. Median agewas 47 years (33-70), 63% of pts had tumor grade 3, Ki67 was >20% in all cases. Nineteen pts completed chemotherapy (median treatment duration 17.1 weeks) and underwent surgery. One pt had a disease progression during chemotherapy and was switched to 2nd-line chemotherapy. Seven pts (36,8%) achieved a pCR (6 pts class 1 and 1 pt class 2). With median follow-up of 33 months, 3-year DFS and OS were 60%. All but one pt with pCR, who developed brain mts shortly after surgery, are currently alive without relapse. In contrast 50% of pts with residual tumor relapsed. Pts with pCR had significantly higher median cumulative dose of doxorubicin (420 mg/m2) than pts with residual disease (300 mg/m2, p=0.046). The dose-limiting toxicities were hand-foot syndrome (26.3% grade 3), mucositis (31.6% grade 3), and neutropenia (31.6% grade 3-4), which resulted in permanent discontinuation of doxorubicin in 4 pts. Conclusions: Despiterelatively hightoxicity metronomic doxorubicin, cyclophosphamide and capecitabine regimen shows promising activity as neoadjuvant treatment of LA TNBC. Achievement of pCR and higher cumulative dose of doxorubicin were strongly associated with improvement of survival.

Computational pathological identification of prostate cancer following neoadjuvant treatment.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e14052-e14052
Author(s):  
Belma Dogdas ◽  
Christopher Kanan ◽  
Patricia Raciti ◽  
Shaozhou Ken Tian ◽  
Sabine Doris Brookman-May ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Practice ◽  
Residual Disease ◽  
Characteristic Curve ◽  
False Negative ◽  
Neoadjuvant Treatment ◽  
Area Under The Curve ◽  
Residual Tumor ◽  
Correct Identification ◽  
Pathological Assessment

e14052 Background: The need for accurate pathological identification and quantitation of prostate cancer (PC) following neoadjuvant treatment with androgen deprivation therapy (ADT) and androgen receptor antagonists is increasing as PC treatment continues to evolve. In clinical practice, pathological assessment of residual tumor is a tedious and time-consuming process due to the volume of tissue from radical prostatectomy (RP). In addition, neoadjuvant treatments can greatly alter both benign and neoplastic prostate tissue morphology making the pathology assessment difficult for even specialized pathologists. Paige Prostate 1.0 is a clinical-grade artificial intelligence (AI) system for PC detection. It was trained and evaluated in over 50,000 prostate biopsy slides with validation across more than 800 institutions worldwide using multiple slide scanners. Methods: We evaluated the performance of Paige Prostate 1.0 at identifying prostatic tumor on 64 hematoxylin and eosin stained slides exhibiting neoadjuvant treatment effect from apalutamide, enzalutamide, and/or ADT. Results: Analysis of the receiver operating characteristic curve demonstrated an area under the curve of 0.96. Using the Paige Prostate 1.0 operating point, it achieved a sensitivity of 91% and a specificity of 94%, corresponding to the correct identification of challenging treated morphology in 59/64 slides using expert pathologists as the reference. False negative cases were typically represented by atypical small acinar proliferation that required expert pathological consensus confirmation. Conclusions: To our knowledge, this is the first AI based evaluation of residual disease in PC with hormone neoadjuvant therapy. Paige Prostate 1.0 effectively identified tumor despite treatment effects. Future work will include optimization of Paige Prostate 1.0 by training with RP specimens from a larger cohort of appropriate samples, as well as precise measurement of residual tumor burden to further improve its accuracy and reproducibility. Paige prostate residual disease detection 1.0 has the potential to impact emerging clinical practice at the patient level and to complement the pathological assessment of RPs in global phase 3 clinical trials, such as PROTEUS, in a standardized, reproducible, and robust way.

