Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Symptoms and General Pathology

Rare Diseases

Prostatic Neoplasms

Neoplastic Cells, Circulating

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Neoplasm Metastasis

Neoplastic Processes

Kennedy Disease

Anti-Inflammatory Agents

Antineoplastic Agents

Antiemetics

Gastrointestinal Agents

All Drugs and Chemicals

Anti-Allergic Agents

Central Nervous System Depressants

Dermatologic Agents

Dexamethasone

Androgens

Dexamethasone acetate

Histamine Antagonists

Histamine H1 Antagonists

Histamine

Diphenhydramine

Promethazine

Histamine H2 Antagonists

Histamine phosphate

Ranitidine

Ranitidine bismuth citrate

Dexchlorpheniramine

Neurotransmitter Agents

Treatment intervention with Cabazitaxel with premedication as necessary (antihistamine, corticosteroid, H2 antagonist, antiemetic prophylaxis)

Cabazitaxel

As intravenous premedication (dexchlorpheniramine 5 mg, diphenhydramine 25 mg, or equivalent)

Antihistamine

As intravenous premedication (dexamethasone 8 mg or equivalent)

Corticosteroid

As intravenous premedication (ranitidine or equivalent)

H2 antagonist

Antiemetic prophylaxis is recommended and can be given orally or intravenously if necessary

Antiemetic

After failure on docetaxel, which has been the standard first line therapy for patients with metastatic castration-resistant prostate cancer (mCRPC), several treatment options are currently available.

In retrospective studies, resistance has been described to two of the treatment options, enzalutamide and abiraterone, when a splice variant of the Androgen Receptor (AR-V7) is present on circulating tumor cells (CTCs). The investigators hypothesize that patients with AR-V7 positive CTCs do have a meaningful response to cabazitaxel.

After failure on docetaxel, which has been the standard first line therapy for patients with metastatic castration-resistant prostate cancer (mCRPC), several treatment options are currently available.

Two of the treatment options are directed against the androgen receptor (AR), enzalutamide and abiraterone. A third option is cabazitaxel, a next generation taxane. No head-to-head comparisons have been done for these three therapies in second-line mCRPC and as of yet, the optimal choice is unknown.

Resistance to the AR-targeted therapies is at least in part a consequence of signaling through constitutively active AR splice variants (AR-Vs). Because AR splice variants only occur after conversion to a castration-resistant tumor, and can be acquired during systemic therapy for mCRPC, analysis of the castration-naïve primary tumor is not informative in the setting of second-line treatment of mCRPC.

Circulating tumor cells (CTCs) can be analyzed repetitively and in real-time. Recently, AR-V7 messenger ribonucleid acid (mRNA) expression in CTCs was shown to be associated with lack of response to AR-targeted therapy (reference 1). AR-V7 mRNA expression does not seem to hinder response to cabazitaxel in our retrospective pilot study (reference 2) nor in two recently published retrospective studies (reference 3 and reference 4).

Therefore we hypothesize that the mRNA expression of AR-V7 in CTCs assessed before start of second-line treatment for mCRPC does not affect prostate-specific antigen (PSA) response to cabazitaxel in patients who have progressed to docetaxel.

Patients who are eligible to undergo second or third line treatment will be asked to undergo prescreening consisting of a CTC count and, in case ≥3 CTCs are detected, AR V7 determination. Patients with ≥3 CTCs with AR-V7 expression will be asked to sign a second informed consent to enter the treatment study. In this study they will receive Cabazitaxel 25 mg/m² every 3 weeks plus prednisone 10 mg daily, and undergo repeated blood sampling for biomarker sample collection.

During the prescreening in all patients, 2 x 10 mL blood will be drawn for enumeration and isolation of CTCs. All patients with ≥3 CTCs with AR-V7 expression will be asked to sign consent for the treatment study.

All patients included in the treatment study will be administrated cabazitaxel intravenously at a dose of 25 mg/m², during a one-hour infusion every 3 weeks, as well as continuous treatment with prednisone 5 mg orally twice daily, or 10 mg once daily. In the treatment study patients, an additional 2 x 10 mL blood will be drawn after the third cycle of treatment for CTC enumeration and isolation. An additional 10 mL blood will be drawn for storage of plasma at baseline and before start of every cycle (i.e., every 3 weeks) for analysis of cell-free DNA (cfDNA). Moreover, 4 x 5 mL blood (baseline; end of infusion, 2 and 6 hours after end of the first cabazitaxel infusion) will be drawn for pharmacokinetic studies, in order to explore a cabazitaxel exposure effect relation.

