Chemosensitivity Testing Research Articles

Tidal expiratory flow limitation during exercise is unrelated to peripheral hypercapnic chemosensitivity

We sought to determine if peripheral hypercapnic chemosensitivity is related to expiratory flow limitation (EFL) during exercise. Twenty participants completed one testing day which consisted of peripheral hypercapnic chemosensitivity testing and a maximal exercise test to exhaustion. The chemosensitivity testing consisting of two breaths of 10% CO2 (O2∼21%) repeated 5 times during seated rest and the first 2 exercise intensities during the maximal exercise test. Following chemosensitivity testing, participants continued cycling with the intensity increasing 20 W every 1.5 minutes till exhaustion. Maximal expiratory flow-volume curves were derived from forced expiratory capacity maneuvers performed before and after exercise at varying efforts. Inspiratory capacity maneuvers were performed during each exercise stage to determine EFL. There was no difference between the EFL and non-EFL hypercapnic chemoresponse (mean response during exercise 0.96 ± 0.46 and 0.91 ± 0.33 l min−1 mmHg−1, p=0.783). Peripheral hypercapnic chemosensitivity during mild exercise does not appear to be related to the development of EFL during exercise.

Fitness Level- and Sex-Related Differences in Pulmonary Limitations to Maximal Exercise in Normoxia and Hypoxia.

Both maximal-intensity exercise and altitude exposure challenge the pulmonary system that may reach its maximal capacities. Expiratory flow limitation (EFL) and exercise-induced hypoxemia (EIH) are common in endurance-trained athletes. Furthermore, because of their smaller airways and lung size, women, independently of their fitness level, may be more prone to pulmonary limitations during maximal-intensity exercise, particularly when performed in hypoxic conditions. The objective of this study was to investigate the impact of sex and fitness level on pulmonary limitations during maximal exercise in normoxia and their consequences in acute hypoxia. Fifty-one participants were distributed across four different groups according to sex and fitness level. Participants visited the laboratory on three occasions to perform maximal incremental cycling tests in normoxia and hypoxia (inspired oxygen fraction = 0.14) and two hypoxic chemosensitivity tests. Pulmonary function and ventilatory capacities were evaluated at each visit. EIH was more prevalent (62.5% vs 22.2%, P = 0.004) and EFL less common (37.5% vs 70.4%, P = 0.019) in women than men. EIH prevalence was different ( P = 0.004) between groups of trained men (41.7%), control men (6.7%), trained women (50.0%), and control women (75.0%). All EIH men but only 40% of EIH women exhibited EFL. EFL individuals had higher slope ratio ( P = 0.029), higher ventilation (V̇ E ) ( P < 0.001), larger ΔVO 2max ( P = 0.019), and lower hypoxia-related V̇ E increase ( P < 0.001). Women reported a higher EIH prevalence than men, regardless of their fitness level, despite a lower EFL prevalence. EFL seems mainly due to the imbalance between ventilatory demands and capacities. It restricts ventilation, leading to a larger performance impairment during maximal exercise in hypoxic conditions.

In vitro chemosensitivity testing of the feline large granular lymphocyte cell line (S87).

Feline large granular lymphocyte (LGL) lymphoma is an aggressive neoplasia characterised by short survival and poor response to chemotherapy. In this study, the effect of different chemotherapeutic agents on the growth kinetics of the feline cell line S87, a non-MHC-restricted feline LGL cell line, was investigated. Where possible, IC50 (inhibitory concentration 50) values were determined. The IC50 values of the cell line as lymphoma models can provide clues to the situation in vivo and serve as a basis for studying resistance mechanisms. Cells were incubated with various concentrations of vincristine, doxorubicin, 4-hydroperoxycyclophosphamide, prednisolone, methotrexate and L-asparaginase for 24 and 48h, respectively. The IC50 values could be determined as 14.57 (7.49-28.32) μg/mL at 24h incubation and 5.72 (4.05-8.07) μg/mL at 48h incubation for doxorubicin and 9.12 (7.72-10.76) μg/mL at 24h incubation and 4.53 (3.74-5.47) μg/mL at 48h incubation for 4-hydroperpoxycyclophosphamide. Treatment with vincristine and methotrexate resulted in relatively high cell resistance whereas L-asparaginase and prednisolone treatment led to a reduction in cell number compared to control while cell viability was not affected (cytostatic effect). Overall, the feline LGL cell line S87 proves to be relatively sensitive to doxorubicin and 4-hydroperoxycyclophosphamide and relatively resistant to treatment with vincristine, prednisolone, methotrexate and L-asparaginase. The results of this study can be used for further investigations on resistance mechanisms in feline LGL lymphoma. Doxorubicin and cyclophosphamide can be interpreted as promising candidates for the therapy of feline LGL lymphomas.