SURGERY FOR RESIDUAL DISEASE AFTER RADIOTHERAPY IN LOCALLY ADVANCED CERVICAL CANCER

2019 ◽  
Vol 65 (5) ◽  
pp. 721-725
Author(s):  
Elmira Shakirova ◽  
Andrey Panov ◽  
Alevtina Akhmetzyanova ◽  
Aliya Gafiullina ◽  
L. Ibragimova ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Residual Disease ◽  
Locally Advanced ◽  
Residual Tumor ◽  
Advanced Cervical Cancer ◽  
Mri Imaging ◽  
Recurrent Cervical Cancer ◽  
Locally Advanced Cervical Cancer ◽  
Visible Effect ◽  
Adjuvant Hysterectomy

Aims: Chemoradiation (CRT) is the standard treatment for locally advanced cervical cancer (LACC). However part of the patients develop recurrence during the first year after treatment despite good visible effect at the first follow-up. The role of completion surgery after radiotherapy (RT) is still debated. A number of papers have showed that up to 60% of patients have residual tumor after CRT and RT. But such a surgery is not widely recommended because of increased morbidity of the treatment. The aim of this study was to assess the results of surgery after radiotherapy of LACC. Method: We retrospectively evaluated data on 86 patients with cervical cancer IB - IIIB stages (mostly stage IIB) who underwent surgery in different modalities after CRT and RT with good clinical response in our department in 2015-2018. Results: When small asymptomatic residual disease was detected early after radiotherapy radical hysterectomy was feasible in most of the cases. Patients with clinical manifestation of recurrence had very poor prognosis. Surgery of recurrent cervical cancer sufficiently deteriorates quality of life, even if possible. Conclusion: Thorough examination with adding MRI imaging after initial treatment of cervical cancer needed to identify patients who may benefit from adjuvant hysterectomy.

Early results of surgery in patients with nonfunctioning pituitary adenoma and analysis of the risk of tumor recurrence

2008 ◽  
Vol 108 (3) ◽  
pp. 525-532 ◽  
Author(s):  
Marco Losa ◽  
Pietro Mortini ◽  
Raffaella Barzaghi ◽  
Paolo Ribotto ◽  
Maria Rosa Terreni ◽  
...  
Keyword(s):  
Tumor Recurrence ◽  
Postoperative Radiotherapy ◽  
Residual Tumor ◽  
Benign Tumors ◽  
Surgical Removal ◽  
Tumor Diameter ◽  
Tumor Removal ◽  
Early Results ◽  
Results Of Surgery

Object Nonfunctioning pituitary adenomas (NFPAs) are benign tumors of the pituitary gland that typically cause visual and/or hormonal dysfunction. Surgery is the treatment of choice, but patients remain at risk for tumor recurrence for several years afterwards. The authors evaluate the early results of surgery and the long-term risk of tumor recurrence in patients with NFPAs. Methods Between 1990 and 2005, 491 previously untreated patients with NFPA underwent surgery at the Università Vita-Salute. Determinations of recurrence or growth of the residual tumor tissue during the follow-up period were based on neuroradiological criteria. Results Residual tumor after surgery was detected in 173 patients (36.4%). Multivariate analysis showed that invasion of the cavernous sinus, maximum tumor diameter, and absence of tumor apoplexy were associated with an unfavorable surgical outcome. At least 2 sets of follow-up neuroimaging studies were obtained in 436 patients (median follow-up 53 months). Tumors recurred in 83 patients (19.0%). When tumor removal appeared complete, younger age at surgery was associated with a risk of tumor recurrence. In patients with incomplete tumor removal, adjunctive postoperative radiotherapy had a marked protective effect against growth of residual tumor. Conclusions Complete surgical removal of NFPAs can be safely achieved in > 50% of cases. Visual symptoms and, less frequently, pituitary function may improve after surgery. However, tumor can recur in patients after apparently complete surgical removal. In patients with incomplete tumor removal, radiation therapy is the most effective adjuvant therapy for preventing residual tumor growth.

Pathology of durable stable disease in melanoma patients treated with ipilimumab, nivolumab, or ipilimumab, and nivolumab combination therapy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9567-9567
Author(s):  
Elizabeth Iannotti Buchbinder ◽  
Kathleen L. Pfaff ◽  
Michael P. Manos ◽  
Olivia Ouyang ◽  
Patrick Alexander Ott ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Stable Disease ◽  
Residual Disease ◽  
Residual Tumor ◽  
Cell Content ◽  
Tissue Samples ◽  
Pet Ct ◽  
Melanoma Patients ◽  
Residual Lesions

