Digestive System Diseases

Symptoms and General Pathology

All Conditions

Liver Cirrhosis

Fibrosis

Liver Diseases

Gastrointestinal Diseases

Hematinics

All Drugs and Chemicals

Liver Extracts

Current care study. Data collection on oncological efficacy (Clinical, biological, imaging) Data collection on hepatology (clinical, biological, imaging)

Observational study in two parts:

1. Cross-sectional study of patients with digestive or ENT cancer with indication for conventional chemotherapy treatment according to management guidelines, the objective of which is to determine the frequency of cirrhosis.
2. Exposed/non-exposed cohort study of patients receiving a first course of conventional chemotherapy initiated in outpatient oncology clinic. (safety population).

Exposed subjects will be patients with cirrhosis, included consecutively. Non-exposed subjects will be non-cirrhotic patients. They will be selected non-consecutively according to the following criteria, for matching to exposed subjects: age (±5 years), type of cancer (digestive vs. ENT), treatment stage (curative vs. palliative). Two unexposed subjects will be selected for 1 exposed subject.

Current care study

Massih Ningarhari, MD

Gautier Lefebvre, MD

Anthony Turpin, MD

Cirrhosis and cancers of the upper digestive tract, colorectal and ENT share common risk factors. Liver cirrhosis can change the elimination of cancer drugs.

Precise data on management and outcome of patients with liver cirrhosis undergoing chemotherapy are lacking. Most patients have been excluded from clinical trials evaluating conventional therapies.

The study of tolerance, side effects, and outcome in patients with cirrhosis could help improve chemotherapy management for better tolerance and efficacy.

The main objective is to estimate the frequency of liver cirrhosis among patients evaluated in CPR for ENT, upper digestive or colorectal cancer.

Secondary objective includes the evaluation ofthe impact of cirrhosis on the management of chemotherapy by comparing cirrhotic patients' outcomes with a control group of matched non-cirrhotic patients.

Chemotherapy and Liver Cirrhosis in Frequently-associated Cancers

Prospective Observational Study Studying the Influence of the Presence of Liver Cirrhosis During Chemotherapy for ENT Cancer, Upper Digestive Tract Cancer or Colorectal Cancer.

Survival time defined as the difference between the date of initiation of chemotherapy,

Progression-free survival time defined as the difference between the date of initiation of chemotherapy, the date of progression or death, the date of last news or the point date (12 months).

University Hospital, Lille

Neoplasms

Rare Diseases

Stomach Neoplasms

Carcinoma

Peritoneal Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Abdominal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Peritoneal Diseases

Stomach Cancer

Esophageal Cancer

Antineoplastic Agents

Paclitaxel

Albumin-Bound Paclitaxel

Tubulin Modulators

Antimitotic Agents

3 patients will be allocated to PIPAC arm at Paclitaxel 15mg/m2. If there is 1 dose limiting toxicity (DLT), an additional 3 patients will be allocated to PIPAC arm at 15mg/m2. If there is 2 - 3 DLT, study had exceeded its Maximum Tolerable Dose (MTD) and we will proceed to stop recruitment.

Should there be no DLT, recruitment at PIPAC 30mg/m2 and ePIPAC 15mg/m2 will occurs concurrently in an alternating fashion. PIPAC/ePIPAC dose escalation will continue until a MTD has been reached. Should there be no DLT at PIPAC 30mg/m2 and ePIPAC 15mg/m2, recruitment at PIPAC 45mg/m2 and ePIPAC 30mg/m2 will occurs concurrently in an alternating fashion. Finally, should there be no DLT, recruitment at ePIPAC 45mg/m2 will occurs.

Should there be no DLT under PIPAC arm at Paclitaxel 15mg/m2, recruitment at ePIPAC 15mg/m2 and PIPAC 30mg/m2 will occurs concurrently in an alternating fashion. PIPAC/ePIPAC dose escalation will continue until a MTD has been reached. Should there be no DLT at PIPAC 30mg/m2 and ePIPAC 15mg/m2, recruitment at PIPAC 45mg/m2 and ePIPAC 30mg/m2 will occurs concurrently in an alternating fashion. Finally, should there be no DLT, recruitment at ePIPAC 45mg/m2 will occurs.