Cabazitaxel in mCRPC Patients With AR-V7 Positive Circulating Tumor Cells (CTCs)

A Single Arm Phase 2 Multicenter Study Determining the Response to Cabazitaxel in Metastatic Prostate Cancer (mCRPC) Patients With AR-V7 Positive Circulating Tumor Cells (CTCs)

Information can be shared by importing it into another databases

The primary endpoint is PSA response, defined as a ≥50% PSA decline from baseline during therapy.

CTC response defined as a decrease from ≥5 CTCs per 7.5 mL blood at baseline to \<5 CTCs per 7.5 mL blood

PSA change from baseline at 12 weeks defined as the percent change in PSA from baseline at 12 weeks, according to PCWG2 criteria

Maximum PSA decrease defined according to PCWG2 criteria

Progression-free survival (PFS) defined as time from prescreening to the date of the first documentation of disease progression (PCWG2)

Overall survival (OS) calculated from the date of prescreening to death due to any cause

Grade 3-4 adverse events (AEs) and serious adverse events (SAEs) during cabazitaxel according to CTCAE v4.03 in second and third-line treatment

Cumulative administered dose of cabazitaxel in second and third-line treatment

AR-V7 mRNA expression as well as mRNA expression of other splice variants in CTCs indicated as absent (-) or present (+)

Cabazitaxel concentration in the blood and total systemic exposure to cabazitaxel, measured by the calculated area under the curve (AUC)

To explore the value of ctDNA quantification during cabazitaxel treatment to predict tumor progression

Sanofi

Erasmus Medical Center

Carcinoma

Carcinoma, Renal Cell

Kidney Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenocarcinoma

Urologic Neoplasms

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Kidney Diseases

Urologic Diseases

Renal Cell Carcinoma

Clear Cell Renal Cell Carcinoma

Amino Acids

Immune Checkpoint Inhibitors

Angiogenesis Inhibitors

Immunomodulating Agents

Tyrosine Kinase Inhibitors

Tyrosine

Therapeutic combination tyrosine kinase inhibitor (TKI) + immune checkpoint inhibitors (ICI)

Therapeutic combination with different immune checkpoint inhibitors (ICI)

Systematic extra blood sampling at inclusion, 6 weeks after inclusion and in case of progression of the cancer

Blood collection

reuse of tumour tissue collect in usual patient care

Tumour samples

Natacha Nohilé

Laetitia MAUGE, PharmD, PhD

Marie AUVRAY-KUNITZ, MD

Olivier HUILLARD, MD

Olivier HUILLARD, MD, PhD

This is a multicenter, exploratory, prospective study to identify angiogenesis and immune-related biomarkers predictive of progression free survival in patients with metastatic or advanced renal cell carcinoma treated by a combination of immunotherapy and antiangiogenic.

Recently, the management of renal cell carcinoma has undergone major changes with the emergence of combined therapies associating tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI) as first line treatments. However, there are no criteria to guide the choice between the different combinations validated and or between ICI combinations. Angiogenesis and immunity are intimately linked and some markers related have could be interesting to predict the efficacy of these combinations. Angiogenesis and immunity are highly related. This link may lead to new biomarkers to be explored to predict the response to TKI + ICI therapy combinations. On this basis, the investigators propose to conduct an open-label exploratory, multicenter prospective trial to study the association between angiogenesis and immune markers and the effect of combined TKI+ICI treatments.

Biomarkers of Angiogenesis for Response to Therapeutic Combination in Advanced or Metastatic Kidney Cancer

Predictive Role of Circulating Biomarkers Involved in Angiogenesis in Metastatic Kidney Cancer in the Era of New Therapeutic Associations: Immunotherapies, Anti-angiogenic

Individual participant data (IPD) that underlie results in publication could be shared. IPD detailed in the protocol of a planned metaanalysis could be shared

Time from inclusion to progression documented by imaging and based on RECIST 1.1 and iRECIST criteria or patient death. The iRECIST criteria use the same methods of monitoring tumor lesions as the RECIST 1.1 criteria but a confirmation 4-6 weeks after suspicion of progression is required to confirm or rule out progression because patients undergoing immunotherapy may present pseudo-progressions.

