Disease Progression In Patients Research Articles

CT-guided percutaneous implantation of 125I particles in treatment of early lung cancer.

BackgroundTo analyze the efficacy of computed tomography (CT)-guided implantation of 125I radioactive particles in treatment of early lung cancer.MethodsSix patients were analyzed, including 4 squamous cell carcinoma, 1 adenocarcinoma, and 1 small cell lung cancer. TPS software was used to calculate the therapeutic dose amount of particles implanted, and the spacing and distribution of seeds in the target area and adjacent tissues. Under the guidance of CT, 20–55 particles were implanted at each site, with the total number of radioactive particles being 226, the particle spacing being 0.5–1.0 cm, and the implantation being performed in accordance with the principle of uniform implantation. The patients were each followed up with repeated pulmonary CT scans at 1, 3, 6, 12, 18, 24, 30 and 36 months after the procedure. In accordance with the response evaluation criteria in solid tumors (RECIST), the following definitions for responses were used: complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD).ResultsThere were 2 CRs and 4 PRs one month after procedure; six patients were followed up 3 months after procedure, including 2 CRs and 4 PRs; one patient was lost in follow-up, and 5 patients were followed up 6 months after procedure, including 3 CRs and 2 PRs; five patients were followed up 12 months after procedure, including 3 CRs, 1 PR and 1 PD. The single PD patient was again given CT-guided implantation of 125I radioactive particles for the treatment of recurrent lesions. The pulmonary CT was repeated 6 months after procedure, and the response was evaluated as SD. Four patients were followed up 18 months after procedure, including 3 CRs and 1 PR; one patient was lost in follow-up and 3 patients were followed up 24 months after the procedure with the response being evaluated as CR for all of them; one patient was followed up 36 months after procedure, and the response was evaluated as PD. During the follow-up, no serious complications occurred in any of the patients.ConclusionsThe preliminary clinical observation showed that 125I radioactive particle implantation was a safe, reliable and effective therapeutic method for early lung cancer.

Predictors of Response and Survival Outcomes of Triple Negative Breast Cancer Receiving Neoadjuvant Chemotherapy

Background: In triple negative breast cancer (TNBC) patients receiving neoadjuvant chemotherapy (NACT), pre-treatment predictors for pathological complete response (pCR) have been reported; however, those for progressive disease (PD) remain unidentified. Methods: We investigated pre-treatment clinicopathological predictors associated with pCR and PD by retrospectively reviewing data for 165 patients treated between 2015 and 2018. Patients with pCR and PD were compared to those without pCR and PD, respectively, using logistic regression and Kaplan-Meier methods. Results: Lack of androgen receptor (AR) was an independent predictor of pCR, while high histological grade, low Ki-67 index, and incomplete NACT courses were independent predictors of PD. Mean disease-free survival and overall survival were significantly poorer in PD patients than in pCR patients (15.7, 21.3 vs. 52.4, 56.3 months). Conclusions: Insights into the chemo-resistance mechanisms and exploration of novel targeted agents in subgroups as per AR and Ki-67 status are needed to improve survival outcomes in TNBC patients.

Retrospective Multicenter Analysis of the Outcome of a Re-Induction with Immune Checkpoint Inhibitors in Advanced Merkel Cell Carcinoma

Significant progress has been made in the treatment of advanced Merkel cell carcinoma (MCC) by establishing immune checkpoint inhibitors (ICI). Tumor progression, durable response, or adverse events may lead to ICI discontinuation in MCC patients. If in these patients tumor progression occurs, the question remains if re-induction with ICI achieves renewed tumor response. This retrospective multicenter study evaluated patients in with re-induction of anti-PD-1/anti-PD-L1 therapy for advanced MCC. Clinical data were extracted at treatment initiation, tumor response, treatment cessation, and subsequent tumor response to re-induction. Eight patients from seven centers (mean age 67.8 years) were included. The median duration of initial therapy with anti-PD-1/anti-PD-L1 was 9.6 months (2–21 months). Two patients achieved complete response (CR), four patients partial response (PR), one patient stable disease (SD), while in one patient progressive disease (PD) occurred as best overall response (BOR) to ICI. Reason for discontinuation of ICI was PD in three patients and severe adverse events in five patients. Following a median anti-PD-1/anti-PD-L1 therapy-free interval of 9.5 months (3–18 months), re-induction with ICI therapy was initiated. Five of eight patients (62.5%) achieved an objective response upon re-induction, while in three patients, no response could be observed. Notably, adverse events, which had led to the discontinuation of the first ICI treatment line, were not observed upon re-induction. The initial response to immune checkpoint inhibitors seems to be an important marker for successful re-induction. Interestingly, adverse events leading to treatment discontinuation were not observed during re-induction.

