Relevance of a medicosurgical strategy combining cetuximab and chronomodulated (Chrono) chemotherapy (chemo) with metastases resection as 3rd line treatment for patients (pts) with metastatic colorectal cancer (MCRC)

14505 Background: Metastases surgery offers long tem survival for pts with chemo-downstaged MCRC (Adam et al. Ann Surg 2004). The relevance of this medicosurgical strategy was investigated in pts given cetuximab (Cetux) and Chrono after chemo failure. Methods: 56 pts with progressive MCRC on prior chemo received Cetux (400 mg/m2 on 1st dose then 250 mg/m2/week) and q2w Chrono based on irinotecan (34 pts), oxaliplatin (14 pts) or both (8 pts). Toxicity grades (G) and response were assessed q2w and q8w, respectively. Tumour EGFR was determined by immunohistochemistry (all pts) and gene copies by fluorescence in situ hybridisation (27 pts). Metastases surgery was attempted whenever complete resection was foreseen. Results: Median of 3 prior chemo (1 to 8); median age: 61 years (35 to 79); M/F: 34/22; WHO PS 0/1/2/3: 37/14/4/1; colon/rectum: 32/24; M sites 1/2/=3: 15/22/19; liver/lung: 45/40. EGFR was detected in the tumor of 39 pts (69.6%). 3 pts had G4 allergy. 53 evaluable pts received a median of 5 courses of Cetux-Chrono (1–22). G2–3 acneiform rash occurred in 36 pts (67.8%; G3: 30.4%). Main G3–4 toxicities were diarrhea (26.5%), neutropenia (23.1%) and neuropathy (22.6%). The objective response rate (ORR) was 32% [95% CI, 19.4 to 44.6] (13 PR and 3 CR). ORR was correlated positively with acneiform rash (p= 0.019) but negatively with the detection of EGFR+ tumor cells (0%, ORR=54.5%; 1–10%, 33%; >10%, 16.7%; p = 0.044). No EGFR amplification was documented including 8 OR. Median progression-free survival (PFS) and overall survival were 5.1 [3.2–6.9] and 13.9 months [6.5–21.3] respectively. Metastases surgery was performed in 10 pts (8 R0, 2 R1) after 3–15 courses of Cetux-Chrono as 2nd-5th line. Median PFS in resected pts was 11.7 months [5.8–17.6], with a survival estimate of 80% at 21 months. Conclusions: Cetux-Chrono safely reverted MCRC resistance and allowed successful metastases resection in 17.8% of these pts, like 1st line chemo. This medicosurgical strategy impacted favourably on long term survival, despite its application as 3rd treatment line. Supported by ARTBC, Hôpital Paul Brousse, Villejuif, France No significant financial relationships to disclose.

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Crizotinib in patients with advanced or metastatic ROS1-rearranged lung cancer (EUCROSS): A European phase II clinical trial–Updated report on progression-free and overall survival.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.9066 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 9066-9066

Author(s):

Sebastian Yves Friedrich Michels ◽

Jeremy Franklin ◽

Bartomeu Massuti ◽

Martin Sebastian ◽

Hans-Ulrich Schildhaus ◽

...

Keyword(s):