Observation of a partial or complete response according to RECIST 1.1 criteria during the follow-up

Time between the observation of an objective response (partial or complete according to RECIST 1.1 criteria) and the progression

Institut National de la Santé Et de la Recherche Médicale, France

FONCER contre le cancer

Assistance Publique - Hôpitaux de Paris

patients without CTCs or AR-V7 negative CTCs are treated according to their physician's discretion

patients with AR-V7 positive CTCs are treated with cabazitaxel 25mg/m2 q3w

cabazitaxel

After failure on docetaxel, which has been the standard first line therapy for patients with metastatic castration-resistant prostate cancer (mCRPC), several treatment options are currently available. In retrospective studies, resistance has been described to two of the treatment options, enzalutamide and abiraterone, when a splice variant of the Androgen Receptor (AR-V7) is present on circulating tumor cells (CTCs). The investigators hypothesize that patients with AR-V7 positive CTCs do have a meaningful response to cabazitaxel.

Rationale: After failure on docetaxel, which has been the standard first line therapy for patients with metastatic castration-resistant prostate cancer (mCRPC), several treatment options are currently available. Two of the treatment options are directed against the androgen receptor (AR), enzalutamide and abiraterone. A third option is cabazitaxel, a next generation taxane. No head-to-head comparisons have been done for these three therapies in second-line mCRPC and as of yet, the optimal choice is unknown. Resistance to the AR-targeted therapies is at least in part a consequence of signaling through constitutively active AR splice variants (AR-Vs).

Because AR splice variants only occur after conversion to a castration-resistant tumor, and can be acquired during systemic therapy for mCRPC, analysis of the castration-naïve primary tumor is not informative in the setting of second-line treatment of mCRPC. Circulating tumor cells (CTCs) can be analyzed repetitively and in real-time. Recently, AR-V7 mRNA expression in CTCs was shown to be associated with lack of response to AR-targeted therapy. AR-V7 mRNA expression does not seem to hinder response to cabazitaxel in the investigator's retrospective pilot study nor in a recently published small retrospective study.

Therefore the investigators hypothesize that the mRNA expression of AR-V7 in CTCs assessed before start of second-line treatment for mCRPC does not affect PSA response rate to cabazitaxel in patients who have progressed to docetaxel.

Objective: The primary objective of this study is to explore the PSA response rate to cabazitaxel in mCRPC patients who have progressed to docetaxel and have detectable AR-V7 expression in CTCs. Exploratory objectives include documenting the PSA response to cabazitaxel after enzalutamide or abiraterone treatment in initially AR-V7 negative patients, describing the toxicity of cabazitaxel in second and third-line treatment as well as exploring if response measured by CTC counts and PSA is related to systemic cabazitaxel exposure.

Study design: This is a multicenter, non-randomized phase 2 study. Patients will be allocated to one of the following treatment groups according to the results of CTC enumeration and characterization in the screening phase:

Group A: Patients with \<3 CTCs and patients with ≥3 CTCs without AR-V7 expression will receive physician's choice of treatment Group B: Patients with ≥3 CTCs with AR-V7 expression will receive Cabazitaxel 25 mg/m² every 3 weeks plus prednisone 10 mg daily.

Patients in group A who are treated with enzalutamide or abiraterone and experience disease progression, can then again enter the screening phase and, after additional eligibility check, subsequently be treated with cabazitaxel in group B if ≥3 CTCs are present and AR-V7 mRNA expression is now detected. These patients will not be re-included in the study.

Study population: Adult mCRPC patients, age≥18 years, who progressed during docetaxel treatment. Prior enzalutamide or abiraterone treatment is permitted.