This is a prospective, two armed phase I trial in a 3 + 3 dose escalation evaluating the safety and tolerability of PIPAC/ePIPAC using paclitaxel in patients with peritoneal carcinomatosis.

Bok Yan Jimmy So, MBChB

Peritoneal carcinomatosis (PC) is a miserable disease with poor treatment outcome. Intraperitoneal administration of anticancer drugs enables an extremely high concentration of drugs to directly contact the target cancer lesions in the peritoneal cavity. However, its effectiveness is limited by the intraperitoneal distribution and penetration of the drug. Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is an innovative intraperitoneal chemotherapy concept that enhances efficacy by taking advantage of the physical properties of gas and pressure. Electrostatic precipitation pressurized intraperitoneal aerosol chemotherapy (ePIPAC) may further enhance these benefits.

This research study serves to determine the safety profile and tolerability of PIPAC/ePIPAC with paclitaxel. It will determine the maximal tolerated dose (MTD) and evaluate the safety and tolerability, and pharmacokinetics of PIPAC/ePIPAC paclitaxel in pre-treated patients with peritoneal carcinomatosis (PC). It may offer a novel and effective option of treatment for patients with PC, who, at present have limited options involving the use of systemic chemotherapy and who suffer from poor life expectancy and poor quality of life.

In patients with histologically proven unresectable or recurrent gastric cancer limited to the peritoneum, the combination of intraperitoneal (IP) paclitaxel with systemic chemotherapy reported a one-year survival rate of 78%. However, the effectiveness of IP chemotherapy may be limited by its distribution, tissue penetration and associated catheter-related complications.

Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) is a novel drug delivery technique for PC taking advantage of physical laws (gaseous nature, hydrostatic pressure) with superior pharmacological properties (homogeneous distribution, deeper tissue penetration). It is applied through laparoscopy and is minimally invasive. Adding electrostatic loading (ePIPAC) as an adjunct would further improve the pharmacological properties of PIPAC since it should induce precipitation of the aerosolized drug, increasing the ratio between the dose applied and the dose in the target tissue.

Systemic toxicity is significantly reduced due to the peritoneum/blood barrier and the low dose applied (about 20% of the usual systemic dose). A systematic review highlighted that PIPAC combines the benefits of a minimally invasive approach with pharmacokinetic advantages of intraperitoneal administration and pressurized vaporization. It concluded that PIPAC is feasible, safe, and warrants further prospective studies. PIPAC may be combined with systemic palliative chemotherapy with minimal additional organ toxicity. This method of treatment avoids the morbidity and mortality of HIPEC. PIPAC has been shown in pre-clinical studies to be potentially more efficacious than catheter-based IP-chemotherapy due to better drug distribution and penetration. In clinical use, PIPAC can be repeated at intervals of 6 weeks to 3 months. This allows repeated objective assessment of therapy effect over time.

To date, PIPAC has only been utilized to administer Oxaliplatin or a combination of Doxorubicin/Cisplatin. Paclitaxel is an approved drug for systemic chemotherapy for several cancers, and also has well-documented intraperitoneal use for ovarian cancer and gastric cancer. It is a hydrophobic, high molecular weight compound resulting in low absorption through the lymphatic system after IP administration with a much higher peritoneal to plasma peak concentration and AUC ratios (\>1000 versus 25 and \>1000 versus 16 respectively). As such, IP Paclitaxel may be potentially more efficacious with less systemic toxicity than IP Oxaliplatin. However, no clinical data exists in the published literature for PIPAC/ePIPAC paclitaxel.

This proposed prospective study is the first clinical study of PIPAC/ePIPAC with Paclitaxel. It will determine the maximal tolerated dose (MTD) and evaluate the safety and tolerability, and pharmacokinetics of PIPAC/ePIPAC paclitaxel in pre-treated patients with PC. Peritoneal biopsies will be collected prior to and after PIPAC/ePIPAC to assess tissue drug concentration and depth of drug penetration. Collection of biospecimens including peritoneal tissue, peritoneal fluid and blood will be used for correlative studies including paclitaxel resistance analysis and development of cancer modelling platforms. For the individual patient, repeated biopsies and molecular profiling may also facilitate individualized therapy. For medical research, PIPAC/ePIPAC may deliver measurable progress in 3-5 years because the assessment interval is short (6 weeks) in this disease with rapid progression (6-12 months to death).