Lung Cancer ◽

Clinical Trial ◽

Overall Survival ◽

Primary Endpoint ◽

Objective Response ◽

In Situ Hybridisation ◽

Progression Free Survival ◽

Fluorescence In Situ Hybridisation ◽

Eligibility Criteria ◽

Tp53 Mutations

9066 Background: ROS1 rearrangements are found in 1% of non-small cell lung cancer (NSCLC) patients. Early clinical trials in the US and East Asia have proven the therapeutic efficacy of crizotinib in this subset of patients. EUCROSS is the first prospective European trial to evaluate the acitivity of crizotinib in ROS1-positive lung cancer. Here we present an updated analysis of the investigator-assessed progression-free survival (PFS) and overall survival (OS). Methods: EUCROSS is a multi-centre, single arm phase 2 trial (NCT02183870). Key eligibility criteria: ≥18 years of age, advanced/metastatic lung cancer, centrally confirmed ROS1-rearranged (fluorescence-in situ hybridisation). Treatment with crizotinib was initiated at a dose of 250 mg twice daily. Primary endpoint of the trial: investigator-assessed objective response rate (ORR) in the response-evaluable population (Response Evaluation Criteria in Solid Tumors, version 1.1). Key endpoints of this report: updated PFS and OS and updated molecular characterization of tumour tissue. Results: Thirty-four patients received treatment with crizotinib and were included in the intention-to-treat analysis. Four patients were excluded from the primary endpoint analysis due to violation of eligibility criteria (response-evaluable set, N = 30). Median follow-up period was 44.9 months. At the time of data cut-off for this report 19 patients (63%) discontinued treatment due to progression or death. Investigator ORR was 70% (95% CI, 51–85; 21/30), disease control rate was 90% (95% CI, 73.5-97.9; 27/30) and median PFS was 19.4 months (95% CI, 10.1-31.2). Median OS was not reached, but 24-months-OS probability was 66% (95% CI, 48.3-82.9). Tissue of 18 patients was available for hybrid-capture-based sequencing. Co-occurring genetic aberrations were found in 61% (11/18). TP53 mutations were most frequent (28%; 5/18). PFS (24-months probability, TP53-mut. 0% vs. TP53 wild-type (wt) 61%; p = 0.0219) and OS (24-months, TP53-mut. 40% vs. TP53 wt 83%; p = 0.015) were significantly shorter in TP53-mutant patients. Differences in OS and PFS stratified by number of prior treatment lines (0-1 vs. > = 2), brain metastases (yes vs. no) or CD74-rearrangement ( CD74- ROS1 vs. other fusion type) status were not significant. Conclusions: Updated PFS and OS results show that crizotinib is highly effective in ROS1-rearranged lung cancer. Co-occurring TP53 mutations were associated with a significantly worse outcome. Clinical trial information: NCT02183870.

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Serial horizontal transfer of vitamin-biosynthetic genes enables the establishment of new nutritional symbionts in aphids’ di-symbiotic systems

The ISME Journal ◽

10.1038/s41396-019-0533-6 ◽

2019 ◽

Vol 14 (1) ◽

pp. 259-273 ◽

Cited By ~ 13

Author(s):

Alejandro Manzano-Marı́n ◽

Armelle Coeur d’acier ◽

Anne-Laure Clamens ◽

Céline Orvain ◽

Corinne Cruaud ◽

...

Keyword(s):

In Situ Hybridisation ◽

Essential Amino Acids ◽

Aphid Species ◽

Fluorescence In Situ Hybridisation ◽

The Novel ◽

Buchnera Aphidicola ◽

Biosynthetic Genes ◽

Obligate Symbiont

Abstract Many insects depend on obligate mutualistic bacteria to provide essential nutrients lacking from their diet. Most aphids, whose diet consists of phloem, rely on the bacterial endosymbiont Buchnera aphidicola to supply essential amino acids and B vitamins. However, in some aphid species, provision of these nutrients is partitioned between Buchnera and a younger bacterial partner, whose identity varies across aphid lineages. Little is known about the origin and the evolutionary stability of these di-symbiotic systems. It is also unclear whether the novel symbionts merely compensate for losses in Buchnera or carry new nutritional functions. Using whole-genome endosymbiont sequences of nine Cinara aphids that harbour an Erwinia-related symbiont to complement Buchnera, we show that the Erwinia association arose from a single event of symbiont lifestyle shift, from a free-living to an obligate intracellular one. This event resulted in drastic genome reduction, long-term genome stasis, and co-divergence with aphids. Fluorescence in situ hybridisation reveals that Erwinia inhabits its own bacteriocytes near Buchnera’s. Altogether these results depict a scenario for the establishment of Erwinia as an obligate symbiont that mirrors Buchnera’s. Additionally, we found that the Erwinia vitamin-biosynthetic genes not only compensate for Buchnera’s deficiencies, but also provide a new nutritional function; whose genes have been horizontally acquired from a Sodalis-related bacterium. A subset of these genes have been subsequently transferred to a new Hamiltonella co-obligate symbiont in one specific Cinara lineage. These results show that the establishment and dynamics of multi-partner endosymbioses can be mediated by lateral gene transfers between co-ocurring symbionts.

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Pertuzumab and trastuzumab emtansine in patients with HER2-amplified metastatic colorectal cancer: the phase II HERACLES-B trial

ESMO Open ◽

10.1136/esmoopen-2020-000911 ◽

2020 ◽

Vol 5 (5) ◽

pp. e000911

Author(s):