Intervention: In all patients, 2 x 10 mL blood will be drawn for enumeration and isolation of CTCs at baseline. In group B, cabazitaxel will be administrated intravenously at a dose of 25 mg/m², during a one-hour infusion every 3 weeks, as well as continuous treatment with prednisone 5 mg orally twice daily, or 10 mg once daily, according to standard care. In these patients, an additional 2 x 10 mL blood will be drawn after the second cycle of treatment for CTC enumeration and isolation. In group B, an additional 10 mL blood will be drawn for storage of plasma at baseline and before start of every every cycle (i.e., every 3 weeks) for analysis of cell-free DNA (cfDNA) as part of a side-study. In group B, also 4 x 5 mL blood (baseline; end of infusion, 2 and 6 hours after end of the first cabazitaxel infusion) will be drawn for a pharmacokinetic side-study, to explore a cabazitaxel exposure effect relation. Patients in group A will be treated according to their physician's choice. In group A, an additional 10 mL blood will be drawn for storage of plasma at baseline, at 12 weeks after start of treatment and upon progression to enzalutamide or abiraterone for analyses of cell-free DNA (cfDNA) as part of a side-study. Patients in group A who receive abiraterone or enzalutamide and subsequently experience disease progression can again enter the screening phase of the study, and if eligible, be included in group B.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness:

For the CTC enumeration and isolation, a total of 40 mL additional blood will be drawn at the time of regular blood draws (treatment group A: 1 x 20 mL at baseline and 1 x 20 mL upon progression to enzalutamide or abiraterone; treatment group B: 1 x 20 mL at baseline and 1 x 20 mL after the second cycle of cabazitaxel).

For storage of plasma for cfDNA analysis, a total of 100 mL additional blood will be drawn at the time of regular blood draws (at baseline and before each treatment cycle) from patients in group B. In group A, for storage of plasma for cfDNA analysis, a total of 30 mL additional blood will be drawn at the time of regular blood draws (at baseline, at 12 weeks after start of treatment and upon disease progression).

For pharmacokinetic analysis, in patients in group B, a total of 20 mL (4 x 5 mL) additional blood will be drawn at baseline, end of infusion, 2 and 6 hours after the first cabazitaxel infusion.

Cabazitaxel is standard second-line chemotherapy for mCRPC patients. In the TROPIC trial, the most common observed grade 3-4 toxicity was neutropenia (82%). Despite the high incidence of neutropenia, febrile neutropenia was rare (8%). The most frequent non-hematologic adverse event (AE) was diarrhea, occurring in 47% (grade ≥3 6%) of patients treated with cabazitaxel, compared to 11% (grade ≥3 \<1%) of patients treated with mitoxantrone. In the TROPIC trial, a total of 18 (5%) patients treated with cabazitaxel died within 1 month of the last drug infusion due to adverse effects. This compares to 3 drug-related deaths (2%) in the mitoxantrone group. The most common cause of death in patients treated with cabazitaxel was neutropenia and its clinical consequences. The frequency of hematological adverse events and related deaths demonstrates that cabazitaxel treatment requires careful monitoring and management of emerging symptoms. Dose reductions as well as supportive treatment (i.e. the administration of granulocyte colony-stimulating factor \[G-CSF\]) will be considered to manage the toxic effects of treatment.

Patients in group B will have scheduled study visits frequently, in accordance with standard-of-care cabazitaxel treatment. Patients will return for regularly scheduled study visits for as long as they continue study treatment, or discontinued study treatment but have not yet experienced disease progression. All patients will be followed for survival after discontinuing treatment. For the primary endpoint, serial blood samples will be collected every three weeks to quantify PSA. Radiographic evaluations (bone scans and CT/MRI-scans of the abdomen and pelvis) will be employed after four and eight cycles of cabazitaxel to assess the status of the disease according to modified RECIST 1.1 criteria.

The safety of cabazitaxel in second and third-line treatment will be assessed by monitoring the frequency of treatment related (serious) adverse events, which will be recorded according to the Common Terminology Criteria (CTCAE) scale version 4.03.

Cabazitaxel in mCRPC Patients With AR-V7 Positive CTCs

Non-randomized Phase 2 Open-label Multicenter Study Determining the Response to Cabazitaxel in Metastatic Prostate Cancer (mCRPC) Patients With AR-V7 Positive Circulating Tumor Cells (CTCs): CARVE

PSA response rate is defined as a reduction of at least 50% from baseline during therapy, confirmed after ≥4 weeks by an additional PSA evaluation.