Establishment and Thorough Characterization of Xenograft (PDX) Models Derived from Patients with Pancreatic Cancer for Molecular Analyses and Chemosensitivity Testing.

Patient-derived xenograft (PDX) tumor models are essential for identifying new biomarkers, signaling pathways and novel targets, to better define key factors of therapy response and resistance mechanisms. Therefore, this study aimed at establishing pancreas carcinoma (PC) PDX models with thorough molecular characterization, and the identification of signatures defining responsiveness toward drug treatment. In total, 45 PC-PDXs were generated from 120 patient tumor specimens and the identity of PDX and corresponding patient tumors was validated. The majority of engrafted PDX models represent ductal adenocarcinomas (PDAC). The PDX growth characteristics were assessed, with great variations in doubling times (4 to 32 days). The mutational analyses revealed an individual mutational profile of the PDXs, predominantly showing alterations in the genes encoding KRAS, TP53, FAT1, KMT2D, MUC4, RNF213, ATR, MUC16, GNAS, RANBP2 and CDKN2A. Sensitivity of PDX toward standard of care (SoC) drugs gemcitabine, 5-fluorouracil, oxaliplatin and abraxane, and combinations thereof, revealed PDX models with sensitivity and resistance toward these treatments. We performed correlation analyses of drug sensitivity of these PDX models and their molecular profile to identify signatures for response and resistance. This study strongly supports the importance and value of PDX models for improvement in therapies of PC.

KS-EMPD-1: a novel cell line of primary extramammary Paget's disease.

Extramammary Paget's disease (EMPD) is a rare skin cancer that mainly occurs in apocrine sweat gland-rich areas in elderly people. The prognosis of metastatic EMPD is unfavorable because of the lack of fully effective systemic therapies. However, the difficulty in establishing a model of EMPD has hampered basic research for exploring its pathogenesis and optimal treatments. Here, we established for the first time an EMPD cell line (named KS-EMPD-1) from a primary tumor on the left inguinal region of an 86-year-old Japanese male. The cells were successfully maintained for more than 1year, with a doubling time of 31.2 ± 0.471h. KS-EMPD-1 exhibited constant growth, spheroid formation, and invasiveness, and was confirmed to be identical to the original tumor by short tandem repeat analyses, whole exome sequencing, and immunohistochemistry (CK7+CK20-GCDFP15+). Western blotting of the cells revealed the protein expression of HER2, NECTIN4, and TROP2, which have recently attracted attention as potential therapeutic targets for EMPD. KS-EMPD-1 was highly sensitive to docetaxel and paclitaxel on chemosensitivity test. The KS-EMPD-1 cell line is a promising resource for basic and preclinical research on EMPD to better define the tumor characteristics and treatment strategy of this rare cancer.

P-207 Analysis of chemotherapy-induced subtype shifts in patient-derived tumoroids and parallels to functional in-vitro chemosensitivity testing in pancreatic ductal adenocarcinoma

P-207 Analysis of chemotherapy-induced subtype shifts in patient-derived tumoroids and parallels to functional in-vitro chemosensitivity testing in pancreatic ductal adenocarcinoma

Establishment of Zebrafish Patient-derived Xenografts from Pancreatic Cancer for Chemosensitivity Testing.

Cancer is one of the main causes of death worldwide, and the incidence of many types of cancer continues to increase. Much progress has been made in terms of screening, prevention, and treatment; however, preclinical models that predict the chemosensitivity profile of cancer patients are still lacking. To fill this gap, an in vivo patient-derived xenograft model was developed and validated. The model was based on zebrafish (Danio rerio) embryos at 2 days post fertilization, which were used as recipients of xenograft fragments of tumor tissue taken from a patient's surgical specimen. It is also worth noting that bioptic samples were not digested or disaggregated, in order to maintain the tumor microenvironment, which is crucial in terms of analyzing tumor behavior and the response to therapy. The protocol details a method for establishing zebrafish-based patient-derived xenografts (zPDXs) from primary solid tumor surgical resection. After screening by an anatomopathologist, the specimen is dissected using a scalpel blade. Necrotic tissue, vessels, or fatty tissue are removed and then chopped into 0.3 mm x 0.3 mm x 0.3 mm pieces. The pieces are then fluorescently labeled and xenotransplanted into the perivitelline space of zebrafish embryos. A large number of embryos can be processed at a low cost, enabling high-throughput in vivo analyses of the chemosensitivity of zPDXs to multiple anticancer drugs. Confocal images are routinely acquired to detect and quantify the apoptotic levels induced by chemotherapy treatment compared to the control group. The xenograft procedure has a significant time advantage, since it can be completed in a single day, providing a reasonable time window to carry out a therapeutic screening for co-clinical trials.