Comparison of Image-Guided Iodine-125 Seed Interstitial Brachytherapy and Local Chemotherapy Perfusion in Treatment of Advanced Pancreatic Cancer

Objective To compare the efficacy and safety of iodine-125 seed interstitial brachytherapy and local chemotherapy perfusion in treatment of advanced pancreatic cancer. Methods The present open prospective randomized control study included a total of 165 cases of advanced pancreatic cancer patients who were admitted in our hospital during December 2016 to April 2019. All patients were randomized into two groups with 84 cases in iodine-125 group and 81 cases in chemotherapy perfusion group. Basic clinical characteristics and demographic data were collected. The main outcome was the tumor efficiency. The pain condition was measured by visual analogue scale (VAS) and the Karnofsky score was also measured at different time points, before the treatment, 1 d, 7 d, 14 d, 1 mon, 2 mon and 3 mon after treatment. Serum levels of CEA, CA19-9 and CA50 were measured by immunochemiluminescence. The overall survival was analyzed by K-M curve. Results The ratio of partial remission patients was significantly higher, and the ratio of stable disease (SD)+progressive disease patients was also remarkably lower in iodine-125 group than the chemotherapy perfusion group. The mean VAS scores decreased markedly after treatment and were significantly lower and the mean Karnofsky scores were remarkably higher in iodine-125 group than the chemotherapy perfusion group. The levels of CA19-9 and CA50 were remarkably lower in iodine-125 group, however no significant difference was found for CEA. The survival analysis by K-M curve showed the iodine-125 patients had longer overall survival time than the chemotherapy perfusion group. No infection, pancreatic fistula, biliary fistula, intestinal fistula, gastrointestinal obstruction or radiation enteritis was found in both groups. Conclusion Iodine-125 seed interstitial brachytherapy could achieve better efficacy with no increased side complications than chemotherapy perfusion in advanced pancreatic cancer.

CT volume of enhancement of disease (VED) can predict the early response to treatment and overall survival in patients with advanced HCC treated with sorafenib

ObjectivesTo analyse the predictive value of the volume of enhancement of disease (VED), based on the CT arterial enhancement coefficient (ΔArt%), in the evaluation of the sorafenib response in patients with advanced hepatocellular carcinoma (HCC).MethodsPatients with sorafenib-treated advanced HCC, who underwent a multiphase contrast-enhanced CT before (T0) and after 60–70 days of starting therapy (T1), were included. The same target lesions utilised for the response evaluation according to modified Response Evaluation Criteria in Solid Tumors criteria were retrospectively used for the ΔArt% calculation ([(HUarterial phase − HUunenhanced phase) / HUunenhanced phase] × 100). ΔArt% was weighted for the lesion volume to obtain the VED. We compared VEDT0 and VEDT1 values in patients with clinical benefit (CB) or progressive disease (PD). The impact of VED, ancillary imaging findings, and blood chemistries on survival probability was evaluated.ResultsThirty-two patients (25 men, mean age 65.8 years) analysed between 2012 and 2016 were selected. At T1, 8 patients had CB and 24 had PD. VEDT0 was > 70% in 8/8 CB patients compared with 12/24 PD patients (p = 0.011). Patients with VEDT0 > 70% showed a significantly higher median survival than those with lower VEDT0 (451.5 days vs. 209.5 days, p = 0.032). Patients with VEDT0 > 70% and alpha-fetoproteinT0 ≤ 400 ng/ml had significantly longer survival than all other three combinations. In multivariate analysis, VEDT0 > 70% emerged as the only factor independently associated with survival (p = 0.037).ConclusionIn patients with advanced HCC treated with sorafenib, VED is a novel radiologic parameter obtained by contrast-enhanced CT, which could be helpful in selecting patients who are more likely to respond to sorafenib, and with a longer survival.Key Points• To achieve the best results of treatment with sorafenib in advanced HCC, a strict selection of patients is needed.• New radiologic parameters predictive of the response to sorafenib would be essential.• Volume of enhancement of disease (VED) is a novel radiologic parameter obtained by contrast-enhanced CT, which could be helpful in selecting patients who are more likely to respond to therapy, and with a longer survival.

Abstract LB-076: Targeted Natural Killer (NK) cell based adoptive immunotherapy for the treatment of patients with non-small cell lung cancer (NSCLC) after radiochemotherapy - results of a randomized phase II clinical trial (NSCLC-TKD/IL-2) (Eudra-CT Number 2008-002130-30)