CTC Response rate is defined as a decrease from ≥5 CTCs per 7.5 mL blood at baseline to \<5 CTCs per 7.5 mL blood, as measured by the CellSearch system

• PSA change from baseline at 12 weeks defined as the percent change in PSA from baseline (rise or fall) at 12 weeks, according to PCWG2 criteria.

Maximum PSA decrease is defined according to PCWG2 criteria (30), i.e., the maximal change (rise or fall) at any time through study completion, illustrated by a waterfall plot

Progression defined as:

* At least 2 consecutive PSA rises over a reference value, with an interval of ≥ 1 week between each determination. PSA at screening visit should be ≥ 2.0 μg/l; the date of progression will be the first of the 2 consecutive dates.
* Soft tissue disease progression defined by modified RECIST criteria (1.1) (baseline LN size must be ≥ 2.0 cm to be considered target or evaluable lesion).
* Bone disease progression defined by the appearance of new lesions on a bone scan, confirmed on a second bone scan ≥ 6 weeks later. Ambiguous results should be confirmed by other imaging modalities (e.g., CT or MRI). The date of progression will be the first of the 2 consecutive dates.

oncologist

patients with resectable GEA (including Siewert I) which are candidate to receive either peri-op treatments or upfront surgery followed by adjuvant treatments, if recommended.

Chiara Alessandra Cella, MD

Cristina Mazzon

Gastric cancer (GC) is the second leading cause of cancer mortality and remains the fourth common cancer worldwide. Gastric and esophageal cancers treated with curative intent both have a poor prognosis with five-year survival rate varying between 30% and 40% \[Hagen\]. Therefore, even in the localized or locally advanced (LA) disease, relapse-related death remains a major challenge for curative treatment. Currently, there are several strategies for the curative treatment of GC including perioperative chemotherapy (peri-Op cht), adjuvant chemotherapy and adjuvant chemoradiotherapy. Despite the therapeutic management of localized or LA GC is well established, there is uncertainty about the power of prognostic and predictive factors to tailor anticancer treatments. In addition to that, further investigation is needed to investigate if pre-existing environment factors may act on carcinogenesis and to explore the molecular mechanisms that underlying cancer growth and invasiveness.

Gastric cancer (GC) is the second leading cause of cancer mortality and remains the fourth common cancer worldwide. Gastric and esophageal cancers treated with curative intent both have a poor prognosis with five-year survival rate varying between 30% and 40%. Therefore, even in the localized or locally advanced (LA) disease, relapse-related death remains a major challenge for curative treatment. Currently, there are several strategies for the curative treatment of GC including perioperative chemotherapy (peri-Op cht), adjuvant chemotherapy and adjuvant chemoradiotherapy. Despite the therapeutic management of localized or LA GC is well established, there is uncertainty about the power of prognostic and predictive factors to tailor anticancer treatments. In addition to that, further investigation is needed to investigate if pre-existing environment factors may act on carcinogenesis and to explore the molecular mechanisms that underlying cancer growth and invasiveness.

Gastric carcinogenesis arises as a consequence of a complex interaction between host and environmental factors. It is known that dietary, lifestyle and metabolic factors are implicated in GC. However, although their impact in terms of cancer prevention have been already addressed, we disregard if nutritional disorders and dietary habits may have a potential predictive or prognostic power in LA GC. Therefore, further knowledge is strongly warranted to realize the actual impact of dietary- and lifestyle-factors in GC risk and - conversely - to examine if nutritional disorders are able to negatively impact the outcome of anticancer treatments.

