bluuebunny/crossref_metadata_2025 huggingface dataset:
Secondary resection in a general mCRC population with cetuximab-based first-line treatment: Interim analysis of the German noninterventional study ERBITAG.
Authors: Neumann Ulf P , Goehler Thomas , Reich Gernot , Schwerdtfeger Michael , Stuebs Patrick , Stenzel Karsten G , Overkamp Friedrich
Published: March 2020

e14532

Background: Resection of liver and/or lung metastases (LM) are a potentially curative option for patients with mCRC. Cetuximab in combination with irinotecan- or oxaliplatin-based chemotherapy has shown to increase the resection rate of primarily unresectable LM in mCRC patients. After approval of cetuximab in Germany for first-line treatment of pts with unresectable mCRC, this noninterventional study was initiated to evaluate safety and efficacy of cetuximab in combination with various first-line chemotherapy regimens in patients with unresectable mCRC. Methods: We conducted an interim analysis of the first 124 fully documented pts to evaluate the response rate (RR) and resection rate of LM. Enrolment was restricted to pts with mCRC with proven KRAS wildtype mutation status without prior systemic treatment in the metastatic stage. Predefined endpoints were amongst others RR, LM resection rate, TTF, PFS, OS, and safety. Results: From May 2010 to May 2012 360 eligible pts were enrolled at 109 sites (75% office-based physicians), documentation for 124 was finalised (data cut-off for this analysis 03 May 2012) and evaluated. The median age was 68 [range 34-84] years, ECOG performance status was 0, 1, 2 in 29%, 60%, and 9% of pts, respectively, in 2% of pts ECOG performance status was missing. Resection rate was 18.5% (n=23) performed at 18 sites with 16.9% R0 resections (n=21). 42% of pts (n=52) had liver-limited disease (LLD). Resection rate in pts with LLD was 34.6% (n=18) with a 30.6% R0-resection rate (n=16). Median treatment duration from start of cetuximab-based therapy to resection of LM was 3.7 months [0.7-12.0]. Objective response rate was 46.8% (CR 4.8%, PR 41.9%) and 59.6% (CR 5.8%, PR 53.8%) for pts with LLD. Conclusions: In a clinical practice setting cetuximab-based first-line treatment of an unselected population with KRAS wildtype mCRC resulted in an R0-resection rate of 16.9% overall, and 30.6% for LLD pts. These data compare fairly well with data from clinical trials: CRYSTAL, OPUS, and CELIM.
Multimodality treatment combining chemotherapy, liver surgery, peritoneal resection and hyperthermic intraperitoneal chemotherapy (HIPEC) for metastatic colorectal cancer (mCRC) patients with synchronous liver metastases (LM) and peritoneal carcinomatosis (PC): A multicenter study of the French Association of Surgery.
Authors: Lo Dico Rea , Passot Guillaume , Elias Dominique , Lorimier Gerard , Quenet Francois , Pocard Marc
Published: March 2020

e14534

Background: Pts with synchronous PC and LM are generally considered for exclusive systemic palliative chemotherapy only. Aggressive surgical approaches combining hepatectomy associated to peritoneal resection with curative intent remain controversial in such a setting and almost no data are available on such patients.The aim of this prospective cohort was to assess morbidity, mortality, disease-free survival (DFS) and overall survival (OS) of peritoneal and liver mCRC patients (pts) treated with an aggressive therapeutic approach combining surgical treatment of liver and peritoneal lesions followed by HIPEC. Methods: All patients registered in the French Association of Surgeryprospective database with PC and synchronous LM who had undergone cytoreductive surgery and LM resection followed by intraperitoneal chemotherapy were analysed. The primary endpoint was survival from the time of surgery. The following criteria were recorded and analyzed: sex, age, differentiation and localization of the primary tumor, lymph node involvement (pN+), peritoneal cancer index (PCI), completeness of cytoreduction of peritoneal carcinomatosis, number of associated liver metastases. Results: From 1993 to 2011, 101 pts with PC and LM were analyzed. After a mean follow-up of 25 months, the median OS and DFS, were respectively 24.9 and 9.5 months. Post-operative morbidity and mortality was 14.8 and 0%, respectively. In pts with a complete cytoreductive surgery OS was 29 months (n=), as compared to 4 months in pts (n=) with incomplete cytoreduction (p=0.0001). Rectal primary tumor, PCI of 13 or more, pN+ status, and more than 3 LM were not identified as independent factors for poor OS. Conclusions: This multicenter study confirms that prolonged survival can be achieved in selected patients suitable for PC and LM surgery if they underwent multimodality treatment including surgical treatment of PC and LM with curative intent, using intraperitoneal chemotherapy.
Connecting gene expression subtypes of colorectal cancer (CRC) with cell lines and drug resistance.
Authors: Budinska Eva , Wilding Jenny , Popovici Vlad Calin , Missiaglia Edoardo , Roth Arnaud , Bosman Fred , Delorenzi Mauro , Bodmer Walter , Tejpar Sabine
Published: March 2020