Abstract Membrane-bound heat shock protein 70 (mHsp70) is indicative for high-risk tumors with negative prognosis but also serves as a target for NK cells that are stimulated with Hsp70 peptide TKD and low dose IL-2 (TKD/IL-2). Herein, the efficacy of ex vivo TKD/IL-2 activated, autologous NK cells was tested in a randomized, investigator initiated phase II clinical trial in patients with mHsp70 positive advanced stage NSCLC after radiochemotherapy (RCT, 60-70 Gy, platinum-based chemotherapy). The interventional (INT) group received 4 cycles TKD/IL-2 activated, autologous NK cells every 2-6 weeks subsequent to standard RCT and the control (CTRL) group received best supportive care. The primary objective of the study was to examine whether the adjuvant treatment of NSCLC patients with TKD/IL-2 activated NK cells is feasible and effective with respect to progression-free survival (PFS). Secondary objectives were the assessment of treatment and biological responses, toxicity, quality-of-life (QoL, QLQ-LC13). Eight patients were randomized into the INT and eight into the CTRL arm. None of the patients died between randomization and final tumor assessment 18 months after randomization. In the INT group one patient had complete response (CR), one patient partial response (PR), two patients stable disease (SD) and one patient progressive disease (PD) at the last documented visit, whereas in the CTRL group only 2 patients showed clinical responses (PR, SD) and five patients had PD. The clinical response of patients in the INT group appeared to be mediated by activated NK cells whereas in the CTRL group by CD8+ T cells. The NK cell therapy after RCT was well tolerated, no differences in QoL were observed between both study groups. Citation Format: Gabriele Multhoff, Stephanie E. Combs, Sophie Seier, Stefan Stangl, Wolfgang Sievert, Maxim Shevtsov, Christiane Blankenstein, Martin Hildebrandt, Konrad Kokowski, Matthias Hautmann, Hubert Hautmann, Claus Roedel, Rainer Fietkau, Rudolf M. Huber, Bernhard Haller, Christina Ertl, Michal Devecka, Robert Offner, Norbert Ahrens. Targeted Natural Killer (NK) cell based adoptive immunotherapy for the treatment of patients with non-small cell lung cancer (NSCLC) after radiochemotherapy - results of a randomized phase II clinical trial (NSCLC-TKD/IL-2) (Eudra-CT Number 2008-002130-30) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-076.

Incorporating longitudinal biomarkers for dynamic risk prediction in the era of big data: A pseudo-observation approach.

Longitudinal biomarker data are often collected in studies, providing important information regarding the probability of an outcome of interest occurring at a future time. With many new and evolving technologies for biomarker discovery, the number of biomarker measurements available for analysis of disease progression has increased dramatically. A large amount of data provides a more complete picture of a patient's disease progression, potentially allowing us to make more accurate and reliable predictions, but the magnitude of available data introduces challenges to most statistical analysts. Existing approaches suffer immensely from the curse of dimensionality. In this article, we propose methods for making dynamic risk predictions using repeatedly measured biomarkers of a large dimension, including cases when the number of biomarkers is close to the sample size. The proposed methods are computationally simple, yet sufficiently flexible to capture complex relationships between longitudinal biomarkers and potentially censored events times. The proposed approaches are evaluated by extensive simulation studies and are further illustrated by an application to a data set from the Nephrotic Syndrome Study Network.

Bisphosphonate Use Is Protective of Radiographic Knee Osteoarthritis Progression Among those With Low Disease Severity and Being Non-Overweight: Data From the Osteoarthritis Initiative.

Antiresorptive medications have been explored for treating knee osteoarthritis (OA); however, little data exist on the effects of today's more potent nitrogen-containing oral bisphosphonates on radiographic disease-progression in patients with varying disease-severity, especially those who are not overweight. The primary objective of this cohort study was to determine if the use of bisphosphonates is protective against 2-year radiographic-progression of knee OA in Osteoarthritis Initiative (OAI) participants, stratified by baseline radiographic disease status. Secondary objectives were to examine effects in non-overweight participants (body mass index [BMI] < 25 kg/m2 ) and cumulative bisphosphonate exposure effects. We identified female OAI participants aged ≥50 years and excluded those missing baseline radiograph readings, bisphosphonate use information, or all clinical questionnaire information at baseline. Participants reporting bisphosphonate use (69% alendronate) were propensity-matched 1:1 to non-bisphosphonate users and followed until first radiographic knee OA progression (1-unit increase in Kellgren and Lawrence [KL] grade) or data were censored (first missed visit or end of 2-year follow-up). Discrete-time logistic regression models estimated hazard ratios (HRs) between bisphosphonate users versus nonusers, with an interaction term for baseline KL grade (KL <2 or KL ≥2). We identified 1977 eligible women (n = 346 bisphosphonate users). Propensity-matched results indicated that bisphosphonate users with KL grade <2 were protected against progression (HRKL<2 0.53; 95% CI, 0.35 to 0.79), while bisphosphonate use was not associated with radiographic progression in those with KL grade ≥2 (HRKL≥2 1.06; 95% CI, 0.83 to 1.35). When restricting analyses to those with BMI <25 kg/m2 , effects were strengthened (HRKL<2 0.49 [95% CI, 0.26 to 0.92]; HRKL≥2 0.69 [95% CI, 0.33 to 1.26]). Duration of bisphosphonate use had no effect on progression, though sample size was limited. Bisphosphonate therapy may be protective against radiographic knee OA progression in early-stage patients, particularly those who are non-overweight, but less so for those with more advanced disease or more weight-bearing joint stress. © 2020 American Society for Bone and Mineral Research (ASBMR).