This study will determine the safety dose range of PIPAC/ePIPAC paclitaxel. This will allow us to design a phase II trial to evaluate clinical efficacy. On a larger scale, the success of this PIPAC/ePIPAC trial would add a valuable treatment option to our arsenal in the treatment of PC.

Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) and Electrostatic PIPAC (ePIPAC) With Paclitaxel In Patients With Peritoneal Carcinomatosis

Phase 1 Study of Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) and Electrostatic PIPAC (ePIPAC) With Paclitaxel for Peritoneal Carcinomatosis - PIPAC2 Study

Dose limiting toxicities are monitored to evaluate the tolerability of PIPAC /ePIPAC

Adverse events are monitored to evaluate the safety profile of PIPAC/ePIPAC

Peritoneal Cancer Index (PCI) is used to measure Clinical response of PIPAC/ePIPAC with Paclitaxel

Peritoneal Regression Grade Scoring (PRGS) System is used to measure Pathological response of PIPAC/ePIPAC

National University Hospital, Singapore

Microsatellite Instability

Colorectal Neoplasms

Intestinal Neoplasms

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Genomic Instability

Herbal and Botanical

Cola

MSI colon tumours (as compared to MSS CRCs and matching normal colonic mucosa) Identification of exon/intron sites affected by aberrant splicing events due to MSI in CRC

Jean-François FLÉJOU, PU-PH

Alex DUVAL

MSI (Microsatellite Instability) colorectal cancer (CRC) show improved survival, are less prone to metastasis and show poor response to chemotherapy (compared to MSS tumors). The underlying reasons for these characteristics are still not understood and no specific therapeutic approach for MSI colon tumours (15% of CRC overall) has yet been developed.

The MSI process is oncogenic when it affects DNA repeat sequences that have a functional role, e.g. Small Coding Repeats (SCR). MSI also frequently affects Long Non-Coding Repeats (LNCR) in tumour DNA. In contrast to SCR, only a few LNCR are endowed with biological activity. Consequently, this area has received very little attention. Our group recently identified HSP110 mutant chaperone protein in MSI CRC that was generated by somatic deletion of a LNCR. Of interest, HSP110 mutant (due to exon skipping) have anti-oncogenic properties and the survival of MSI CRC patients receiving chemotherapy is positively associated with HSP110 mutations in tumour DNA.

The aim of the current project is to identify additional clinically relevant MSI-associated splicing aberrations due to mutations in LNCR located in splice acceptor sites. The four main steps are as follows:

1. To identify exon/intron sites affected by aberrant splicing events due to MSI in CRC . All RNASeq data will be exploited to identify recurrent splicing aberrations (mostly exon skipping) that occur specifically in MSI colon tumours;
2. To investigate for possible functional links between MSI and any detected aberrant splicing events . All specific aberrant splicing events detected by RNAseq in MSI CRC samples will be first confirmed (quantitative RT-PCR) in order to eliminate false positive cases. For validated exon candidates, the allelic profiles of adjacent intronic LNCR will be analysed (PCR and fluorescence genotyping) in CRC cell lines and primary tumours (MSI and MSS), as well as in matching normal mucosa samples in order to assess their polymorphic status;
3. To identify splicing events and LNCR mutations with clinical relevance in MSI CRC patients . All LNCR with a confirmed role in gene splicing in MSI CRC will be analysed. The clinical relevance of candidate genes will be assessed using multivariate survival regression models for Relapse- Free Survival, with interaction terms (response to chemotherapy);
4. To initiate functional studies on a limited number of clinically relevant, cancer-related genes whose splicing is perturbed in MSI cancer cells, and to develop biological tools to simplify screening in future clinical assays Similar to HSP110, we will focus on 4 or 5 mutant proteins that are promising drug therapeutic targets. Functional assays will be developed to further elucidate their role in the pathophysiology of MSI tumours. We also aim to develop biological tools for these candidate genes, such as the detection of wild-type or mutant proteins by immunohistochemistry.