e14544

Background: We identified CRC gene expression subtypes (ASCO 2012, #3511), which associate with established parameters of outcome as well as relevant biological motifs. We now substantiate their biological and potentially clinical significance by linking them with cell line data and drug sensitivity, primarily attempting to identify models for the poor prognosis subtypes Mesenchymal and CIMP-H like (characterized by EMT/stroma and immune-associated gene modules, respectively). Methods: We analyzed gene expression profiles of 35 publicly available cell lines with sensitivity data for 82 drug compounds, and our 94 cell lines with data on sensitivity for 7 compounds and colony morphology. As in vitro, stromal and immune-associated genes loose their relevance, we trained a new classifier based on genes expressed in both systems, which identifies the subtypes in both tissue and cell cultures. Cell line subtypes were validated by comparing their enrichment for molecular markers with that of our CRC subtypes. Drug sensitivity was assessed by linking original subtypes with 92 drug response signatures (MsigDB) via gene set enrichment analysis, and by screening drug sensitivity of cell line panels against our subtypes (Kruskal-Wallis test). Results: Of the cell lines 70% could be assigned to a subtype with a probability as high as 0.95. The cell line subtypes were significantly associated with their KRAS, BRAF and MSI status and corresponded to our CRC subtypes. Interestingly, the cell lines which in matrigel created a network of undifferentiated cells were assigned to the Mesenchymal subtype. Drug response studies revealed potential sensitivity of subtypes to multiple compounds, in addition to what could be predicted based on their mutational profile (e.g. sensitivity of the CIMP-H subtype to Dasatinib, p<0.01). Conclusions: Our data support the biological and potentially clinical significance of the CRC subtypes in their association with cell line models, including results of drug sensitivity analysis. Our subtypes might not only have prognostic value but might also be predictive for response to drugs. Subtyping cell lines further substantiates their significance as relevant model for functional studies.
Safety and efficacy of 90y resin microspheres in elderly (≥70 years) compared to younger patients with colorectal liver metastases (mCRC).
Authors: Kennedy Andrew S. , Ball David , Cohen Steven J. , Cohn Michael , Coldwell Douglas M. , Drooz Alain , Ehrenwald Edward , Kanani Samir , Moeslein Fred M , Nutting Charles W. , Putnam Samuel G. , Rose Steven C. , Savin Michael , Schirm Sabine , Sharma Navesh K , Wang Eric
Published: March 2020

e14545

Background: The effects of advanced age on the clinical outcomes following 90Y treatment in elderly patients with mCRC are relatively unknown. Methods: A retrospective review was conducted to evaluate clinical outcomes among 160 elderly (≥70 years) and 446 younger (<70 years) patients with unresectable mCRC consecutively treated using 90Y resin microspheres (SIR-Spheres; Sirtex) from July 2002 to December 2011 at 11 US institutions. Data on background characteristics, prior chemotherapy or other procedures, 90Y therapy, subsequent adverse events and survival were documented. Results: The mean age (+ SD) of the elderly patients was 77.2 + 4.85 years and 55.9 + 9.45 years in the younger cohort. Regardless of age, patients receiving 90Y treatment were very similar in the elderly and younger cohorts in terms of sex, race, ECOG performance status and other characteristics. However, elderly patients were more likely to have had their primary resected (7.1% vs. 15.1%; p=0.009), received fewer lines of chemotherapy (p=0.036; 13.1% vs. 2.8% had no prior chemo, p<0.001), a longer period between diagnosis and 90Y therapy (median 26.9 vs. 20.5 months; p=0.011), and received only one 90Y treatment (58.8% vs. 46.4%; p=0.007). Overall survival following 90Y therapy did not deteriorate in elderly patients (median 9.3 vs. 9.7 months; p=0.335). 90Y treatment was equally well tolerated in both cohorts, with no significant increase in grade 3+ adverse events in elderly patients, but significantly fewer grade 1+ events for abdominal pain (26.3% vs. 41.3%; p<0.001) and nausea (20.6% vs. 29.4%; p=0.038). The most common grade 3+ events included: abdominal pain (3.1% vs. 6.1%), GI ulceration 0.6% vs. 1.3%), nausea (0.6% vs. 1.3%), vomiting (1.3% vs. 1.3%), fatigue (5.6% vs. 4.5%), ascites (1.3% vs. 2.0%), hyperbilirubinemia (3.8% vs. 2.7%) and anorexia (0.6% vs. 0.9%). Analysis of the 98 patients ≥75 years compared to younger patients confirmed equivalent outcomes for survival and toxicity. Conclusions: For patients with unresectable mCRC liver metastases that meet eligibility criteria, 90Y therapy appears to be as effective and well-tolerated for the elderly as it is for younger candidates.
Severe falls among older adults with resected stage II/III colon cancer receiving chemotherapy.
Authors: LoConte Noelle K. , Allen Glenn , Leal Ticiana A.B. , Weiss Jennifer , Neuman Heather B. , Greenblatt David Y , Schmacher Jessica , Gayle Arlene Angela , O'Connor Erin S , Smith Maureen
Published: March 2020

e14550

Background: Falls have significant implications for morbidity and mortality. The etiology of falls in elders includes cognitive change, polypharmacy, dizziness and anemia, all of which can be exacerbated by chemotherapy (chemo). We sought to determine the relation between chemotherapy receipt and falls resulting in injury and/or death among elders with colon cancer. Methods: Medicare beneficiaries >64 years with resected stage II or III colon cancer diagnosed from 1992-2005 were identified from the Surveillance, Epidemiology, and End Results-Medicare database. Falls within one year of surgery that resulted in hospitalization or ER visit were defined by E-codes. χ2 and 2-way ANOVA assessed differences in falls resulting or not resulting in death. Multivariable multinomial logistic regression models predicted a four-level falling/mortality variable (not falling (death), falling (death), not falling (no death), and falling (no death)) for patients receiving or not receiving chemo. Models controlled for patient demographics and tumor characteristics. We further controlled for use of mobility device, surgical complications, falls, hospitalizations and ER visits in the year before surgery, comorbidity risk score, frailty including dementia, and Medicaid status. Adjusted predicted probabilities and 95% CIs were calculated to assess the probability of each of the four outcome categories by receipt of chemotherapy. Results: Among 36,781 elders, falling was not increased among those who received adjuvant chemo. 14% of the total population fell during the year following surgery. The receipt of chemotherapy was not associated with increased rates of falls. Conclusions: Falling is not increased with the use of adjuvant chemo for stage II and III colon cancer among adults aged 65 years and above. The results suggest that oncologists may choose patients at least risk for functional decline when deciding upon chemo. [Table: see text]
Association between angiotensin-converting enzyme I gene I/d polymorphism and bevacizumab activity in advanced colorectal neoplasm.
Authors: E Aranda , de la Haba-Rodriguez Juan , A Martinez , Gomez M.Auxiliadora , G Pulido , R Serrano , B Rodriguez , R Rodriguez , P Cantizani , Antonio Rodriguez
Published: March 2020