MiR‑221 and miR‑222 regulate cell cycle progression and affect chemosensitivity in breast cancer by targeting ANXA3.

Breast malignancy remains one of the most common causes of cancer-associated mortalities among women. MicroRNA (miR)-221 and miR-222 are homologous miRs and have a substantial impact on cancer progression. In the present study, the regulatory mechanisms of miR-221/222 and its target annexin A3 (ANXA3) in breast cancer cells were investigated. Breast tissue samples were collected to evaluate the expression patterns of miR-221/222 levels in breast cancer cell lines and cancer tissues according to clinical characteristics. The levels of miR-221/222 were increased or decreased in cancer cell lines compared with normal breast cell lines according to cell line subtype. Subsequently, the changes in the progression and invasion of breast cancer cells were investigated using cell proliferation, invasion assay, gap closure and colony formation assays. Western blotting of cell cycle proteins and flow cytometry were performed to evaluate the possible pathway of miR-221/222 and ANXA3 axis. Chemosensitivity tests were performed to explore the suitability of the miR-221/222 and ANXA3 axis as a therapeutic target in breast cancer. The expression levels of miR-221/222 were associated with aggressive characteristics of breast cancer subtypes. Cell transfection assay demonstrated the regulation of breast cancer proliferation and invasiveness by miR-221/222. MiR-221/222 directly targeted the 3'-untranslated region of ANXA3 and suppressed the expression of ANXA3 at the mRNA and protein levels. In addition, miR-221/222 negatively regulated cell proliferation and the cell cycle pathway in breast cancer cells by targeting ANXA3. In combination with adriamycin, downregulation of ANXA3 may sensitize adriamycin-induced cell death to induction of persistent G2/M and G0/G1 arrest. Decreased expression of ANXA3 through increased expression of miR-221/222 reduced breast cancer progression and increased the effectiveness of the chemotherapy drug. The present results indicated the miR-221/222 and ANXA3 axis to be a possible novel therapeutic target for the treatment of breast cancer.

Peripheral hypercapnic chemosensitivity in trained and untrained females and males during exercise.

Hypercapnic chemosensitivity is the response to the increased partial pressure of carbon dioxide and results from central and peripheral chemosensor stimulation. The hypercapnic chemosensitivity of the peripheral chemoreceptors is potentially impacted by acute exercise, aerobic fitness, and sex. We sought to determine the peripheral chemoresponse to transient hypercapnia at rest and during exercise in males and females of various fitness. We hypothesized that 1) higher fitness participants would have lower hypercapnic chemosensitivity compared with those with lower fitness and 2) males would have a higher chemoresponse than females. Forty healthy participants (20 females) participated in one test day involving transient hypercapnic chemosensitivity testing and a maximal exercise test. Chemosensitivity testing involved two breaths of 10% CO2 repeated five times (45 s to 1 min between repeats) at rest and the first two stages of a maximal exercise test. There was no significant difference between higher and lower aerobic fitness groups, (mean difference 0.23 ± 0.22 rest; -0.07 ± 0.04 stage 1; 0.11 ± 0.17 stage 2 L/mmHg·min) during each stage (P = 0.472). However, we saw a significant increase in the hypercapnic response during stage 1 (0.98 ± 0.4 L/mmHg·min) compared with rest (0.79 ± 0.5 L/mmHg·min; P = 0.01). Finally, at 80 W, males had a higher chemoresponse compared with females, which persisted following body surface area correction (0.56 ± 0.2 vs. 0.42 ± 0.2 L/mmHg·min·m2, for females and males respectively (P = 0.038). Our findings suggest that sex, unlike aerobic fitness, influences peripheral hypercapnic chemosensitivity and that context (i.e., rest vs. exercise) is an important consideration.NEW & NOTEWORTHY The hypercapnic chemoresponse to transient CO2 showed an increase during acute physical activity; however, this response did not persist with further increases in intensity and was not different between participants of different aerobic fitness. Males and females show a differing response to CO2 during exercise when compared with an iso-V̇co2. Our results suggest that adaptations that lead to increased aerobic fitness do not impact the hypercapnic ventilatory response but there is an effect of sex.