WP1 - To identify exon/intron junctions that are specifically affected by aberrant splicing events in MSI CRC. Sequences will first be evaluated at CNG using Illumina's Pipeline CASAVA (Consensus Assessment of Sequence And Variation) software. This program converts intensity scores into base calls, quality scored alignments and additional formats for downstream analysis, thus rapidly transforming data into biologically relevant information. The filtered data will then be transferred to the CIT platform (Carte d'Identité des Tumeurs; http://cit.ligue-cancer.net, dir: A. de Reynies) to be analysed by our bio-informatics expert. The Cufflinks workflow will be used to quantify transcript expression levels in MSI tumours. This allows transcript assembly, discovery and differential expression measures at transcript-level resolution. Because the standard Cufflinks workflow does not support gene fusion discovery or quantification, several new features will be incorporated into it. Firstly, SoapFuse will be used to detect fusion break points and to predict fusion junction sequences. These will be integrated into the human reference genome and gene annotation from the Gencode project to provide a comprehensive, integrated annotation of gene features for mapping of splicing reads. The integration INCa - PRTK 2014 17/51 process will abide by several rules to minimise the potential to disturb the quantification of expression level in forthcoming analyses. With the help of our customised reference genome and annotation, TopHat, an aligner that supports splice junction and gene fusion mapping will be used for RNASeq mapping. Cufflinks will then be used to find new splice variants, including new exon skipping isoforms.

These will be integrated into the annotation using Cuffmerge. Depending on the alignment results obtained with TopHat, several filters will be applied to remove low quality candidates for splice variation and gene fusion, as well as candidates that are incompatible with existing annotated transcripts. Where necessary, reads will be assembled by AbySS and then aligned onto the reference genome by BLAT to provide more information for refining the annotation. This will produce a transcriptome assembly containing high confidence gene fusion and exon skipping events. Identification of these events will then be performed in individual samples. Cuffdiff will be used to analyse the mapping result, also based on this transcriptome assembly, for calling differentially expressed genes and transcripts and for detecting differential splicing changes. Finally, CummeRbund will be used to interpret and visualise the results.

The reliability of RNA-seq analysis will be verified by searching for aberrantly spliced transcripts already reported in MSI cancers (eg. MRE11 and HSP110) and for point mutations in the coding sequences of target genes for MSI (eg.TGFBR2, IGF2R, TCF7L2, AXIN2, PTEN, RIZ) and in other cancer-related genes that serve as internal positive controls (eg. KRAS, BRAF, TP53, PIK3CA). It is worth noting this project is part of several others developed jointly with CIT-Ligue and that are aimed at characterizing MSI CRC using Omics technologies. Importantly, this data is already available for a significant number of samples and could therefore be exploited if required.

Data from the RNASeq cohort of patients will be comprehensively analysed to identify recurrent splicing aberrations (expected to be mostly exon skipping) that occur specifically in MSI colon tumours compared to MSS CRCs and matching normal colonic mucosa. Amongst these, the study will focus on splicing aberrations that are due to MSI and that affect exons with a flanking upstream intron containing a ≥ 15 bp LNCR that is located ≤ 6 bp from the intron-exon junction (splice acceptor site) (RNASeqMSI-exon pre-list). As stated above, about 2,000 human genes contain at least one intron with a LNCR very close to the AG splice acceptor site at the intron-exon junction. Approximately 100 human genes could be affected by recurrent and specific aberrant splicing events due to MSI in CRC (mostly exon skipping; deduced from experiments performed in a limited series of CRC cell lines and primary tumours using exon arrays; preliminary and unpublished results).

WP2 - To investigate for functional links between MSI and aberrant splicing events.

Following the RNASeq analysis, confirmation of the aberrant splicing events due to MSI will be required using another methodological approach in order to eliminate false positive events. This will be achieved with real-time quantitative INCa - PRTK 2014 18/51 RT-PCR using internal, specific probes (Applied biosystems). For each skipped exon in the RNASeqMSI-exon pre-list, a common pair of forward and reverse primers located in the flanking exons will be designed.

Two internal probes will be designed, located either within the skipped exons or spanning the flanking exons at their junction in order to detect normal or aberrantly spliced mRNA in a competitive manner, respectively. It is highly sensitive and also avoids false positive signals due to contamination with genomic DNA. Candidate exons that will be retained are those that display aberrant and recurrent skipping in MSI CRC cell lines and primary tumors as compared to MSS CRC controls.