e14559

Background: Previous studies have found relation between the secondary hypertension to bevacizumab treatment and response in colorectal cancer. Some authors have suggested a critical role of the angiotensin converting enzyme (ACE) in blood pressure regulation. Furthermore, up-regulation of ACE gene expression has been observed in patients with hypertension. Over the past decade, the insertion/deletion (I/D) polymorphism of a 287-bp Alu element in intron 16 of the ACE gene has been extensively investigated and a positive association between the DD genotype and an increased risk of in hypertension has been demonstrated. We have studied the association between the ACE I/D polymorphism and the response and time to progression to bevacizumab treatment in advanced colorectal cancer. Methods: Sixty-four patients treated with the combination of fluoropirimidins oxaliplatin and bevacizumab were included in this study. The median of time to progression was 37 weeks(CI95%:9528.7-45.23) with a global rate response of 73.4%(CR:9.4%, PR:35.9%, SD:28.1%). Genomic DNA is purified from peripheral blood using the MagNaPure LC DNA isolation kit I. The ACE insertion / deletion (I / D) polymorphisms (rs1799752) was analyzed by real time PCR. We will perform SNP genotyping with SimpleProbe probes in a LightCycler 480 Real-Time PCR System (Roche Applied Science), in a 96 multiwell-plated format. We analyzed the serum levels of ECA and VEGF-A by ELISA. Results: We found a higher rate global response in the genotype D/D (In/In:57.2%, In/Del: 93.1% and Del/Del: 100%) X2:16.887 p:0.031. The worst time to progression was observed in the genotype In/In.(In/In:14w, In/Del:37w and Del/Del: 36w) p:n.s. There was a significant correlation between the ACE and VEGF-A serum levels (Pearson test:0.201, p:0.03). Conclusions: There is an association between angiotensin-converting enzyme I gene I/D polymorphism and the activity of bevacizumab plus chemotherapy in advanced colorectal neoplasm. These results strongly support the hypothesis for a relationship between response to antiangiogenic therapy and hypertension.
Safety and efficacy of the addition of simvastatin to cetuximab in KRAS mutant metastatic colorectal cancer patients.
Authors: Baas Jara M , Krens Lisanne , Ten Tije Albert J. , Erdkamp Frans , Guchelaar Henk-jan , Gelderblom Hans
Published: March 2020

e14586

Background: Epithelial growth factor receptor (EGFR) inhibitors are not effective in KRAS mutant colorectal tumors. In these tumors the k-ras protein is activated by post-translational modification by binding farnesyl (C15) and geranylgeranyl (C17) moieties. Both are products of the mevalonate pathway, as is cholesterol. Statins (HMG-CoA-reductase inhibitors) not only inhibit synthesis of cholesterol, but also of C15 and C17 and thus may reduce post-translational activation of ras proteins. Therefore, statins may inhibit the expression of the mutant KRAS phenotype and normalize the phenotype into KRAS wild type. In a phase II study we investigated whether simvastatin treatment renders KRAS mutant colorectal tumors sensitive to cetuximab. Methods: Major eligibility criteria were metastatic colorectal cancer failing 5-FU, oxaliplatin and irinotecan containing regimens, with a mutation in codon 12, 13 or 61 of KRAS gene in a tumor sample. Patients were treated with simvastatin 80mg once daily and cetuximab 250mg/m2 weekly (after a starting dose of 400mg/m2). Primary objective was to investigate the percentage of patients free from progression and alive 12.5 weeks after the first administration of cetuximab, similar to the results of the KRAS wild type population of the phase III study. This phase II study was performed in a Simon two stage design, performing an interim analysis after enrolment of 15 patients. If at least 6 of these patients (i.e. 40%) were to be alive and free from progression at 12.5 weeks after the start of cetuximab, another 31 patients would be included during stage II. Results: Fifteen evaluable patients were enrolled at 3 study sites. Four patients (i.e. 27%) were free from progression at time of the primary endpoint. Three patients experienced serious adverse events; an allergic reaction during cetuximab infusion, rhabdomyolysis and intracranial haemorrhage due to cerebral metastases. Conclusions: Though 4 patients experienced stable disease at 12.5 weeks, the predefined efficacy boundary was not met in order to continue enrolment to stage II. Simvastatin 80mg once daily does not induce sensitivity to cetuximab in colorectal cancer patients with a mutation in the KRAS gene. Clinical trial information: NCT01190462.
TGFBR1 SNP’s are a genetic marker potentially useful for colorectal cancer screening.
Authors: Pauly Marc , Mahon Garry , Metzger Brigitte , Menzel Alain , Weber Ben , Dicato Mario-A
Published: March 2020

e14591

Background: Colonoscopy (CS) used for colorectal cancer (CRC) screening is relatively expensive and intrusive. We have shown that CRC in Caucasian patients have a high frequency of certain TGFBR1 SNP’s relative to normal controls. Here we extend the results to these SNP frequencies in normal tissue of the patients and the concordance of three different SNP’s in the TGFBR1 gene across patients and subjects. Methods: Tumor samples were obtained from 188 CRC patients and from 98 healthy control. After gDNA extraction, selected amplicons were amplified by PCR, followed by melting curve analysis. The statistical evaluation of the genotype frequency for the different SNPs comparing CRC patients with controls was carried out using logistic regression. Results: Results previously reported were confirmed:- a highly significant association between TGFBR1 SNP genotype and colorectal cancer (P<0.000001). For example, with the TGFBR1 SNP rs334348, the frequency of the GG genotype was 43% for patients but 11% for controls, while the AA frequency was only 18% for patients and 43% for controls. All CRC patients and controls were typed for three SNP's in the TGFBR1 gene and the concordance was found to be perfect. That is, only 3 of the 27 possible genotypes were observed:- (i) rs334348, AA; rs334349, AA; rs1591, CC; (ii) rs334348, AG; rs334349, AC; rs1591, CT; and (iii) rs334348, GG; rs334349, CC; rs1591, TT. Blood and tumor samples from patients had the same identical SNP pattern. Conclusions: The perfect concordance of the three SNP types in tumors and leukocytes shows that it reflects the underlying genotype of the patient rather than a somatic mutation in the tumour. Thus SNP type is a characteristic of subjects and a potential genetic marker for CRC susceptibility. We suggest that subjects aged 50 years or older be offered a test for a TGFBR1 variant. In case of a positive result, subjects should be informed that they are at risk of CRC, and strongly encouraged to have a colonoscopy. For this suggestion to become a definitive recommendation a cost-effectiveness analysis of the use of TGFBR1 SNP typing would be useful ( although such typing is inexpensive) and a prospective study of colonoscopy with TGFBR1 typing is mandatory.
Oxaliplatin given by hepatic arterial infusion (HAI) or systemic (SYS) with capecitabine in patients (pts) with unresectable liverlimited metastasis (Ur-LLM) from colorectal cancer (CRC).
Authors: Jensen Benny Vittrup , Noergaard Henrik , Bergenfeldt Magnus , Larsen Ole , Hoegdall Estrid Vilma Solyom , Johansen Jakob , Hermann Kirstine , Nielsen Dorte
Published: March 2020