Andrea Sartore-Bianchi ◽

Sara Lonardi ◽

Cosimo Martino ◽

Elisabetta Fenocchio ◽

Federica Tosi ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Phase Ii ◽

Objective Response ◽

In Situ Hybridisation ◽

Progression Free Survival ◽

Trastuzumab Emtansine ◽

Registration Number ◽

Low Toxicity

BackgroundHER2 is a therapeutic target for metastatic colorectal cancer (mCRC), as demonstrated in the pivotal HERACLES-A (HER2 Amplification for Colo-rectaL cancer Enhanced Stratification) trial with trastuzumab and lapatinib. The aim of HERACLES-B trial is to assess the efficacy of the combination of pertuzumab and trastuzumab-emtansine (T-DM1) in this setting.MethodsHERACLES-B was a single-arm, phase II trial, in patients with histologically confirmed RAS/BRAF wild-type and HER2+ mCRC refractory to standard treatments. HER2 positivity was assessed by immunohistochemistry and in situ hybridisation according to HERACLES criteria. Patients were treated with pertuzumab (840 mg intravenous load followed by 420 mg intravenous every 3 weeks) and T-DM1 (3.6 mg/kg every 3 weeks) until disease progression or toxicity. Primary and secondary end points were objective response rate (ORR) and progression-free survival (PFS). With a Fleming/Hern design (H0=ORR 10%; α=0.05; power=0.85), 7/30 responses were required to demonstrate an ORR ≥30% (H1).ResultsThirty-one patients, 48% with ≥4 lines of previous therapies, were treated and evaluable. ORR was 9.7% (95% CI: 0 to 28) and stable disease (SD) 67.7% (95% CI: 50 to 85). OR/SD ≥4 months was associated with higher HER2 immunohistochemistry score (3+ vs 2+) (p = 0.03). Median PFS was 4.1 months (95% CI: 3.6 to 5.9). Drug-related grade (G) 3 adverse events were observed in two patients (thrombocytopaenia); G≤2 AE in 84% of cycles (n = 296), mainly nausea and fatigue.ConclusionsHERACLES-B trial did not reach its primary end point of ORR; however, based on high disease control, PFS similar to other anti-HER2 regimens, and low toxicity, pertuzumab in combination with T-DM1 can be considered for HER2+mCRC as a potential therapeutic resource.Trial registration number2012-002128-33 and NCT03225937.

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LGG-55. OUTCOME OF BRAF V600E PEDIATRIC GLIOMAS TREATED WITH TARGETED BRAF INHIBITION

Neuro-Oncology ◽

10.1093/neuonc/noaa222.433 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii377-iii377

Author(s):

Liana Nobre ◽

Michal Zapotocky ◽

Vijay Ramaswamy ◽

Scott Ryall ◽

Julie Bennet ◽

...

Keyword(s):

Objective Response ◽

Progression Free Survival ◽

Homozygous Deletion ◽

Braf V600e ◽

Low Grade ◽

Term Survival ◽

Braf Inhibition ◽

Outcome Information

Abstract Children with pediatric gliomas harboring BRAF V600E mutation have a poor outcome with current chemoradiation strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors. We collected clinical, imaging, molecular and outcome information from BRAF V600E glioma patients treated with BRAFi across 29 centers from multiple countries. Sixty-seven patients were treated with BRAFi (56 pediatric low grade gliomas, PLGG and 11 pediatric high grade gliomas, PHGG) for up to 5.6 years. Objective responses were observed in 80% of PLGGs compared to 28% with conventional chemotherapy (p<0.001). These responses were rapid (median, 4 months), and sustained in 86% of tumors up to 5 years while on therapy. PLGG which discontinued BRAFi, 76.5% (13/17) progressed rapidly after discontinuation (median 2.3 months). However, upon re-challenge with BRAFi therapy, 90% achieved an objective response. Poor prognostic factors to conventional therapies, such as concomitant homozygous deletion of CDKN2A, were not associated with a lack of response to BRAFi. In contrast, only 36% of PHGG responded to BRAFi with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95%CI, 35.3% to 69.5%) vs 29.8% (95% CI, 20% to 44.4%) for BRAFi vs chemotherapy respectively (p=0.02). The use of BRAFi results in robust and durable responses while on therapy in BRAF V600E PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAFi therapy in childhood gliomas.

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Rapid Multi-Hybridisation FISH Screening for Balanced Porcine Reciprocal Translocations Suggests a Much Higher Abnormality Rate Than Previously Appreciated

Cells ◽

10.3390/cells10020250 ◽

2021 ◽

Vol 10 (2) ◽

pp. 250

Author(s):

Rebecca E O’Connor ◽

Lucas G Kiazim ◽

Claudia C Rathje ◽

Rebecca L Jennings ◽

Darren K Griffin

Keyword(s):