9567 Background: As immunotherapy with checkpoint blockade becomes the backbone of melanoma treatment there is a need to better understand the biology associated with long term benefit. One particularly interesting set of patients are those with prolonged stable disease or response with residual findings on imaging. It is unknown if immunotherapy has led to scarring at the site of prior disease or if there are residual tumor cells being controlled by an ongoing immune response. Evaluating tissue from patients with prolonged responses provides a unique opportunity to determine the composition of residual lesions. Correlation with PET/CT helps determine if this is an accurate modality to reflect presence of residual viable tumor tissue. Methods: Metastatic melanoma patients that have attained long term stable disease after treatment with ipilimumab, nivolumab, or ipilimumab plus nivolumab were identified. Patients must have received ipilimumab, nivolumab or combination therapy 2+ years prior to enrollment and must have had stable disease for ≥ 6 months. Patients were consented and underwent PET/CT scans and biopsies of residual areas of stable disease. Pre- and post-treatment tissue samples underwent pathologic assessment to look at tumor cell content, fibrotic content, and inflammation. Results: Ten patients were consented for evaluation but only 7 met the screening criteria and underwent PET/CT and tissue biopsy. Six patients had FDG avid lesions on PET/CT which ranged in intensity from SUV 2.4-22. One patient had no FDG avidity in the areas of residual disease observed on CT. Biopsies from the residual stable lesions demonstrated predominantly necrosis and fibrosis with prominent pigment containing macrophages. One patient with an axillary nodal lesion with an SUV of 22 had active melanoma on pathology which was resected, and the patient has subsequently remained without progression of disease. Conclusions: Patients with durable stable disease after treatment with ipilimumab, nivolumab or ipilimumab and nivolumab combination therapy represent a unique population of melanoma patients treated with immune checkpoint inhibition. An examination of the residual lesions observed in these patients demonstrated predominantly necrosis and fibrosis consistent with resolving lesions. The presence of melanophages in these samples may suggest some ongoing immune surveillance. One patient did demonstrate residual melanoma suggesting the need for ongoing monitoring of this patient population.

Minimal residual disease by circulating tumor DNA analysis for colorectal cancer patients receiving radical surgery: An initial report from CIRCULATE-Japan.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3608-3608
Author(s):  
Hiroki Yukami ◽  
Yoshiaki Nakamura ◽  
Jun Watanabe ◽  
Masahito Kotaka ◽  
Kentaro Yamazaki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dna Analysis ◽  
Residual Disease ◽  
Clinical Stage ◽  
Circulating Tumor Dna ◽  
Patient Specific ◽  
Detection Rates ◽  
Initial Report ◽  
Post Surgery ◽  
Tumor Dna

3608 Background: Circulating tumor DNA (ctDNA) analysis can be used to predict the risk of recurrence by detecting molecular residual disease (MRD) in patients with colorectal cancer (CRC). We are conducting a prospective observational study to monitor MRD status in patients with clinical stage II–IV or relapsed CRC amenable to radical surgical resection (GALAXY study), as part of the CIRCULATE-Japan, a nationwide ctDNA-guided precision adjuvant therapy project. Methods: Analysis of ctDNA is being performed at pre- and post-surgery timepoints and will continue periodically for up to 2 years using Signatera, a personalized, tumor-informed ctDNA assay that is designed to track 16 patient-specific somatic variants based on whole-exome sequencing of tumor tissue. The association of peri-operative ctDNA status with clinicopathological characteristics was investigated. Results: As of January 13, 2021, 941 patients have been enrolled in the GALAXY study, of which 400 patients had their pre-operative ctDNA status evaluated. Of the 400 patients, baseline ctDNA was detected in 92% (367/400) of the patients: consisting of 35 patients with pathological stage (pStage) I, 135 with pStage II, 152 with pStage III, and 78 with pStage IV or relapsed disease (pStage IV/R). Patient-specific Signatera assays targeting 16 variants were designed for 100% of the patients. Out of the 6400 designed variants 99.3% passed quality control in the plasma analysis and produced the final results. Among 4425 genes selected for 400 patients, 3330 genes were selected for only one patient, while TP53 was the most commonly selected in 113 patients (28%). Median ctDNA levels, measured in mean tumor molecules per mL of plasma and ctDNA detection rate, stratified by stage are presented in table. Positive ctDNA status post-surgery was significantly associated with advanced pStage, pT and pN, and lymphovascular invasion. Of the 13 patients with recurrence, 10 were detected with a positive ctDNA at 4-weeks post-surgery, before confirmation of recurrence by the radiological imaging. Conclusions: Preoperative ctDNA detection rates were observed to be in >90% in patients with pStage II–III by personalized ctDNA assay based on unique somatic variants, specific to each patient. ctDNA- based MRD detected post-surgery (4W) was significantly associated with certain known clinicopathological factors for recurrence with ctDNA positivity associated with a very short-term of recurrence. Clinical trial information: 000039205. [Table: see text]

scholarly journals Role of discoidin domain receptor 2 (DDR2) and microRNA-182 in survival of women with high-grade serous ovarian cancer