e14593

Background: Whether therapy of Ur-LLM from CRC by HAI is superior to SYS is unknown. Methods: First line phase II study of pts. with Ur-LLM from CRC. Included were 88 pts. HAI oxaliplatin (100 mg/m2) was given to 66 pts. every 2nd week (wk) for a median of 11 series (1-12) and capecitabine 3500 mg/m2 day 1-7 every 2nd wk for a median of 12 (2-14) series. Vessel variation made HAI unsuitable for 22 pts. They had systemic oxaliplatin (130 mg/m2) for a median of 8 (1-10) series with capecitabine 2000 mg/m2 day 1-14 every 3rd wk for a median of 8 series (1-45) with bevacizumab 7½ mg/kg day 1 in 14 pts. Primary endpoints were response, secondary median overall and therapy free survival (mOS) and toxicity. KRAS mutation status was determined in all pts. with the DxS kit. Survival was evaluated by the Kaplan Meier method and differences with the log rank test. 95% confidence interval are given in brackets. Results: Pts. treated with HAI and SYS were comparable. HAI yielded higher response rates than SYS (table 1). Pts. with KRAS-WT tumors treated with HAI had a mOS of 61 (43-80) mths, with KRAS-MT tumors 28 (21-35) mths (p< 0.0001). SYS in KRAS-WT and MT types yielded equal mOS 36 (27-45) mths and 27 (12-44) mths. Pts. with KRAS-WT tumors treated with HAI lived longer than when treated with SYS (p=0.05). Pts. with HAI with KRAS-WT tumors lived without any kind of therapy for a median of 27 (16-37) mths with 42% living more than 40 mths. with KRAS-MT tumors 8 (3-13) mths (p<0.0001) with 12% living more than 40 mths. Therapy free mOS with SYS in patients with KRAS-WT and KRAS-MT tumors was19 (0-39) mths.for pts. and 12 (4-20) mths respectively with 17% and 22% living more than 2 years.The findings were independent of cetuximab-based therapy in later lines. The toxicity was comparable. Conclusions: Effect of HAI oxaliplatin combined with capecitabine on response and survival is restricted to pts. with KRAS-WT tumors. [Table: see text]
Expression of serpin B5 in colorectal cancer: Its relationship with CEA expression.
Authors: Baek Ji Yeon , Kim Sun Young , Chang Hee Jin , Park Ji Won , Choi Hyo Seong , Kim Dae Yong , Oh Jae Hwan , Yeo Hyun Yang , Kim Kyunghee
Published: March 2020

e14606

Background: Serpin B5 is a candidate tumor suppressor but its oncogenic activity has been also reported. Its function may be affected by interacting proteins. The aim of this study was to assess the relationship between serpin B5 and carcinoembryonic antigen (CEA) expressions in CRC. We also analyzed the clinicopathological significance of serpin B5 expression in colorectal cancer (CRC) patients. Methods: Two-dimensional gel electrophoresis (2-DE) analysis and matrix-associated laser desorption ionization mass spectrometry (MALDI-MS) were used to identify differentially expressing proteins according to CEA suppression. Serpin B5 and CEA expressions were evaluated by western blot and ELISA assays. Immunohistochemical expression of serpin B5 was assessed retrospectively in tissues from 377 CRC patients, and correlations between serpin B5 and clinicopathological parameters were analyzed. Results: Downregulation of serpin B5 was identified in CEA-suppressed LoVo cell line using 2-DE and MALDI-MS analyses, and further significant positive correlations between serpin B5 and CEA levels were also found in human CRC cell lines and in blood of CRC patients. Tissue expression of serpin B5 in CRC was significantly associated with serum CEA, histologic grade, stage, lymph node metastasis, liver metastasis, lymphatic and perineural invasion, and infiltrative border. High expression of serpin B5 was also associated with a reduced DFS (P = 0.001) and OS (P = 0.017). Conclusions: This is the first study describing relationship between serpin B5 and CEA expression in CRC. High expression of serpin B5 was also associated with worse prognosis in patients with CRC, and its expression may correlate with CEA levels in CRC.
hSRBC promoter CpG island hypermethylation as resistant predictive biomarker of oxaliplatin based chemotherapy in metastasic colorectal cancer patients.
Authors: Moutinho Catia , Martinez-Cardus Anna , Santos Cristina , Navarro-Perez Valentín , Martinez-Balibrea Eva , Abad Esteve Albert , Salazar Ramon , Esteller Manel
Published: March 2020