H. pylori infection is the major risk factor associated with non-cardia gastric cancer, and data has emerged with regard to the role of H. pylori eradication for primary prevention of gastric cancer. Smoking has also been implicated as a risk factor for non-cardia cancer. Furthermore, host genetic polymorphisms have an impact on host responses to gastric inflammation and acid secretion, thereby interacting with H. pylori infection and other environmental factors in gastric carcinogenesis. In contrast to non-cardia cancer, H. pylori infection does not play an important role in cardia cancer, with obesity and smoking identified as the main risk factors. Although dietary, lifestyle and metabolic risk factors have been identified, and addressing these lifestyle and metabolic risk factors may contribute to health, the actual impact in modulating cancer response and outcomes is still debated. Results from epidemiological studies reported that dietary factors may play an important role in gastric cancer etiology. Malnutrition is an independent predictor of increased morbidity and mortality. Additionally, weight loss and sarcopenia leads to higher chemotherapy-induced toxicity. In addition, neoadjuvant chemotherapy and chemoradiation therapy, which often worsen a patient's nutritional status, have become a standard treatments. In some cases, anti-cancer treatments may induce weight gain; on the other hand, overweight and obesity represent a risk factor for metabolic syndrome and they may foster disease recurrence. Therefore, it is challenging to estimate how anti-cancer treatments affect nutritional status and vice versa. These serious changes in nutritional status are also associated with marked deterioration in quality of life and can affect the ability to resist infection and recover from surgery. Screening for nutritional risk as early as possible allows for the identification of patients at risk of becoming malnourished. Screening should be done as early as possible, and recent literature suggests that it should be done at diagnosis or at hospital admission; screening should be repeated in the course of treatment for referral for evaluation if needed.Another source of investigation concerns the human microbiome, since microbiota is involved in human health and in several disease. Growing interest in microbiome and immune interaction in oncology lead to the awareness that cancer therapies perturb the microbiota and the host immune response, with resulting dysbiosis. On the other hand, existing evidence supports the hypothesis that gut microbiota can modulate the pharmacological effects and the toxicity profile of anticancer treatments. Therefore, it would be addressed if gut microbiota can shape the efficiency of drugs through several key mechanisms: metabolism, immunomodulation, translocation, enzymatic degradation, reduction of diversity, and ecological variability. Accordingly, microbiome is emerged as a novel target to be explored in different cancer settings. The strongest known risk factor for GC is infection with H.pylori, which drives the development of premalignant lesions (such as gastric atrophy, intestinal metaplasia, and dysplasia) that can lead to gastric cancer. However, although H.pylori is the most common bacterial infection worldwide and colonizes greater than 50% of the global population, only 1%-3% of infected individuals ever develop gastric cancer. In conclusion, although great advances have been made in understanding the complex interplay between the gastric microbiota and H.pylori in the development of gastric inflammation and cancer, further studies are still needed in well-defined human populations to compare differences in the microbiota of H.pylori-infected persons with and without neoplastic lesions. Cross-sectional studies can provide initial insights into microbial associations with cancer; however, reverse effects are a concern, as it is difficult to discern whether carcinogenesis leads to changes in the local microenvironment that creates a new niche for microbes or whether alterations in the microbial population or its functions contribute to carcinogenesis.The study aims to create a unique platform to integrate clinical, biological and imaging data regarding patients with resectable gastric and esophageal adenocarcinoma (GEA). This innovative approach looks at either implementing the data source in resectable GEA and mapping the complex interaction among the aforementioned features (nutrition-microbiome-genomics-radiomics), in order to sharpen the actual precision medicine toward a patient-centric model.

blood samples, tissue samples, salivary swabs and fecal samples

Dissecting the Role of MIcrobioMe in gastroEsophageal Tumor: a multIdisCiplinary Longitudinal Study

Tumor regression grading (TRG) system, which aims to categorize the amount of regressive changes after cytotoxic treatment mostly refer onto the amount of therapy induced fibrosis in relation to residual tumor or the estimated percentage of residual tumor in relation to the previous tumor site. Commonly used TRGs for upper gastrointestinal carcinomas are the Mandard grading and the Becker grading system. We will apply the Backer grading system.

Pathological complete response (pCR) is defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the resected specimens.

Relapse free survival (RFS) is defined as the time from random assignment until first recurrence (loco-regional or distant metastasis) or death due to any cause.

Past dietary consumption will be measured at baseline using the validated and self-administered food frequency questionnaire (FFQ) developed for the European Prospective Investigation into Cancer and Nutrition Italian section (EPIC) study.

Nutritional Status will be assessed, using the following Nutrition risk screening - Nutrition Risk Screening 2002 (NRS-2002).

Nutritional Status will be assessed, using the following Patient Generated Subjective Global Assessment (PG-SGA)

Nutritional Status will be assessed, using the Prognostic nutritional index calculated as follows: 10 x serum albumin (g/dL) + 0.005 x total peripheral lymphocyte count (1000/mcl)

Upper digestive endoscopy with a core biopsy or excisional biopsy will be performed at baseline and one year after surgery .to obtain tissue from tumor tissue and surrounding normal mucosa (1 to 3 cm far from tumor site) for microbiota analysis. The analysis of the microbiota is performed through the use of the most up-to-date bacterial DNA sequencing techniques (Next Generation Sequencing) to guarantee complete and reliable identification of the intestinal microbiota.