Tumor Biology ◽  
2019 ◽  
Vol 41 (1) ◽  
pp. 101042831882398
Author(s):  
Susana Ramalho ◽  
Liliana AL De Angelo Andrade ◽  
Cássio Cardoso Filho ◽  
Rodrigo de Andrade Natal ◽  
Marina Pavanello ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Residual Disease ◽  
Figo Stage ◽  
Stage I ◽  
High Grade ◽  
Serous Ovarian Cancer ◽  
Discoidin Domain Receptor ◽  
Post Surgery ◽  
Platinum Based Chemotherapy ◽  
Discoidin Domain Receptor 2

The objective of this study is to evaluate the relationship between discoidin domain receptor 2 (DDR2) and miR-182 expression with response to platinum-based chemotherapy and survival in women with high-grade serous ovarian cancer (HGSOC). We evaluated 78 women with HGSOC stages I-IV, diagnosed between 1996 and 2013, and followed up until 2016. DDR2 expression was assessed using immunohistochemistry on tissue microarray slides. The microRNAs were evaluated by qRT-PCR. DDR2 expression was high in 11 (14.1%) women. PFS was significantly lower in women with FIGO stage I/II – versus III/IV, post-surgery residual disease and high expression of DDR2. Women with postsurgery residual disease, FIGO stage I/II – versus III/IV and DDR2 expression had worse OS, but only post-surgery residual disease remained an independent prognostic factor for worse OS in multivariable analysis. miR-182 expression levels were significantly lower in patients harboring tumors with higher expression of DDR2 (p < 0.001). In this relatively large cohort of women with HSGOC, higher DDR2 expression was associated with lower miR-182 levels and worse PFS, suggesting that these molecules may be associated with mechanisms of HGSOC progression.

Surgical Approach to Cervical Lymph Node Metastasis in Differentiated Thyroid Cancer

2002 ◽  
Vol 88 (3) ◽  
pp. S47-S48 ◽  
Author(s):  
M Goss ◽  
S D'Amico ◽  
A Mobiglia ◽  
A Sargiotto ◽  
M Deandrea
Keyword(s):  
Lymph Node ◽  
Residual Disease ◽  
Intraoperative Complications ◽  
Residual Tumor ◽  
Cervical Lymph Node Metastasis ◽  
Regional Lymph Nodes ◽  
Tumor Spread ◽  
Metastatic Lesions ◽  
Tissue Specimens

Background Precautionary locoregional lymph node dissection in thyroid carcinomas for diagnostic and/or staging purposes is useless both in differentiated (papillary and follicular) and undifferentiated forms. It is only indicated in medullary carcinomas because of their frequent spread to regional lymph nodes. The objective of lymphadenectomy is to contain tumor spread; however, the procedure may be associated with intraoperative complications and postoperative sequelae. In order to improve the therapeutic management of patients with thyroid carcinoma, diagnostic scintigraphy with 201Tl or 99mTc-sestamibi is used in the advanced and undifferentiated forms of this tumor. Methods We have treated a woman submitted three years previously to total thyroidectomy for papillary carcinoma (pT3) without subsequent radiometabolic treatment. On physical examination we noticed a swelling on the left side of the neck. The lesion was confirmed by ultrasonography, CT scan, and scintigraphic examination with 99mTc-sestamibi 24 hours before planned lymphadenectomy. During the surgical procedure we performed radiodetection to localize metastatic lesions. Results Intraoperative radiodetection may help to identify residual disease, which is often difficult to trace in the presence of post-surgical fibrosis. In our patient, histological examination of the removed tissue specimens demonstrated that intraoperative radiolocalization had been highly accurate. The eradication of residual disease was confirmed by scintigraphic follow-up after 12 months. Discussion and conclusions Scintigraphy with 99mTc-sestamibi has been proposed as a means to localize metastatic spread and possible residual disease after a supposedly radical thyroidectomy. Surgical eradication of all residual tumor guarantees the best disease control without having to resort to radiometabolic therapy. This approach will reduce the incidence of iatrogenic comorbidity and consequently improve the patients' quality of life.

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