Role of Collagen Gel Droplet-Embedded Culture-Drug Sensitivity Testing (CD-DST) for Assessing the Sensitivity of Gastric Cancer to Chemotherapy Drugs Combined with Other Cancer Therapeutic Drugs.

Chemosensitivity tests have long been a widely discussed research topic. Our group performed collagen gel droplet-embedded culture-drug sensitivity testing (CD-DST) of patients with advanced gastric cancer during the period from December 2012 to December 2017. To verify how CD-DST should be used, we invested correlations of sensitivities to cisplatin (CDDP), docetaxel (DOC), paclitaxel (PTX), and CPT11 with clinical outcome. Patients with advanced gastric cancer underwent gastrectomy with lymph node dissection at Nippon Medical School Tama Nagayama Hospital, and surgical samples were retrospectively examined by CD-DST to assess chemosensitivity. The patients later received adjuvant chemotherapy as standard adjuvant therapy or chemotherapy. The CD-DST test was not performed for S-1 because it is commonly used in chemotherapy for gastric cancer. Although oxaliplatin has also recently become a key drug for advanced gastric cancer, it had not been adopted for gastric cancer in 2012, so CD-DST testing was not performed. The χ2 test was used for all statistical analyses. A p-value of <0.05 was assumed to indicate statistical significance. Three-year survival rates were estimated using the Kaplan-Meier method, and the log-rank test was used to compare the obtained curves. Of the tumors from gastric cancer patients, 67.0% (77/115) could be cultured. The rate of sensitivity was 41.1% (30/73) for CDDP, 82.6% (57/69) for DOC, 82.8% (58/70) for PTX, and 49.2% (33/67) for CPT11. CDDP sensitivity and outcome were not correlated in patients who received CDDP. Sensitivities to CDDP, DOC, PTX, and CPT11 were not correlated with any patient characteristic. Patients with poorly differentiated adenocarcinoma tended to be sensitive to CDDP (P=0.051). No difference between CDDP sensitivity or outcome was observed in patients receiving CDDP. The CD-DST showed a high sensitivity to DOC and PTX in the present patients.

Dissolved Oxygen-Sensing Chip Integrating an Open Container Connected with a Position-Raised Channel for Estimation of Cellular Mitochondrial Activity.

The measurement of oxygen consumption of adherent cells is a profoundly important issue for estimating the bioenergetic health and metabolism activity of cells. The study describes the construction of a microfluidic chip consisting of an open container connected with a position-raised channel and dissolved oxygen (DO)-sensing gold ultramicroelectrodes for quantifying the oxygen consumption rate (OCR) of adherent cells. The microfluidic chip design can reduce the action of shear force on the adherent cells during medium replacement. The residual concentration of analytes in the open container was only 4.4% after solution replacement via the position-raised channel. The DO reduction current measured by ultramicroelectrodes averaged in the range of 40-60 s presented high reproducibility with a 1.1% relative standard deviation suitable for OCR calculation. After short-term (90 min) cultivation, the microfluidic chip can monitor the time-dependent change in the OCR of 3T3-L1 cells for several hours by repeatedly replacing the culture medium or with the stimulation of different mitochondrial inhibitors. The presented microfluidic cell-based chip has great promise for drug screening and chemosensitivity testing by measuring OCR to evaluate the mitochondrial function of adherent cells.