European Institute of Oncology

Carcinoma, Neuroendocrine

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Nerve Tissue

Neuroendocrine Tumor

Neuroepithelioma

patients with extra-pulmonary, advanced neuroendocrine carcinomas

composed at least by 30% of a neuroendocrine (NE) and a non-neuroendocrine (non-NE) component based on the 2019 World Health Organization (WHO) classification

Francesca Spada, MD

Extra-pulmonary (EP) poorly differentiated neuroendocrine carcinomas (NECs) represent a rare and aggressive category of neoplasms. Mixed adeno-neuroendocrine carcinomas (MANEC) are a group of rare neoplasms composed by a neuroendocrine (NE) and a non-neuroendocrine (non-NE) component, each representing at least the 30% of the neoplasm.

Considering their rarity, low prevalence and poor prognosis a clear clinical, morphological and biomolecular characterization of these neoplasms has been prevented and a clinical approach universally shared is still lacking.

Extra-pulmonary (EP) poorly differentiated neuroendocrine carcinomas (NECs) represent a rare and aggressive category of neoplasms. They occur in almost 1 / 100.000 patients and the largest part is represented by gastro-entero-pancreatic (GEP) NECs (39%).

Moreover, mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) represent an even more rare entity, with a crude incidence of 0.1 / 100.000 / year, composed at least by 30% of a neuroendocrine (NE) and a non-neuroendocrine (non-NE) component based on the 2019 World Health Organization (WHO) classification. Focusing on the neuroendocrine counterpart, although the term MiNEN includes both well and poorly differentiated morphologies, the main part of them are represented by high grade neuroendocrine neoplasms categorized as MANECs in previous 2010 WHO classification that is a term still used in clinical practice is still lacking.

While for localized disease, surgery represents the cornerstone and virtually the unique curative approach, patients with metastatic disease are mostly managed with chemotherapy. Although any specific clinical practice guideline by Oncological and / or Neuroendocrine Societies has been yet developed worldwide, based on the clinical and morphological similarity with small and large cell lung NECs, cis / carbo-platinum based chemotherapy, is the most often chemotherapeutic regimen proposed in clinical practice both in NECs and MANECs from each site of origin. Other proposed options include regimens containing 5-fluorouracil/folinic-acid and irinotecan or oxaliplatin which are used also in the treatment of colo-rectal adenocarcinomas. Moreover, considering their rarity, low prevalence and poor prognosis a clear clinical, morphological and biomolecular characterization of these neoplasms has been prevented and a clinical approach universally shared is still lacking.

Therefore, a comprehensive clinical and biological characterization of these neoplasms represents an unmet medical need and a major challenge and could improve the awareness of clinicians in the management of EP-NECs and MANECs.

tumor tissue samples, peripheral blood samples

PrognostIc and Predictive Factors in Unresectable Locally Advanced NEC and MANEC

Retrospective and Prospective Observational Study on prognostIc and Predictive Factors in Patients With Extra-pulmonary, adVanced Neuroendocrine cArciNomas and Mixed Adeno-neuroendocrine Carcinomas (NIRVANA)

The primary clinical endpoint will be the overall survival.

The secondary clinical endpoint will be the progression free survival

Mutational patterns such as BRAF, KRAS, NRAS, MSI, TP53, RB1 will be analyzed.

The progression free survival and overall survival of patients with mutations will be evaluated.

Herbal and Botanical

Cassava

Histological diagnosis of well-differentiated neuroendocrine tumor G3 performed or reviewed by a NEN-dedicated pathologist.

The 2017 World Health Organization (WHO) introduced a new category of high-grade, well-differentiated neuroendocrine neoplasms (NENs) that called neuroendocrine tumors (NETs) G3 in pancreatic NENs classification and, then, in 2019, for all gastro-entero-pancreatic (GEP) tract NENs.

The new classification made it possible to separate NETs G3 from high-grade, poorly-differentiated, NENs that are called neuroendocrine carcinomas (NECs).