In line with our working hypothesis, the study will then determine whether each confirmed splicing aberration is MSI-driven. This will be achieved as described earlier for T17 deletions in intron 8 of HSP110 that were identified specifically in MSI CRC and lead to exon 9 skipping. Briefly, allelic profiles of adjacent intronic LNCR (see above) will be analyzed using fluorescence-based genotyping in the panel of MSI and MSS CRC cell lines, as well as in the complete series of MSI primary tumors from the RNASeq patient cohort and paired normal mucosa (in order to assess polymorphic status). This will be performed using the same method developed earlier in our laboratory for analysis of the HSP110 T17 DNA repeat. Following migration of PCR products on an ABI 3100 Genetic Analyzer with GS400HD ROX size standards and POP-7 polymer (Applied Biosystems), GeneMapper V4.0 software (Applied Biosystems) will be used to analyze LNCR traces, with application of an AFLP (Amplified Fragment Length Polymorphism) method. Traces will be considered acceptable when the peak amplitudes are between 100 and 6,000 fluorescence units. An MSI Perl script has been developed to automatically compare LNCR traces in normal and tumour samples, thus allowing detection of aberrant LNCR peaks that fall outside of the polymorphic zone observed in the normal population. As with HSP110, it is expected (i) to detect somatic deletions/insertions in some of the candidate LNCRs using this approach, and (ii) to identify those whose somatic alterations due to MSI are significantly associated with exon skipping-related events at the RNA level (MSI exon final list).

WP3 - To identify splicing events and/or LNCR mutations with clinical relevance in MSI CRC patients. The clinical relevance of candidate genes (MSI exon final list) will be assessed using multivariate survival regression models for RFS (Relapse-Free Survival). The number of candidate splicing events and/or LNCR mutations is approximately 100 (see WP1 and WP2 above) and INCa - PRTK 2014 19/51 other known clinical determinants such as stage, treatment and age at diagnosis will be considered in the multivariate models. False positives are one of the major pitfalls in identifying potentially relevant markers amongst dozens of candidates. As the number (p) of covariates to be considered will be of the same order as the number of individuals, the "high-dimensional setting" will be reached. Consequently, the usual algorithms for survival regression models (e.g. coxph in R) will fail to estimate the parameters and to identify events with clinical relevance. In our analysis, three main methodological issues require special attention, particularly at the algorithmic level.

WP3 will be divided into two main steps, the first of which concerns comparisons and the development of statistical algorithms. Once tuned, the algorithms will be run to identify a prognostic biomarker(s) that involves splicing events and/or LNCR mutations with clinical relevance.

High-dimensional regression models and lasso algorithms. In the first step only splicing mutations and clinical determinants in the survival regression models will be considered. In this case, variable selection and parameter estimation will be conducted with a lasso (or elastic net) algorithm (see Simon et al. for the Cox model, and Gaiffas et al. for Aalen model, both implemented in R).

In previous publications it was demonstrated that cut-point values resulted in maximal survival differences between patient groups with large or small deletions in the HSP110 T17 LNCR, and with high or low expression of mutant HSP110 mRNA due to exon 9 skipping at the INCa - PRTK 2014 20/51 mRNA level. Since other splicing events could present with the same threshold effect, the cut-points for up to 100 candidate splicing events will be carefully determined. Even in classical statistics, cut-point determination is a known difficulty because of overdetection. As recently proposed in a related context, the "lasso with pre-screening algorithm" could be adapted to incorporate the cut-point determination into the main algorithm.

Other points. Missing data will be handled by multiple imputations from nearest-neighbour or regression methods. The study will consider possible interactions with the use of chemotherapy. As a final step, estimations will be run on the training cohort (Saint-Antoine) to derive a prognostic biomarker that will include splicing events and/or LNCR mutations with clinical relevance. This biomarker will be validated on the test cohort (multi-centre). Bootstrap analysis will be conducted to ascertain the biomarker.