Analysis of Multiple Drug Resistance Mechanism in Different Types of Soft Tissue Sarcomas: Assessment of the Expression of ABC-Transporters, MVP, YB-1, and Analysis of Their Correlation with Chemosensitivity of Cancer Cells

Chemotherapy of soft tissue sarcomas (STS) is restricted by low chemosensitivity and multiple drug resistance (MDR). The purpose of our study was the analysis of MDR mechanism in different types of STS. We assessed the expression of ABC-transporters, MVP, YB-1, and analyzed their correlation with chemosensitivity of cancer cells. STS specimens were obtained from 70 patients without metastatic disease (2018–2020). Expression level of MDR-associated genes was estimated by qRT-PCR and cytofluorimetry. Mutations in ABC-transporter genes were captured by exome sequencing. Chemosensitivity (SI) of STS to doxorubicin (Dox), ifosfamide (Ifo), gemcitabine (Gem), and docetaxel (Doc) was analyzed in vitro. We found strong correlation in ABCB1, ABCC1, and ABCG2 expression. We demonstrated strong negative correlations in ABCB1 and ABCG2 expression with SI (Doc) and SI (Doc + Gem), and positive correlation of MVP expression with SI (Doc) and SI (Doc + Gem) in undifferentiated pleomorphic sarcoma. Pgp expression was shown in 5 out of 44 STS samples with prevalence of synovial sarcoma relapses and it is strongly correlated with SI (Gem). Mutations in MDR-associated genes were rarely found. Overall, STS demonstrated high heterogeneity in chemosensitivity that makes reasonable in vitro chemosensitivity testing to improve personalized STS therapy, and classic ABC-transporters are not obviously involved in MDR appearance.

Screening of Chemotherapeutic Drugs Against Colorectal Cancer Based on Different Oxygen Environments in Vitro

With the deepening of tumor research, the concept of the tumor microenvironment has gradually come into people’s view. A significant characteristic of the microenvironment is hypoxic. A large number of vitro experiments have confirmed that hypoxic environments can induce angiogenesis, anti-apoptosis, changes in drug sensitivity, and tumor metastasis. Now, chemosensitivity tests are all carried out under normoxic conditions. Therefore, some scholars have pointed out that if it is possible to simulate the hypoxic state of the tumor microenvironment during the chemosensitivity tests in vitro, it may be able to match better the effect of chemotherapeutic drugs on killing tumor cells in vivo. This study clarified the differences in the chemosensitivity for colorectal cancer cells in normoxic and hypoxic environments. The result of CCK-8 detections has shown that the toxicity of drugs to cells is much higher under normoxic conditions. To further figure out the different mechanisms of the chemotherapy drugs under normoxic and hypoxic conditions, we conducted cellular uptake analysis and western blot, which demonstrated that the uptake of Doxorubicin in normoxic cells was significantly higher than that in hypoxic cells. While the result of the western blot has shown that the expression of VDAC (Voltage-dependent anion channel) and cleaved caspase-3 is higher under normoxic conditions. This study provides a specific basis for future research on the chemosensitivity of chemotherapy drugs in hypoxic environments.

Chemosensitivity Evaluation using Circulating Tumor Cells Predicts Chemotherapy Outcomes in Patients with Advanced Cancer.

Chemotherapy is a clinically recognized effective technique for systemic treatment of malignant tumors. However, the tumor heterogeneity and multiple drug resistance (MDR) to the chemotherapeutic agents often lead to a failure of response to chemotherapy. We utilized a novel in vitro chemosensitivity test to identify sensitive and effective chemotherapeutic drugs and further elucidated the correlation between the in vitro chemosensitivity and clinical outcomes. We developed a circulating tumor cell-based in vitro drug sensitivity test to evaluate the sensitivity of different chemotherapeutic agents. High glucose uptake combined with negative CD45 marker were exploited to distinguish the CTCs from leukocytes. The altered glucose metabolism of single cell was measured by custom-designed computational algorithm, and the toxicity of different drug combinations was assessed by different fluorescent intensity on CTCs in the treated and control group. We analyzed the potential of CTCs in predicting chemotherapy response in 92 patients with different cancer types. Our data showed that the isolated CTCs accurately predicted chemotherapy outcomes, especially in patients with late-stage cancer. CTC-based chemosensitivity evaluation can help guide clinical decision making and identify patients who are likely to benefit from chemotherapy. CTC-based chemosensitivity evaluation is an effective methodology to study the chemosensitivity of tumor cells in vitro. Our results using CTC-based chemosensitivity evaluation method were well correlated with the clinical outcomes of chemotherapy. The clinical implementation of our CTC-based chemosensitivity evaluation method can help spare patients with primary chemoresistance from the unnecessary toxicities of chemotherapy and improve chemotherapy outcomes.

Objective Evaluation of Olfactory and Taste Dysfunction Among COVID-19 Patients: A Cross Sectional Study from Tribal India.