Evaluación del papel de la PET/TC con [68Ga]Ga-PSMA I&T en la evaluación de la respuesta a la terapia con docetaxel en pacientes con cáncer de próstata resistente a la castración

ObjectiveThere have been only few studies investigating the role of PSMA ligands in the therapy response assessment of metastasized castration resistant prostate cancer (mCRPC) cases. In this study we aimed at evaluating the capability of 68Ga- prostate-specific membrane antigen (PSMA) I&T positron emission tomography/computerized tomography (PET/CT) in the assessment of therapeutic response in patients under docetaxel therapy for prostate cancer (PCa). Material and methodsThe clinical records of all mCRPC patients treated with docetaxel and referred to our department for 68Ga-PSMA I&T PET/CT imaging were retrospectively analysed. Sixteen patients (mean age 69 years, range 52–82 years) with castration-resistant prostate cancer patients receiving palliative docetaxel therapy and had undergone 68Ga-PSMA I&T PET/CT scan were included in the study. 68Ga-PSMA I&T PET/CT imaging was done and prostate specific antigen (PSA) levels were measured at baseline before administration of docetaxel (PET1) and after at least 3 cycles (range 4–12) of chemotherapy (PET2). Patient-based as well as lesion-based comparison of PET2 findings with PET1 findings were done. ResultsThe change (decrease) observed in lymph node and prostate gland/prostatic bed SUVmax values after treatment compared to pretreatment was found to be statistically significant (P=.033).3/16 patients (19%) were classified as progressive disease (PD), 4/16 (25%) as stable disease (SD), 9/16 (56%) as partial remission (PR) radiologically. An increasing PSA trend (IT) was observed in 4 patients (25%) and a decreasing PSA trend (DT) in 3 patients (18%). Nine patients showed a PSA response of ≥ 50% (56%). Of the 4 patients showing SD, 3 had IT, 3 had BR. Of the 9 patients who showed PR on PET studies, 8 patients showed BR and 1 patient showed DT. ConclusionImaging with 68Ga-PSMA PET/CT showed great concordance with biochemical response evaluation in terms of PSA levels, especially in patients showing good response to therapy. 68Ga-PSMA PET/CT was also successful in identifying progressive disease in patients showing paradoxical decline in PSA levels.

Clinical outcomes of nivolumab in patients with advanced non-small cell lung cancer in real-world practice, with an emphasis on hyper-progressive disease.

Although immune checkpoint inhibitors have been shown to be effective in many clinical trials, real-world data remain limited. We investigated the outcomes of non-small cell lung cancer (NSCLC) patients who received nivolumab, with an emphasis on hyper-progressive disease (HPD). This retrospective study enrolled stage IV NSCLC patients who received nivolumab after progression on prior chemotherapy between July 2016 and June 2018 at a single center in Korea. HPD was defined by response evaluation criteria in solid tumors as progression at the first evaluation, with a ≥ two-fold increase in the tumor growth rate during nivolumab treatment. A total of 83 patients with a median age of 60years were enrolled [squamous, 25(30%) and non-squamous, 58(70%)]. The median progression-free survival (PFS) and overall survival (OS) were 2.6months [95% confidence interval (CI) 0.82-4.31] and 8.6months (95% CI 5.56-11.59), respectively. HPD developed in 16 (19.2%). The median OS of HPD patients was 2.2months (95% CI 0.92-3.75) compared with 4.1months for progressive disease (PD) patients without HPD (95% CI 1.54-6.67). Among patients with pleura or pericardium metastasis, increased effusion was seen more frequently in HPD patients compared with PD patients without HPD [90% (9/10) vs. 28.6% (4/14); p = 0.005]. HPD patients also showed a significant decrease in circulating albumin after treatment with nivolumab (p = 0.030). Although the efficacy of nivolumab in real-world patients was comparable to that seen in clinical trials, clinicians should be aware of HPD because it is not uncommon and represents a worse prognosis.

The Attitudes of Progressive Neurological Disease Patients and Their Family Members to End of Life Care: A Cross-Sectional Study.

The objective was to identify the attitudes of progressive neurological disease (PND) patients and their family members regarding end-of-life care, and their worries about dying. The sample included 327 participants. The Attitudes of Patients with PND to End-of-Life Care questionnaire was used to collect the data. Statistically significant differences in the assessment of attitudes towards end-of-life care between patients and family members were identified (p < 0.001). Family members more frequently favored patients being kept alive at any cost; patients more commonly wished to have their end of life under control. Respondents most frequently deferred to doctors when it came to decisions on treatment to keep patients alive. However, both patients and family members wanted patients to be able to decide on their treatment by leaving a written record of their previously stated wishes. The demands of patients and their families regarding end-of-life care should be documented in individual care plans.