e14609

Background: Resistance acquisition to chemotherapeutic agents is one of the main problems that come up during cancer treatment. hSRBC is a tumor suppressor gene whose inactivation has been associated with malignant tumor progression. In a previous work, we investigated the influence of hSRBC promoter methylation alterations in oxaliplatin (OXA) resistance acquisition by using a CRC “in vitro” model, detecting an hSRBC promoter hypermethylation in OXA–resistant derived cells when compared with the sensitive counterpart. These results were validated by functional analyses in the same model. Taking this into account, our aim in the present work is to determine the role of hSRBC methylation status as a potential biomarker of OXA resistance, in metastatic CRC patients, treated at first line with fluouropirimidines plus OXA based chemotherapy. Methods: hSRBC promoter hypermethylation was analyzed in DNA extracted from paraffin embebbed tissue of 111 metastatic CRC tumors by using Methylation Specific PCR. Methylation data was correlated to overall response (OR) and progression free survival (PFS) by using F-Fisher test and Kaplan-Meyer Survival curves respectively. A multivariate analysis was carried out by Cox regression. p-values under 0.05 were considered statistic significant. Results: Two independent cohorts of stage IV CRC tumors were included. Twenty-two out of 111 patients received radical surgery for metastasis, that became to be a positive prognostic factor (p-value = 0.04). Gene hypermethylation was detected in a 33% of cases. Although OR was not associated with hSRBC methylation, we observed a significant correlation between hypermethylation of gene and a worse PFS in patients without metastasis surgery (Log Rank; p-value = 0.04). Conclusions: Remarkably, hSRBC promoter hypermethylation is associated with worse PFS in metastatic CRC patients. We suggest hSRBC methylation status as a predictive biomarker of OXA-based treatment outcome in metastatic CRC patients. However, further studies are warranted in order to elucidate the clinical application of these findings.
Multiplatform assessment of anaplastic lymphoma kinase (ALK) gene rearrangement in signet ring cell carcinoma of the gastrointestinal tract.
Authors: Alese Olatunji Boladale , El-Rayes Bassel F. , Sica Gabriel , Zhang Guojing , Rossi Michael R. , Adsay Volkan , Alexis Dianne , La Rosa Francisco G. , Varella-Garcia Marileila , Chen Zhengjia , Kauh John S. , Ramalingam Suresh S. , Khuri Fadlo Raja , Owonikoko Taofeek Kunle
Published: March 2020

e14612

Background: ALK-EML4 translocation is an established driver aberration in NSCLC, with reported predilection for cases with signet ring histology. We assessed the presence of ALK gene rearrangements in signet ring cancers arising in the stomach and colon. Methods: Histologically confirmed cases of signet ring adenocarcinoma of the stomach or the colon were identified from the pathology archive of Emory University Hospital. Presence of the classic ALK and EML4 fusion gene was initially determined by fluorescence in-situ hybridization (FISH) method. Cases showing break-apart signal in more than 15% of enumerated cells were considered positive; at least 10% of enumerated cells was considered “possibly positive”. Immunohistochemistry of the fused gene product was assessed using previously validated antibodies ALK1 clone (1:100; DAKO) and 5A4 (Novocastra, Leica Biosystems) and positive controls of ALK-translocated lung cancer. Positive or possibly positive cases by FISH were further analyzed by RT-PCR using specific primers for the most common translocation pairs (EML4 Ex13/ALK Ex20 and EML4 Ex6/ALK Ex20) along with positive (H228, HEK293) and negative (H460, H1975) control cell lines. Results: We retrieved 44 cases of signet ring carcinoma diagnosed between 2001 and 2011; 26 gastric and 18 colon cancer. Median age - 63 yrs; M/F 17/27; Black - 47.5%; White - 47.5%; Others - 5%; Stage I - 21.4%; II - 31%; III - 26.2; IV - 21.4%. One of 44 cases (2.3%) was positive for ALK translocation by FISH using the standard criteria of at least 15% positive cells for the break-apart signal (50-70 cells counted per case). 7 cases (16%) were considered possibly positive [1 of 18 (6%) colon cancer and 6 of 26 (26%) gastric cancer cases]. IHC showed 0 of 44 (0%) cases positive. Molecular analysis using RT-PCR did not confirm the suspected ALK gene rearrangements in any of the 7 cases considered possibly positive by FISH. Conclusions: The overall frequency of ALK gene rearrangement detected by FISH in signet ring cancer of the GI tract was low, but appears comparable to the reported frequency in lung cancer. Signet ring histology failed to enrich for cases with ALK gene translocation in this histologic subtype.
Novel data processing and image co-registration algorithm for region-specific lipid profiling in colorectal cancer tissue using DESI imaging mass spectrometry.
Authors: Mirnezami Reza , Veselkov Kirill , Strittmatter Nicole , Kinross James M , Goldin Robert D , Speller Abigail , Jones Emrys A , Holmes Elaine , Abramov Tigran , Nicholson Jeremy K , Darzi Ara W , Takats Zoltan
Published: March 2020

e14620

Background: Imaging mass spectrometry (iMS) is a promising technique for cancer biomarker discovery. Clinical translation of iMS requires advanced data treatment methods and efficient co-registration of histology and iMS imaging modalities. In this study desorption electrospray ionisation (DESI) iMS has been used to address four aims: 1. To develop a data processing workflow to address current limitations; 2. To design an interactive software platform for image co-registration; 3. To investigate region-specific lipid biochemistry in colorectal cancer (CRC) tissue using the strategy outlined in aims 1-2; 4.To introduce an automated tissue recognition system based on multivariate molecular ion patterns (MIPs). Methods: Fresh CRC tissue sections (n=49) were subjected to DESI-iMS using a Thermo Exactive mass spectrometer coupled with a DESI ion source. Mass spectra were collected in the range m/z = 200-1000. Sections were then H&E stained and scanned at high resolution. DESI-iMS data pre-processing involved peak detection, removal of noise/solvent related peaks and variance stabilising normalisation. An interactive image co-registration interface was developed using a feature-based image alignment algorithm for precise exploration of tissue region-specific biochemistry. A Recursive Maximum Margin Criterion (RMMC) algorithm was introduced for improved extraction of tissue specific MIPs. Results: CRC DESI-iMS profiles consisted mainly of complex lipids including phosphatidyl-inositols, phosphatidyl-serines, and phosphatidyl-ethanolamine plasmalogens. Different histological tissue regions showed characteristic lipid profiles. An automated tissue recognition system using multivariate MIPs derived by the proposed RMMC approach demonstrated highly accurate (classification accuracy >98%) identification of pixels according to tissue type (cancer, healthy mucosa, smooth muscle, fibrous tissue, stroma). Conclusions: This workflow permits accurate tissue-specific lipidomic characterisation of the CRC tumor microenvironment and permits accurate reconstruction of different tissue types based on MIPs.
Global clinical experience with adjuvant oxaliplatin/5-fluorouracil (5-FU)-based chemotherapy for colon cancer: Outcomes of the ACCElox registry.
Authors: Park Young Suk , Ji Jiafu , Zalcberg John Raymond , Elserafy Mostafa M. , Buzaid Antonio C.
Published: March 2020