WP4 - To initiate functional studies on a limited number of clinically relevant, cancer related genes whose splicing is highly perturbed in MSI cancer cells, and to develop biological tools to simplify screening in future clinical assays. As stated earlier, A preliminary study has been performed using exon arrays in a small series of MSI CRC cell lines and primary tumours (unpublished). This was conducted to evaluate feasibility, time, cost, adverse factors, effect size (statistical variability) and to improve upon the study design prior to performing the present full scale research project. The functions of the 100 detected candidate genes (some of which may overlap with those identified from RNAseq screening) were frequently related to a cancer-related processes such as macromolecular synthesis (30%), cell proliferative capacity or cell death (20%), drug resistance (10%) and others (WNT pathway, metastatic process, changes in chromosome structure). The present project expect to identify several robust MSI-driven splice mutants that are clinically relevant (see WP2 and WP3 above). These mutants could have either oncogenic or antioncogenic functions, given that some (such as HSP110) may be produced at high levels even though they have negative impacts on the tumour cell (see our functional hypothesis above concerning the expected detrimental influence of MSI at LNCR in CRC). In this context, in vitro functional studies will be designed to characterize the oncogenic impact of a small number (n=5) of putative clinically relevant mutants. These experiments will be based on transient silencing or overexpression using siRNA or plasmids and ad hoc biological read-out in CRC cellular models already available in our laboratory.

Depending on the results obtained, further investigations could then be planned using stably transfected CRC models xenografted into nude mice. In addition, the study plan to validate biological tools (e.g. Antibodies) to optimize the future screening of patients using routine assays, similar to our work with HSP110 and the HSP110DE9 mutant. Tissue Microarrays (TMAs) will be constructed from routinely prepared, formalin-fixed and paraffin-embedded blocks collected INCa - PRTK 2014 21/51 retrospectively from the Pathology Department of Saint-Antoine hospital. Neoplastic tissue will be sampled, including the tumour invasive front (3 to 6 samples of 0.6 mm diameter tissue cores). When available, paired lymph node metastasis will also be sampled. Immunohistochemistry with antibodies generated specifically (subcontracting) to recognize wild-type or mutant candidate proteins will be performed on TMAs. Exon skipping events are frameshift in 2/3 of cases and thus generate truncated proteins that have immunogenic, aberrant C-terminal tails. Correlations between protein expression and clinico-pathological features will be evaluated, as well as their prognostic and predictive values. TMA slide images will be captured as high-resolution digital files and evaluation of each staining will be done by two pathologists.

Aberrant Splicings Due to Microsatellite Instability in Colorectal Cancer : Physiopathological and Clinical Impact

Aberrant Splicings Due to Microsatellite Instability in Colorectal Cancer : Physiopathological and Clinical Impact (MICROSPLICOTHER)

All RNASeq data will be exploited to identify recurrent splicing aberrations (mostly exon skipping) that occur specifically in MSI colon tumours compared to MSS CRCs and matching normal colonic mucosa.

All specific aberrant splicing events detected by RNAseq in MSI CRC samples will be first confirmed (quantitative RT-PCR) in order to eliminate false positive cases. For validated exon candidates, the allelic profiles of adjacent intronic LNCR will be analysed (PCR and fluorescence genotyping) in CRC cell lines and primary tumours (MSI and MSS), as well as in matching normal mucosa samples in order to assess their polymorphic status.

All LNCR with a confirmed role in gene splicing in MSI CRC will be analysed. The clinical relevance of candidate genes will be assessed using multivariate survival regression models for Relapse- Free Survival, with interaction terms (response to chemotherapy);

We will focus on 4 or 5 mutant proteins that are promising drug therapeutic targets. Functional assays will be developed to further elucidate their role in the pathophysiology of MSI tumours.

We aim to develop biological tools for these candidate genes, such as the detection of wild-type or mutant proteins by immunohistochemistry.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Chemotherapy and Liver Cirrhosis in Frequently-associated Cancers	NCT04179773	Cirrhosis Neoplasms	Current care st...	18 Years -	University Hospital, Lille
Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) and Electrostatic PIPAC (ePIPAC) With Paclitaxel In Patients With Peritoneal Carcinomatosis	NCT05395910	Peritoneal Carc...	Paclitaxel	21 Years - 99 Years	National University Hospital, Singapore
Aberrant Splicings Due to Microsatellite Instability in Colorectal Cancer : Physiopathological and Clinical Impact	NCT03447431	Colorectal Canc... Microsatellite ...		-	Assistance Publique - Hôpitaux de Paris

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