However, in clinical practice, we observed that several clinical, pathological and radiological differences are arising among NET G3 patients, suggesting that a multiparametric definition of NET G3 is needed.

High-grade neuroendocrine neoplasms (NENs) represent the poorest prognosis category within NENs. During the years, the prognostic differences among the subgroups led to identify at least two subcategories of high-grade NENs, according the morphologic features of the two subtypes.

Indeed, the 2017 World Health Organization (WHO) introduced a new category of high-grade, well-differentiated NENs that called neuroendocrine tumors (NETs) G3 for pancreatic NENs and, then, in 2019, for all gastro-entero-pancreatic (GEP) tract NENs, allowing to separate NET G3 from the other high-grade, poorly-differentiated, NENs, so called neuroendocrine carcinomas (NECs).

However, since the new-category has been introduced, NET G3 category seemed to be more heterogeneous than presumed. Indeed, clinical, pathological and radiological features seemed to identify different prognostic subcategories of NET G3. We recently performed a retrospective analysis on a small pool of 48 NET G3 patients, correlating the clinical outcomes with these different features. The results of our study seemed to suggest prognostic and predictive factors that deserve to be prospectively explored to better understand this pathology and that might to be part of NET G3 multiparametric classification system. Based on the results of our retrospective analysis, we underlined the importance of a systematic and well-designed collection of high-quality data in order to improve our knowledge on this topic.

Definition of a Multiparametric Prognostic and Predictive System of Classification of NET G3 Patients

Definition of a Multiparametric Prognostic and Predictive System of Classification of NET G3 Patients: an observAtional, Prospective Analysis of the Correlation Between Functional Imaging and Clinical Outcome (TAPIOCA)

Analysis of the morphology Analysis of proliferation index Ki-67 Analysis of Ki-67 expression (as hotspot or a diffuse expression on the sample) Analysis of Synaptophysin, and chromogranin expression

Analysis of homogeneity or inhomogeneity of radiotracer distribution Analysis of the concordance/discordance between functional imaging. For "late-NET G3", the specialist in nuclear medicine will review both functional imaging (before and after NET G3 diagnosis)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Cabazitaxel in mCRPC Patients With AR-V7 Positive Circulating Tumor Cells (CTCs)	NCT03050866	Circulating Tum... Metastatic Pros...	Cabazitaxel Antihistamine Corticosteroid H2 antagonist Antiemetic	18 Years -	Erasmus Medical Center
Biomarkers of Angiogenesis for Response to Therapeutic Combination in Advanced or Metastatic Kidney Cancer	NCT05285579	Renal Cell Carc... Renal Cancer Renal Cancer Me...	Blood collectio... Tumour samples	18 Years -	Assistance Publique - Hôpitaux de Paris
Cabazitaxel in mCRPC Patients With AR-V7 Positive CTCs	NCT02621190	Prostatic Neopl...	cabazitaxel	18 Years -	Erasmus Medical Center
Cabazitaxel in mCRPC Patients With AR-V7 Positive CTCs	NCT02621190	Prostatic Neopl...	cabazitaxel	18 Years -	Erasmus Medical Center
Dissecting the Role of MIcrobioMe in gastroEsophageal Tumor: a multIdisCiplinary Longitudinal Study	NCT06405035	Adenocarcinoma		18 Years -	European Institute of Oncology
PrognostIc and Predictive Factors in Unresectable Locally Advanced NEC and MANEC	NCT06400654	Neuroendocrine ...		18 Years -	European Institute of Oncology
Dissecting the Role of MIcrobioMe in gastroEsophageal Tumor: a multIdisCiplinary Longitudinal Study	NCT06405035	Adenocarcinoma		18 Years -	European Institute of Oncology
Cabazitaxel in mCRPC Patients With AR-V7 Positive Circulating Tumor Cells (CTCs)	NCT03050866	Circulating Tum... Metastatic Pros...	Cabazitaxel Antihistamine Corticosteroid H2 antagonist Antiemetic	18 Years -	Erasmus Medical Center
Definition of a Multiparametric Prognostic and Predictive System of Classification of NET G3 Patients	NCT06343428	Neuroendocrine ...		18 Years -	European Institute of Oncology

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