e14624

Background: The ACCElox registry assessed the therapeutic management of early stage colon cancer with oxaliplatin/5-FU-based regimen and duration of adjuvant chemotherapy in current clinical practice. Methods: Newly diagnosed patients (N=1,548) with stage II or III colon cancer, who had undergone complete resection of the primary tumor and treated with at least one dose of "oxaliplatin" were enrolled in this prospective observational study (Feb-2006–Jul-2008) and followed up till 36 months post-treatment. Results: 72.7% and 27.3% of the patients were diagnosed with stage III and stage II colon cancer, respectively. 1,152 (74.4%) patients completed the prescribed chemotherapy. The most frequent causes of discontinuation were refusal (9.0%), adverse events (AEs) (8.1%) or relapse/recurrence of disease (3.6%). Overall, 1,512 (97.6%) patients received at least one cycle of oxaliplatin regimen. Treatment delay occurred in 1,013 patients (67%), mainly attributed to AEs (40.9%) and personal inconvenience (35.5%). During the 3-year follow-up period disease relapse/recurrence occurred in 285 (18.4%) patients with similar rates in the three groups (FOLFOX: 18.1%, FLOX: 19%, and XELOX: 18.6%). Overall number of deaths reported at the end of 3- year study period was 72 (4.7%). Majority of AEs reported during treatment were of grade 1–2 and the most common ones were neutropenia (63.9%), thrombocytopenia (23.3%), diarrhea (9.7%), sensory neuropathy (4.5%) and infection (2.6%). Sensory neuropathy was the most frequent AEs reported at 6 and 12 months of post-treatment follow-up. Conclusions: A majority of the patients completed the prescribed oxaliplatin/5-FU regimen. No unexpected AEs were reported. Our results confirm the favorable benefit/risk profile of oxaliplatin/5-FU based regimens in clinical practice. [caption]Distribution and treatment outcomes.[caption] Clinical trial information: NCT01310972. [Table: see text]
Comorbidity and other predictors of survival in veterans with colorectal cancer (CRC) at different stages.
Authors: Zhong Fengming , Tang Ying Margie , Chang Victor Tsu-Shih , Patel Neal , Okoronkwo Nneoma Olivia , Gonzalez Melanie L. , Wang Trent P , Barnes Tanganyika , Paz-Querubin Emma R , Kasimis Basil
Published: March 2020

e14625

Background: We analyzed comorbidity and other predictors of survival for patients (pts) with different stages of CRC. Methods: In an IRB-approved protocol, we reviewed the records of pts diagnosed with CRC at a VA medical center from 01/01/2003 to 12/31/2011 for demographics, stage, grade, ECOG performance status (PS), CEA, Hemoglobin (HGB), and Albumin (ALB) at diagnosis (dx). Comorbidity was assessed with the Charlson Comorbidity Index (CCI), the Cumulative Illness Rating Scales (CIRS), and the Kaplan-Feinstein Index (KFI). Statistical analyses were performed with SAS 9.2/Stata 11.0. We compared the pts with curative stage (0-III) vs late stage (IV) CRC. Results: There were 279 men. 156 pts (55.9%) were Caucasians, 106 pts (38%) African Americans, 15 pts (5.4%) Hispanics, and 2 pts (0.7%) Asians. The median (M) age at dx was 70 (45-90) years. 132 pts (47.3%) were deceased. 209 pts were curative stage at dx, 54 pts late stage and 16 pts unknown stage. Age and race were not different between the two stage groups. The late group had higher histological grades (P<0.001). In univariate analysis, age, stage, grade, ECOG PS, HGB, ALB, CCI, CIRS16, CIRS 17, CIRS 19, and KFI are significant predictors of survival for all stage pts. Significant predictors for curative stage pts are age, ECOG PS, HGB, CCI, CIRS16, CIRS17, and CIRS 18, and for late stage pts are grade, ECOG PS, ALB, and CCI. Significant factors by multivariate analysis are summarized in the table. Conclusions: These findings from this larger population confirm our earlier findings (ASCO 2012 e14125). Grade, stage, ECOG PS, and CIRS 19 (very severe comorbidity) are important independent survival predictors for veterans with CRC. Independent predictors for curative stage pts are ECOG PS and CIRS 16 (comorbidity severity summary score), and for late stage pts are ALB, CCI and CIRS 19. The late stage pts had higher grades. Further studies are needed to confirm this observation. Supported by NJCCR. [Table: see text]
Preoperative chemoradiotherapy (QT-RT) with capecitabine and oxaliplatin (CAPOX) in patients with locally advanced rectal cancer.
Authors: Sancho Aintzane , Marrodan Ines , Calvo Begoña , Muñoz Alberto , Mane Joan Manel , Carrera Sergio , Fuente Natalia , Azkona Eider , Arruti Mikel , Gutierrez Eddy Isabel , Ugalde Irene , Lopez-Vivanco Guillermo
Published: March 2020