Role of PET/CT in Diagnosis and Follow-up of Non-Hodgkin Lymphoma and Assessment of Extranodal Lymphoma

Abstract Background: Malignant lymphoma is the most common hematological malignancy accounts for approximately 8% of all adult malignancies. Lymphomas are broadly divided into Hodgkin lymphoma and non-Hodgkin's lymphoma. Non-Hodgkin lymphoma accounts for about 5% of all cases of cancer. Non-Hodgkin lymphomas have the vast majority of cases and have a greater predilection to disseminate to extra-nodal sites. Aim of Study: The aim of this work is to study the role of PET/CT in the diagnosis and follow-up of Non-hodgkin lymphoma and assess its extranodal extention. Patients and Methods: The study was conducted on thirty patients where the diagnosis of non-hodgkin lymphoma have been pathologically confirmed, 18 males (60%) and 12 females (40%), their ages are ranged between 19 to 73 years old. All patients were subjected to full history taking, laboratory testing, biopsy and histopathology, the studied cases according to pathalogical type of non-Hodgkin lymphoma mostly were of B-cell type (80%) and (20%) T-cell type, CT scan and PET/CT examination. All patients were examined using Siemens Bio-graph true point PET/CT scanner. Results: Extranodal involvement was detected by PET/CT in 16 patients (53.3%). Their distribution was as follows; head and neck: 4 patients (13.3%), lung: 3 patients (10%), abdomen: 12 patients (40%), MSK: 10 patients (33.3%), while CECT detected 8 patients had extra nodal involvement their distribution was as follow; head and neck: 2 patients (6.6%), lung: 1 patient (3.3%), abdomen:7 patients (43.7%), MSK: 6 patients (16.6%). Thirty patients referred for initial assessment SUV max among the 30 patients referred for initial assessment ranged from 3.7-34.0 with mean value of 16.91±8.07 SD. In aggressive type of NHL SUVmax ranged from 10.5- 34.0 with mean value of 19.9±6.65 SD, the aggressive type of NHL is significantly higher (p£0.01) than in indolent type. The cases were staged according to the size in CECT and FDG activity in PET/CT; CECT detected 6 patients (20%) in stage I, 9 patients (29.3%) in stage II, 7 patients (23.3%) in stage III and 8 patients (26.7%) in stage IV. The PET/CT detected 4 patients (13.3%) in stage I, 8 patients (26.7%) in stage II, 5 patients (16.7%) in stage III and 13 (43.3%) patients in stage IV, therefore PET/CT was statistically significant at p£0.0004 in the initial staging. In follow-up assessment among the 20 patients referred after treatment; SUVmax among the 20 patients referred for follow-up assessment, their SUVmax of the initial PET/CT examination ranged from 3.7-34.0 with a mean value of 17.57± 8.54 SD, with a significant change (p£0.046) in their follow-up examination with SUVmax ranged from 0.0-28.0 with a mean value of 11.73±9.25 SD. CECT showed 4 patients (20%) in complete regression, 13 patients (65%) in stable disease and 1 patient (5%) in progressive disease while PET/CT showed 7 patients (35%) in complete remission, 4 patients (20%) in partial remission, 0 (0.0%) patients in stationary disease, 9 (45%) patients in progressive disease. Thus, PET/CT was concordant with CECT in 6 (30%) cases and disagreed with CECT in 14 (70%) cases with significance (p£0.015). Conclusion: PET/CT agreed with CECT in the initial staging of 13 (43.3%) cases while disagreed with CECT in initial staging of 17 (56.7%) cases, where PET/CT upstaged 13 (43.3%) cases and down staged 4 (13.3%) cases. In follow-up PET/CT was concordant with CECT in 9 (45%) cases and disagreed with CECT in 14 (55%) cases with significance (p£0.034).

Propranolol for infantile hepatic hemangioendothelioma: Clinical evaluation of drug efficacy and safety using a single-center patient cohort