There is a varying prevalence of olfactory and taste dysfunction (OTD) in COVID-19 patients, with a higher prevalence reported in the European population as compared to the Asian population. Psychophysical tests are crucial to determine the exact frequency, extent and clinical characteristics of these OTDs. The present study objectively evaluated the OTD for patients treated in the Dedicated COVID-19 Hospital (DCH) in Shahdol. This prospective cross-sectional study was conducted after IEC approval in DCH Shahdol for a period of four months among RT-PCR positive patients, and they were evaluated using validated chemosensitive psychophysical test during ENT consultation to identify OTD. The sample size was calculated as 92 considering prevalence (p) of OTD as 41.3% by applying formula: n = (Z1−a/2)2 × p (1−p) / d2. The information pertaining to the subjects was kept anonymous and confidential. During data analysis, an association was significant for p value < 0.05. It was observed that 45.5% of subjects reported either loss of taste or smell. During objective evaluation, olfactory and taste dysfunction was observed among 42.4% of subjects (95/224). The Chi-square analysis reflected statistically significant difference (p < 0.05) between subjects with OTD and without OTD for the variables such as days from onset of symptoms to admission, and symptoms (fever, sore throat and shortness of breath). Taste and smell are among the important senses and in India they are mostly subjectively evaluated for COVID-19 induced OTD which results in underreporting of these symptoms. So, a gold standard objective evaluation should be taken into consideration to evaluate OTD.

Tumour-Derived Cell Lines and Their Potential for Therapy Prediction in Patients with Metastatic Colorectal Cancer.

Simple SummaryColorectal cancer is a global issue with millions of patients in need for new treatment options. Surgical resection is often the first clinical intervention and can be, especially for primary tumours, curative. However, advanced tumours, recurrences, and metastases require drug treatment. Our aim was to compare material of primary tumours and corresponding metastases to draw conclusions from the first one to the latter. The feasibility of therapy prediction using the primary tumour material for the metastatic situation creates a time window for functional testing, which can realistically be integrated into the strict timeframe of clinical procedures. A reliable treatment recommendation, based on the tumour drug response, would improve treatment success in patients with metachronous metastases and spare them from unnecessary side effects of unsuccessful therapies.The prognosis of metastatic colorectal cancer (CRC) remains poor. Patients and physicians are in need of individual therapies and precise response predictions. We investigated the predictive capacity of primary tumour material for treatment response of metastases. Mutational landscapes of primary tumours and corresponding metastases of 10 CRC patients were compared. Cell line characteristics and chemosensitivity were investigated pairwise for primary and metastatic tumours of four patients. PDX models of one patient were treated in vivo for proof of concept. Driver mutations did not differ between primaries and metastases, while the latter accumulated additional mutations. In vitro chemosensitivity testing revealed no differences for responses to 5-FU and oxaliplatin between primary and metastatic cell lines. However, irinotecan response differed significantly: the majority of metastases-derived cell lines was less sensitive to irinotecan than their matching primary counterpart. Therapy recommendations based on these findings were compared to clinical treatment response and mostly in line with the predicted outcome. Therefore, primary tumour cell models seem to be a good tool for drug response testing and conclusion drawing for later metastases. With further data from tumour-derived cell models, such predictions could improve clinical treatment decisions, both recommending likely effective therapeutic options while excluding ineffective treatments.

Effect of oxaliplatin-based chemotherapy on chemosensitivity in patients with peritoneal metastasis from colorectal cancer treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: proof-of-concept study