e14628

Background: Locally advanced rectal carcinoma is associated with high rate of abdomino-perineal amputation. We analyzed a cohort of patients (pts) diagnosed of locally advanced rectal cancer, treated with neoadjuvant QT-RT with CAPOX followed by four cycles of adjuvant CAPOX after surgery. Methods: Pts with locally advanced rectal cancer (T3-T4 and/or N+) were treated with oxaliplatin (50mg/m2 day 1, 8, 22 and 29) and capecitabine (1650mg/m2 on days 1 to 14 and 22 to 35) combined with pelvic radiotherapy (180cGy/day; 45Gy in 25 fractions). Surgery was scheduled 4 to 6 weeks after completion QT-RT. Four cycles of adjuvant XELOX were administered (capecitabine 2000mg/m2 on days 1 to 14) and oxaliplatin (130mg/m2 day 1) every 3 weeks. The main end points assessed were: rate of sphincter preservation, pathological complete response (pCR) rate, toxicity and feasibility of postoperative chemotherapy. Local staging was done with pelvic MRI and/or EUS. Results: From Sept 2005 to Nov 2012, 201 pts with locally advanced rectal cancer were included. Pts characteristics: M/F 135/66; ECOG 0/1/2: 48/149/4; median age 65 (28-81); upper/mid/distal rectum 29/105/67; stage cT3/N- 21, cT2-T3/N+ 140, cT4/N- 6, cT4/N+ 34. Full dose preoperative QT-RT was administered in 192 (95%). The main toxicities were diarrhea grade 2/3: 42/24 and neurotoxicity grade 1/2: 94/7. After treatment 198 pts underwent surgery. Sphincter preservation and R0 resections were achieved in 125 and 184 respectively. pCR was achieved in 35 pts (17.4%). 145 pts (72%) received all 4 cycles of adjuvant XELOX. Grade 3/4 toxicities included vomiting 3/0, diarrhea 7/0, skin-foot syndrome 2/0, mucositis 1/0, neurotoxicity 6/0, neutropenia 10/1 and thromopenia 6/1. Downstaging in T/N was achieved in 108/144 pts (53.7/71.6%) respectively. 3-year progression-free and overall survival were 75% and 83% respectively. No toxic deaths were reported. Conclusions: Combination QT-RT based in capecitabine and oxaliplatin is a well tolerated regimen and achieved encouring rates of pCR, R0 resection, sphincter preservation and tumor downstaging in patients with locally advanced rectal cancer.
Improving QOL and safety while reducing costs: Evidence-based adjuvant chemotherapy of colorectal cancer (CRC).
Authors: Shimp William S. , Kumar Akhil , Bobolts Laura Rose , Krook James Edward , Fishman Val , Davis Sharon , Anthony Carol , Walton Robert , Huff Dinah , Fishman Marc L. , Hrushesky William J.
Published: March 2020

e14646

Background: The addition of oxaliplatin in adjuvant chemotherapy for stage II CRC and for elderly (≥ 70) patients with stage II or III CRC requires careful consideration. Most patients with stage II or III CRC receive oxaliplatin-based adjuvant regimens (Abrams. J Clin Oncol 2011). Mature results of the adjuvant MOSAIC and C-07 trials, however, failed to show improvement in OS or DFS among the elderly (≥ 70 years) and those with stage II CRC (Tournigand. J Clin Oncol 2012). Oxaliplatin causes neuropathy, increases the incidence and severity of febrile neutropenia, and adds substantial cost for both oxaliplatin and WBC growth factors. Methods: All chemotherapy requests submitted to Oncology Analytics for stage II and III CRC from 2009 through 2012 were analyzed. Utilization of oxaliplatin was retrospectively analyzed, with special attention to its use in those who were elderly (≥ 70 years), and for those of any age with stage II. Results: Our review showed a total of 242 adjuvant chemotherapy requests in stage II/III CRC. The majority of them, 57% (138/242), were elderly (≥ 70 years) with Stage II/III, and 24% (58/242) of any age had stage II. Thirty-four (14%) were both elderly and stage II. Overall, more than two thirds, 71% (171/242), received oxaliplatin containing regimens. More than two thirds of the elderly, regardless of stage, and more than half of all stage II patients, regardless of age, were treated with oxaliplatin containing regimens. Conclusions: The historical predominance of oxaliplatin use in the adjuvant setting, among patients over seventy years of age and/or those with stage II CRC, needs to be addressed as a priority. With mature data from the MOSAIC and C-07 trials, oncologists need to change prescribing behavior to provide less toxic therapies, thereby diminishing the incidence of neuropathy and reducing the risk of febrile neutropenia. The elimination of oxaliplatin in these subsets will also diminish costs for the Medicare population by a quarter billion dollars each year, without an adverse impact on outcome. [Table: see text]
Tolerability of raltitrexed when it is used in monotherapy and in combination with oxaliplatin (TOMOX) as advanced colorectal cancer treatment in normal clinical practice.
Authors: Constenla Manuel , Aparicio Jorge , Gomez M.Auxiliadora , Gravalos Castro Cristina , Lopez-Gomez Miriam , Manzano Jose Luis , Pineda Maria Dolores , Cano Juana Maria , Sevilla Isabel , Vieitez de Prado Jose Maria , Viudez Antonio , Lopez-Gomez Luis , Camara Juan Carlos , Lopez-Vivanco Guillermo , Aranda Fuensanta , Palomo-Jimenez Paloma Isabel , Barbon Ana , Feliu Batlle Jaime
Published: March 2020