Introduction and objectivesInfantile hepatic hemangioendothelioma (IHHE) is a benign liver tumor, associated with hypothyroidism and vascular malformations along the skin, brain, digestive tract and other organs. Here, we determined a single-center patient cohort by evaluating the effectiveness and safety of propranolol and sirolimus for the treatment of IHHE. Patients and methodsWe performed a monocentric and observational study, based on clinical data obtained from 20 cases of IHHE treated with oral propranolol and sirolimus at the Shanghai Children's Medical Center (SCMC), between December 2017 and April 2019. All cases were confirmed by abdominal enhanced CT examination (18/20, 90%) and sustained decrease of alpha fetoprotein (AFP) (2/20, 10%).Propranolol treatment was standardized as once a day at 1.0mg/kg for patients younger than 2 months, and twice a day at 1.0mg/kg (per dose) for patients older than 2 months. Sirolimus was used to treat refractory IHHE patients after 6 months of propranolol treatment, and initial dosing was at 0.8mg/m2 body surface per dose, administered every 12h. Upon treatment, abdominal ultrasound scanning was regularly performed to evaluate any therapeutic effects. All children were followed up for 6–22 months (mean value of 12.75 months). The clinical manifestations and therapeutic effects, including complications during drug management, were reviewed after periodic follow-up. ResultsThe effective rate of propranolol for the treatment of children with IHHE was 85% (17/20). In most cases, the AFP levels gradually decreased into the normal range. A complete response (CR) was achieved in 3 cases, partial response (PR) for 14 cases, progressive disease (PD) for 2 cases and stable disease (SD) was only detected once. Lesions decreased in two PD patients after administration of oral sirolimus. No serious adverse reactions were observed. ConclusionThis study indicates that both propranolol and sirolimus were effective drugs for the treatment of children with IHHE at SCMC.

Effect of genomic and transcriptional alterations in first-line chemotherapy on subsequent immunotherapy in non-small cell lung cancer (NSCLC) patients.

9614 Background: Recent studies have demonstrated that first-line immunotherapy has better therapeutic response than second-line immunotherapy in NSCLC patients. However, the mechanism behind this observation has not been elucidated. The aim of this study is to investigate the mechanism of unfavorable influence that the first-line chemotherapy exerts on subsequent immunotherapy. Methods: 29 NSCLC patients without tyrosine kinase inhibitor (TKI)-related driver gene (EGFR, ALK, ROS1, RET, BRAF, C-MET) mutations were enrolled in this study. Paired cancer tissues before and after chemotherapy were collected, and NGS-based WES and mRNA sequencing were performed. Sequencing data were analyzed with R packages and statistics analysis was performed with SPSS 20 software. P ≤ 0.05 was regarded as statistically significant. Results: We found that the total number of SNV/INDEL mutations and the tumor mutational burden (TMB) decreased significantly following chemotherapy. The decrease of mutation burden correlated well with therapeutic response: patients with partial response (PR) exhibited significant decrease while patients with stable disease (SD) or progression of disease (PD) did not. Meanwhile, a sharp decrease in common mutations before and after chemotherapy was observed in PR and PD patients, but not SD patients, suggesting that mutational change reflected the therapeutic response. The change in copy number variations (CNVs) exhibited similar trends and correlation with therapeutic response. Subsequent analysis on mRNA levels revealed a sharp decrease in the expression levels of genes related to antigen processing and presentation as well as other factors relevant to immunotherapy response. Pathway enrichment analysis showed that the genes with decreased expression mainly represented immune-related signaling pathways or biological processes. Conclusions: Our study revealed a possible mechanism underlying unsatisfactory multiple-line immunotherapy following chemotherapy, and indicated that first-line chemotherapy may influence the tumor microenvironment to exert unfavorable influence on subsequent immunotherapy.

Monitoring of therapeutic efficacy to CDK4/6 inhibitors and early detection of metastatic relapse in breast cancer by ultra-deep sequencing of plasma cell-free DNA.

e15544 Background: CDK4/6 inhibition substantially improves progression-free survival for women with advanced estrogen receptor-positive breast cancer. Despite this, most patients experience acquired resistance. The analyses of cancer specific genomic aberrations in plasma cell free DNA, or commonly referred to as ‘liquid biopsy’, has generated immense interest. The role of liquid biopsy enables monitoring of therapeutic efficacy to detect relapse in a minimally invasive manner. It would drastically impact risk stratification, treatment selection and patient clinical outcome in advanced stage breast cancer. Methods: We have recruited consecutive patients with metastatic breast cancer who received CDK4/6 inhibitor treatment in combination with endocrine therapy between April 2018 and December 2019. Somatic mutations identified by the Oncomine Pan-Cancer cell free assay were used to assess the mutation profiles of circulating tumor DNA (ctDNA) by ultra-deep sequencing (~56,000 depth) of the plasma DNA. Plasma samples (N = 146) were collected before and during treatment (2 years) or until disease progression. Paired white blood cells (WBC) were also sequenced to exclude clonal hematopoiesis-derived mutations. Results: Twenty-eight patients were enrolled. Based on RECIST criteria, 1 patient showed complete response (CR) within 18 months of treatment, 5 patients showed partial response (PR) 6-18 months from start of treatment, 9 patients showed stable disease (SD) condition within 3-18 months and 13 patients developed progressive disease (PD) within 1-12 months. In 22 of 28 patients (79%), ctDNA was detected prior to start of treatment (12 responders; 10 PD) and used as a monitoring marker. Majority of mutations detected in pre-treatment samples were TP53, PIK3CA and ESR1. Among the 12 ctDNA positive responders, ctDNA levels of 9 patients were undetectable within 2 weeks to 6 months from start of treatment (median 3 months). ctDNA profiles were more reflective of clinical response compared to the tumor markers CEA and CA15-3. In 7 of the 10 PD patients with ctDNA monitoring markers, ctDNA showed higher sensitivity to predict disease progression compared to tumor markers that remained stagnant or below normal threshold. ctDNA also predicted PD earlier than radiological images with a median lead time of 3 months. Conclusions: ctDNA assessment for therapy monitoring and early relapse detection in advanced breast cancer is feasible and provides a basis to evaluate early therapeutic interventions.