Semen Analysis ◽

In Situ Hybridisation ◽

Economic Loss ◽

Environmental Damage ◽

Fluorescence In Situ Hybridisation ◽

Reciprocal Translocations ◽

Chromosome Translocations ◽

Farrowing Rate ◽

Significant Economic Loss

With demand rising, pigs are the world’s leading source of meat protein; however significant economic loss and environmental damage can be incurred if boars used for artificial insemination (AI) are hypoprolific (sub-fertile). Growing evidence suggests that semen analysis is an unreliable tool for diagnosing hypoprolificacy, with litter size and farrowing rate being more applicable. Once such data are available, however, any affected boar will have been in service for some time, with significant financial and environmental losses incurred. Reciprocal translocations (RTs) are the leading cause of porcine hypoprolificacy, reportedly present in 0.47% of AI boars. Traditional standard karyotyping, however, relies on animal specific expertise and does not detect more subtle (cryptic) translocations. Previously, we reported development of a multiple hybridisation fluorescence in situ hybridisation (FISH) strategy; here, we report on its use in 1641 AI boars. A total of 15 different RTs were identified in 69 boars, with four further animals XX/XY chimeric. Therefore, 4.5% had a chromosome abnormality (4.2% with an RT), a 0.88% incidence. Revisiting cases with both karyotype and FISH information, we reanalysed captured images, asking whether the translocation was detectable by karyotyping alone. The results suggest that chromosome translocations in boars may be significantly under-reported, thereby highlighting the need for pre-emptive screening by this method before a boar enters a breeding programme.

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Chromosome translocations detected by fluorescence in situ hybridisation (FISH)-a useful tool in population monitoring?

Toxicology Letters ◽

10.1016/s0378-4274(98)00068-x ◽

1998 ◽

Vol 96-97 (1-2) ◽

pp. 189-194 ◽

Cited By ~ 6

Author(s):

S Pressl

Keyword(s):

In Situ Hybridisation ◽

Population Monitoring ◽

Fluorescence In Situ Hybridisation ◽

Chromosome Translocations

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Monitoring HIV-1 treatment in immune-cell subsets with ultrasensitive fluorescence-in-situ hybridisation

The Lancet ◽

10.1016/s0140-6736(05)77222-6 ◽

1999 ◽

Vol 353 (9148) ◽

pp. 211-212 ◽

Cited By ~ 15

Author(s):

Bruce K Patterson ◽

Mary Ann Czerniewski ◽

John Pottage ◽

Michelle Agnoli ◽

Harold Kessler ◽

...

Keyword(s):

Immune Cell ◽

In Situ Hybridisation ◽

Fluorescence In Situ Hybridisation ◽

Immune Cell Subsets ◽

Hiv 1

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Alkylating agent rechallenge in metastatic pancreatic neuroendocrine tumours

Endocrine Related Cancer ◽

10.1530/erc-21-0034 ◽

2021 ◽

Author(s):

Ophelie De Rycke ◽

Thomas Walter ◽

Marine Perrier ◽

Olivia Hentic ◽

Catherine Lombard-Bohas ◽

...

Keyword(s):

Neuroendocrine Tumours ◽

Objective Response ◽

Multivariable Analysis ◽

Progression Free Survival ◽

Tumor Control ◽

Free Survival ◽

Mgmt Expression ◽

Pancreatic Neuroendocrine Tumours

A rechallenge is common after initial efficacy of alkylating-based chemotherapy (ALK) in pancreatic neuroendocrine tumors (PanNET). High MGMT expression seems associated with lower response to ALK. We aimed to evaluate the efficacy and toxicity of ALK rechallenge in PanNET. Secondly, to assess the evolution of MGMT expression under ALK. All consecutive patients with advanced PanNETs who received initial ALK (achieving tumor control) followed by a pause > 3 months, then an ALK rechallenge (ALK2) upon progression were retrospectively studied (Cohort A). Primary endpoint was progression-free survival under ALK2 (PFS2). The MGMT expression was retrospectively assessed by immunohistochemistry (H-score) in consecutive PanNET surgically resected following ALK (Cohort B). We foud that cohort A included 62 patients (median Ki67 8%), for which ALK1 followed by pause achieved an objective response rate of 55%, and a PFS1 of 23.7 months (95% IC, 19.8-27.6). ALK2 achieved no objective response, and stability in 62% of patients. The median PFS2 was 9.2 months (IC 95% 7.1-11.3). At multivariable analysis, a hormonal syndrome (p=0.032) and a pause longer than 12 months (p=0.041) were associated with a longer PFS2. In the cohort B (17 patients), the median MGMT H-score increased from 45 (IQR 18-105) before ALK, to 100 (IQR 56-180) after ALK (p=0.003). We conclude that after initial efficacy of ALK treatment, a pause followed by ALK rechallenge might be appropriate to prolong tumor control, improve quality of life and limit long-term adverse events. Increased MGMT expression under ALK might explain low efficacy of ALK rechallenge.

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