e14648

Background: Fluoropyrimidines (FP) based chemotherapy continue to be the cornerstone of advanced colorectal cancer (aCRC) treatment. However, FP cannot be appropriated for some patients (FP intolerance, DPD deficit, history of ischemic heart disease, etc). In these cases, Raltitrexed (R) in monotherapy or in combination with oxaliplatin (TOMOX) could be an effective alternative to FP. Methods: We assessed in an observational retrospective study the patient profile and the tolerability of R when it is used in monotherapy or in combination with oxaliplatin (TOMOX) as aCRC treatment in the normal clinical practice setting. Data from patients treated between 2010 and 2012 were collected from 15 Spanish hospitals. Reason for choosing R as aCRC treatment, patient and disease characteristics, previous treatment and toxicity were gathered. Results: The data from 144 patients treated with R (72) and TOMOX (72) were included in the analysis (64% male, median age 68 years, ECOG PS 0/1/2 in 18%/62%/19%). The main reasons to choose R were: similar efficacy and safety to other treatments (19%), convenience of the administration (18%), cardiovascular disease (17%), resistance to FP (14%), previous FP inacceptable toxicity (10%) and old age (11%). R was mainly used as third or successive treatment line (64%) while TOMOX was equally used in all treatment lines (37%, 28% and 35%). The mean number of cycles was 5 (1-15). The dose was reduced in 26% of the patients and the treatment administration was delayed in 53%. The creatinine clearance was only calculated in 20% of the cycles. The most common grade 3-4 toxicities were neutropenia (8%), anaemia (5%), nausea (2%), vomiting (1%), diarrhoea (7%) and hepatic toxicity (4%). There were 2 toxic deaths (1.4%). Conclusions: R and TOMOX represent a safe alternative for aCRC patients in which FP are not appropriated. Despite R good tolerance in normal clinical practice, it is a must to assess creatinine clearance before each cycle.
Mortality risk factors and survival of colon cancer patient.
Authors: Shi Runhua , Kodali Manga Devi , Wang Stephani Chang , Lavu Kalyana C , Liu Lihong , Shows Joseph Ryan , Mills Glenn Morris
Published: March 2020

e14653

Background: It is estimated that 142,820 people will be diagnosed and 50,830 will die from colon cancer in U.S. in 2013. The known risk factors include age (>50 years old), personal history of colon polyp(s) and Inflammatory bowel disease, family history of colon cancer, hereditary syndromes, Black race, type II Diabetes Mellitus, obesity, physical inactivity, smoking and alcohol use. In order to improve colon cancer survivorship, current study explores factors that affect it. Methods: Data of 524,613 colon cancer patients between 1973 and 2009 was obtained from the Surveillance Epidemiology and End Results (SEER) program. Factors evaluated in this study were age at diagnosis, gender, race, annual household income, education, unemployment, and smoking. Clinical factors evaluated include SEER historic stage and treatments received. The definition of these factors was based on the SEER data dictionary. Kaplan-Meier method and log rank test was used to estimate and compare survivals. Cox regressions were used to identify risk factors that affect survival. Results: Characteristics of this half millions colon cancer patients were 51.3% of males, 84.4% of whites, and 70% of adjusted household income <$50,000. Primary site: Sigmoid Colon (30.84%), Cecum (22.7%), Ascending Colon (9.42%), and others (9.42%). Stage: Localized (37%), Regional (36.26%), Distant (20.01%), and Unstaged (6.63%). In multivariate analysis, adjusting for other factors, age (≤49 vs. 60-69, HR=0.57), female gender (HR=0.87), stage (localized vs. distant stage, HR= 0.15) and race (Black HR=1.38, vs. Asian) are significant factors in colon cancer survival. People living in areas with a high percentage of smokers have increased risk by 8%. People living in areas of higher unemployment have 6% increased risk. Household income and education level have relatively less effect on colon cancer survival (40-55k vs. 0-40k, HR=1.02). Conclusions: We conclude that in a large database, age, race, stage, smoking, and unemployment have significant impact on colon cancer survival. Other factors such as insurance status, detailed treatments, screening effect, individual life styles and etc. need further investigation.
Comparison of survival predictors in colorectal cancer (CRC) patients of different races.
Authors: Patel Neal , Okoronkwo Nneoma Olivia , Tang Ying Margie , Chang Victor Tsu-Shih , Kasimis Basil , Wang Trent P , Barnes Tanganyika , Cogswell Janet , Gonzalez Melanie L. , Einhorn Jan , Sullivan Maryann , Zhong Fengming
Published: March 2020

e14661

Background: We studied comorbidity and other survival predictors for patients (pts) with CRC and compared the pts of different races. Methods: In an IRB-approved protocol, we reviewed the records of pts diagnosed with CRC at a VA medical center from 01/01/2003 to 12/31/2011 for demographics, stage, grade, ECOG performance status (PS), CEA, hemoglobin (HGB), and albumin (ALB) at diagnosis (dx). Comorbidity was assessed with the Charlson Comorbidity Index (CCI), the Cumulative Illness Rating Scales (CIRS), and the Kaplan-Feinstein Index (KFI). Statistical analyses were performed with SAS 9.2/Stata 11.0. We compared the pts by race groups Caucasian (C) vs African American (A). Results: There were 279 men. 156 pts (55.9%) were race C, 106 pts (38%) race A, 15 pts (5.4%) Hispanics, and 2 pts (0.7%) Asians. The median (M) age at dx was 70 (45-90) years. 132 pts (47.3%) were deceased. Age, grade, stage, ECOG PS, HGB, ALB, and CEA were similar between group A and C. In group A, M CCI is 4.2 (0.8-14), M CIRS 15 3.0 (0-5), M CIRS16 5 (0-13), M CIRS17 2 (0-6), M CIRS18 0 (0-1), M CIRS 19 0 (0-1), M KFI 2 (0-3). In group C, Median (M) CCI is 4.2 (0.4-19.6), M CIRS15 3.0 (0-6), M CIRS16 6 (0-13), M CIRS17 2 (0-13), M CIRS18 0 (0-1), M CIRS 19 0 (0-1) and M KFI 2 (0-3). By univariate analysis, for group A, grade, stage, ECOG PS, HGB, CCI, CIRS16, CIRS 19 and KFI are significant predictors. For group C, age, grade, stage, ECOG PS, HGB, ALB, and CIRS16 are significant predictors for survival. Summary for significant multivariate predictors are shown in the Table. Conclusions: This study from a larger population confirms our earlier findings (ASCO 2012 e14125). Grade, stage, ECOG PS, and CIRS 19 are independent survival predictors for veterans with CRC. Age, stage, ECOG PS, ALB and CIRS19 are independent predictors of survival for group C pts with CRC. Grade, stage, ECOG PS, and CIRS19 are predictors for group A pts with CRC. This variation may suggest biological difference between races. More studies are needed to confirm this. Supported by NJCCR. [Table: see text]