The treatment option of progressive disease in breast cancer during neoadjuvant chemotherapy: a single-center experience

ABSTRACT Patients’ responses to breast cancer neoadjuvant chemotherapy (NACT) differ because of heterogeneous tumor characteristics. Reports about NACT progression are sporadic. Here we enrolled 1187 patients who received NACT in our cancer center between January 1, 2007, and December 31, 2016. We analyzed the characteristics and treatments of patients with progressive disease (PD) or non-PD or pathological complete response (pCR). In total, 45 (3.8%) patients had PD. PD patients were associated with a significantly worse disease–free survival (DFS) (hazard ratio (HR) = 3.77; 95% CI, 1.77 to 8.00; P =.001) and overall survival (OS) (HR = 3.85; 95% CI, 1.77 to 8.35; P =.001). For the PD patients, 28 (62.2%) patients received mastectomy immediately after PD, and 17 (37.8%) changed to chemotherapy. DFS and OS exhibited no significant differences between these two salvage therapies. After a change to second chemotherapy, 58.8% (10/17) patients had PD or SD. With the exception of tumor size, pretreatment T stage, and histology type, no other significant differences were noted between PD and pCR patients. Our results demonstrated that PD patients were associated with a significantly worse prognosis. Based on these results, we suggest to give the addition of trastuzumab to HER-2 positive patients instead of changing the chemotherapy regimen and proceeding to surgery instead of further chemotherapy once patients have PD during NACT. Given that some similar characteristics exist between PD and pCR patients, more studies to identify novel molecular markers to predict disease response to NACT should be performed.

Early detection of progressive disease using thyroglobulin doubling-time in metastatic differentiated thyroid carcinoma treated with radioactive iodine.

Detectable serum thyroglobulin (Tg) in patients with differentiated thyroid carcinoma (DTC) after total thyroidectomy indicates progression of the disease. Thyroglobulin doubling-time (TgDT) is a powerful prognostic predictor in patients with DTC. We aimed to evaluate the value of the dynamic TgDT for early detection of progressive disease (PD) in the patients of metastatic DTC with I radioactive iodine (RAI) therapy. We retrospectively evaluated 21 patients undergoing RAI therapy with metastatic DTC. Patients were defined as PD or non-PD according to Response Evaluation Criteria in Solid Tumors 1.1. TgDT was calculated by Excel-based software using Tg values measured during routine follow-up. Whole data (WDT), initial four data (IDT) and recent four data (RDT) of TgDT after total thyroidectomy were calculated and compared. Among the 21 patients (10 men; median age, 62 years old; range, 33-80), 11 patients were classified into PD and 10 were into non-PD. The initial Tg after total thyroidectomy showed a significant difference between PD and non-PD patients (P = 0.013). Short WDT, IDT and RDT (less than one year) showed a high correlation with PD (P < 0.05). RDT showed the highest predictive value for PD (P < 0.001). All the 11 PD patients showed RDT less than one year before PD (median follow-up, 157 days; range, 88-252). RDT is a powerful PD predictor in patients with metastatic DTC. Dynamic monitoring of RDT should be applied for the early detection of PD in clinic.

Including mRECIST in the Metroticket 2.0 criteria improves prediction of hepatocellular carcinoma-related death after liver transplant