BackgroundChemosensitivity testing, including collagen gel droplet‐embedded culture drug sensitivity test, has proven to be a useful tool in therapeutic decision‐making. This retrospective analysis investigated chemosensitivity testing of peritoneal metastases collected during cytoreductive surgery (CRS), and its impact on survival in patients with colorectal cancer.MethodsAll patients with peritoneal metastasis from colorectal cancer who underwent CRS with or without hyperthermic intraperitoneal chemotherapy (HIPEC) between November 2008 and October 2014 were included. The growth inhibition rate was expressed as the ratio between the image density after treatment (T) and that before treatment (control, C). Tumours with a reduction in T/C ratio of less than 20 per cent were defined as resistant and those with a reduction of 20 per cent or more as sensitive. Groups were compared for overall (OS) and disease‐free (DFS) survival.ResultsOf 84 eligible patients, 81 received neoadjuvant chemotherapy (NACT), including 56 patients with an oxaliplatin‐based regimen. Mean(s.d.) follow‐up was 23·4(22·9) months. The median overall survival of all patients was 19·0 (i.q.r. 5·7–36·1) months, with a progression‐free survival time of 10·1 (4·5–17·0) months. Patients who received oxaliplatin‐based NACT had significantly altered chemosensitivity to oxaliplatin; only 20 of 51 such patients showed chemosensitivity to oxaliplatin compared with 16 of 24 who did not undergo oxaliplatin‐based NACT (P = 0·046). However, patients who showed chemoresistance to oxaliplatin had similar OS to those with chemosensitivity (18·8 versus 18·1 months; P = 0·835). The choice of HIPEC agents in patients who received oxaliplatin‐based NACT did not significantly influence survival (oxaliplatin versus mitomycin C: median OS 20·6 (10·9–24·8) versus 19·0 (10·5–34·6) months, P = 0·811; DFS 6·6 (2·8–25·7) versus 9·3 (4·1–13·9) months, P = 0·191).ConclusionPatients who had oxaliplatin‐based NACT showed a higher rate of chemoresistance to oxaliplatin at the time of CRS and HIPEC. The impact of chemosensitivity testing on OS remains unclear and needs further investigation.

The prospects of tumor chemosensitivity testing at the single-cell level.

Tumor chemosensitivity testing plays a pivotal role in the optimal selection of chemotherapeutic regimens for cancer patients in a personalized manner. High-throughput drug screening approaches have been developed but they failed to take into account intratumor heterogeneity and therefore only provided limited predictive power of therapeutic response to individual cancer patients. Single cancer cell drug sensitivity testing (SCC-DST) has been recently developed to evaluate the variable sensitivity of single cells to different anti-tumor drugs. In this review, we discuss how SCC-DST overcomes the obstacles of traditional drug screening methodologies. We outline critical procedures of SCC-DST responsible for single-cell generation and sorting, cell-drug encapsulation on a microfluidic chip and detection of cell-drug interactions. In SCC-DST, droplet-based microfluidics is emerging as an important platform that integrated various assays and analyses for drug susceptibility tests for individual patients. With the advancement of technology, both fluorescence imaging and label-free analysis have been used for detecting single cell-drug interactions. We also discuss the feasibility of integrating SCC-DST with single-cell RNA sequencing to unravel the mechanisms leading to drug resistance, and utilizing artificial intelligence to facilitate the analysis of various omics data in the evaluation of drug susceptibility. SCC-DST is setting the stage for better drug selection for individual cancer patients in the era of precision medicine.

Abstract IA-08: Clinical advances in pancreas adenocarcinoma

Abstract IA-08: Clinical advances in pancreas adenocarcinoma

Predicting likelihood of in vivo chemotherapy response in canine lymphoma using ex vivo drug sensitivity and immunophenotyping data in a machine learning model.

We report a precision medicine platform that evaluates the probability of chemotherapy drug efficacy for canine lymphoma by combining ex vivo chemosensitivity and immunophenotyping assays with computational modelling. We isolated live cancer cells from fresh fine needle aspirates of affected lymph nodes and collected post‐treatment clinical responses in 261 canine lymphoma patients scheduled to receive at least 1 of 5 common chemotherapy agents (doxorubicin, vincristine, cyclophosphamide, lomustine and rabacfosadine). We used flow cytometry analysis for immunophenotyping and ex vivo chemosensitivity testing. For each drug, 70% of treated patients were randomly selected to train a random forest model to predict the probability of positive Veterinary Cooperative Oncology Group (VCOG) clinical response based on input variables including antigen expression profiles and treatment sensitivity readouts for each patient's cancer cells. The remaining 30% of patients were used to test model performance. Most models showed a test set ROC‐AUC > 0.65, and all models had overall ROC‐AUC > 0.95. Predicted response scores significantly distinguished (P < .001) positive responses from negative responses in B‐cell and T‐cell disease and newly diagnosed and relapsed patients. Patient groups with predicted response scores >50% showed a statistically significant reduction (log‐rank P < .05) in time to complete response when compared to the groups with scores <50%. The computational models developed in this study enabled the conversion of ex vivo cell‐based chemosensitivity assay results into a predicted probability of in vivo therapeutic efficacy, which may help improve treatment outcomes of individual canine lymphoma patients by providing predictive estimates of positive treatment response.