In the context of liver transplantation (LT) for hepatocellular carcinoma (HCC), prediction models are used to ensure that the risk of post-LT recurrence is acceptably low. However, the weighting that 'response to neoadjuvant therapies' should have in such models remains unclear. Herein, we aimed to incorporate radiological response into the Metroticket 2.0 model for post-LT prediction of "HCC-related death", to improve its clinical utility. Data from 859 transplanted patients (2000-2015) who received neoadjuvant therapies were included. The last radiological assessment before LT was reviewed according to the modified RECIST criteria. Competing-risk analysis was applied. The added value of including radiological response into the Metroticket 2.0 was explored through category-based net reclassification improvement (NRI) analysis. At last radiological assessment prior to LT, complete response (CR) was diagnosed in 41.3%, partial response/stable disease (PR/SD) in 24.9% and progressive disease (PD) in 33.8% of patients. The 5-year rates of "HCC-related death" were 3.1%, 9.6% and 13.4% in those with CR, PR/SD, or PD, respectively (p <0.001). Log10AFP (p <0.001) and the sum of number and diameter of the tumour/s (p <0.05) were determinants of "HCC-related death" for PR/SD and PD patients. To maintain the post-LT 5-year incidence of "HCC-related death" <30%, the Metroticket 2.0 criteria were restricted in some cases of PR/SD and in all cases with PD, correctly reclassifying 9.4% of patients with "HCC-related death", at the expense of 3.5% of patients who did not have the event. The overall/net NRI was 5.8. Incorporating the modified RECIST criteria into the Metroticket 2.0 framework can improve its predictive ability. The additional information provided can be used to better judge the suitability of candidates for LT following neoadjuvant therapies. In the context of liver transplantation for patients with hepatocellular carcinoma, prediction models are used to ensure that the risk of recurrence after transplantation is acceptably low. The Metroticket 2.0 model has been proposed as an accurate predictor of "tumour-related death" after liver transplantation. In the present study, we show that its accuracy can be improved by incorporating information relating to the radiological responses of patients to neoadjuvant therapies.

Assessment of the role of Ga-68 PSMA I&T PET/CT in response evaluation to docetaxel therapy in castration resistant prostate cancer patients

ObjectiveThere have been only few studies investigating the role of PSMA ligands in the therapy response assessment of metastasized castration resistant prostate cancer (mCRPC) cases. In this study we aimed at evaluating the capability of 68Ga- prostate-specific membrane antigen (PSMA) -I&T positron emission tomography/computerized tomography (PET/CT) in the assessment of therapeutic response in patients under docetaxel therapy for prostate cancer (PCa). Material and methodsThe clinical records of all mCRPC patients treated with docetaxel and referred to our department for 68Ga-PSMA I&T PET/CT imaging were retrospectively analysed. Sixteen patients (mean age 69 years, range 52–82 years) with castration-resistant prostate cancer patients receiving palliative docetaxel therapy and had undergone 68Ga-PSMA I&T PET/CT scan were included in the study. 68Ga-PSMA I&T PET/CT imaging was done and prostate specific antigen (PSA) levels were measured at baseline before administration of docetaxel (PET1) and after at least 3 cycles (range 4–12) of chemotherapy (PET2). Patient-based as well as lesion-based comparison of PET2 findings with PET1 findings were done. ResultsThe change (decrease) observed in lymph node and prostate gland/prostatic bed SUVmax values after treatment compared to pretreatment was found to be statistically significant (p=0.033).3/16 patients (19%) were classified as progressive disease (PD), 4/16 (25%) as stable disease (SD), 9/16 (56%) as partial remission (PR) radiologically. An increasing PSA trend (IT) was observed in 4 patients (25%) and a decreasing PSA trend (DT) in 3 patients (18%). Nine patients showed a PSA response of ≥50% (56%). Of the 4 patients showing SD, 3 had IT, 3 had BR. Of the 9 patients who showed PR on PET studies, 8 patients showed BR and 1 patient showed DT. ConclusionImaging with 68Ga-PSMA PET/CT showed great concordance with biochemical response evaluation in terms of PSA levels, especially in patients showing good response to therapy. 68Ga-PSMA PET/CT was also successful in identifying progressive disease in patients showing paradoxical decline in PSA levels.

Immunotherapy Potentiates the Effect of Chemotherapy in Metastatic Melanoma-A Retrospective Study.

Melanoma survival increased with targeted- and immunotherapy agents, yet most patients ultimately progress and require salvage therapy. In our experience, some progressive disease patients on immune-checkpoint inhibitors (ICIs) demonstrate deep and sustained responses to chemotherapy. We hypothesized that ICIs improve the response to subsequent chemotherapy in metastatic melanoma. We conducted a retrospective study to compare the efficacy of chemotherapy given with prior immunotherapy, to its efficacy given without it. We measured progression free survival (PFS), overall survival, and response rate. Immune-monitoring was performed on sequential peripheral blood mononuclear cell samples taken from a chemotherapy-responsive patient. The chemotherapy post-immunotherapy group (CpI) included 11 patients, the chemotherapy without prior immunotherapy (CNPI) group included 24 patients. Median PFS was 5.2 months in the CpI vs. 2.5 months in the CNPI groups; HR 0.37 [95% Confidence interval (CI) 0.144–0.983], P = 0.046. Immune-monitoring showed an increased proportion of CD8+ cells, with elevated PD-1 and CD69 expression, while on chemotherapy, as compared with all-time points on ICIs, suggesting immune-activation. Immunotherapy potentiates the effect of chemotherapy in metastatic melanoma possibly through activation of CD8+ T cells.