The influence of high-intensity compared with moderate-intensity exercise training on cardiorespiratory fitness and body composition in colorectal cancer survivors: a randomised controlled trial

Purpose

Following colorectal cancer diagnosis and anti-cancer therapy, declines in cardiorespiratory fitness and body composition lead to significant increases in morbidity and mortality. There is increasing interest within the field of exercise oncology surrounding potential strategies to remediate these adverse outcomes. This study compared 4 weeks of moderate-intensity exercise (MIE) and high-intensity exercise (HIE) training on peak oxygen consumption (V?O₂peak) and body composition in colorectal cancer survivors.

Methods

Forty seven post-treatment colorectal cancer survivors (HIE?=?27 months post-treatment; MIE?=?38 months post-treatment) were randomised to either HIE [85–95 % peak heart rate (HR_peak)] or MIE (70 % HR_peak) in equivalence with current physical activity guidelines and completed 12 training sessions over 4 weeks.

Results

HIE was superior to MIE in improving absolute (p?=?0.016) and relative (p?=?0.021) V?O₂peak. Absolute (+0.28 L.min^?1, p?<?0.001) and relative (+3.5 ml.kg^?1.min^?1, p?<?0.001) V?O₂ peak were increased in the HIE group but not the MIE group following training. HIE led to significant increases in lean mass (+0.72 kg, p?=?0.002) and decreases in fat mass (?0.74 kg, p?<?0.001) and fat percentage (?1.0 %, p?<?0.001), whereas no changes were observed for the MIE group. There were no severe adverse events.

Conclusions

In response to short-term training, HIE is a safe, feasible and efficacious intervention that offers clinically meaningful improvements in cardiorespiratory fitness and body composition for colorectal cancer survivors.

Implications for Cancer Survivors

HIE appears to offer superior improvements in cardiorespiratory fitness and body composition in comparison to current physical activity recommendations for colorectal cancer survivors and therefore may be an effective clinical utility following treatment.

     

Characteristics of <Emphasis Type="Italic">MUTYH</Emphasis> variants in Japanese colorectal polyposis patients

Background

The base excision repair gene MUTYH is the causative gene of colorectal polyposis syndrome, which is an autosomal recessive disorder associated with a high risk of colorectal cancer. Since few studies have investigated the genotype–phenotype association in Japanese patients with MUTYH variants, the aim of this study was to clarify the clinicopathological findings in Japanese patients with MUTYH gene variants who were detected by screening causative genes associated with hereditary colorectal polyposis.

Methods

After obtaining informed consent, genetic testing was performed using target enrichment sequencing of 26 genes, including MUTYH.

Results

Of the 31 Japanese patients with suspected hereditary colorectal polyposis, eight MUTYH variants were detected in five patients. MUTYH hotspot variants known for Caucasians, namely p.G396D and p.Y179D, were not among the detected variants.Of five patients, two with biallelic MUTYH variants were diagnosed with MUTYH-associated polyposis, while two others had monoallelic MUTYH variants. One patient had the p.P18L and p.G25D variants on the same allele; however, supportive data for considering these two variants ‘pathogenic’ were lacking.

Conclusions

Two patients with biallelic MUTYH variants and two others with monoallelic MUTYH variants were identified among Japanese colorectal polyposis patients. Hotspot variants of the MUTYH gene for Caucasians were not hotspots for Japanese patients.

     

A high frequency of PALB2 mutations in Jamaican patients with breast cancer

Purpose

Jamaica is an island nation with one of the highest breast cancer incidence rates in the Caribbean (40/100,000 per year). The contribution of cancer susceptibility gene mutations to the burden of breast cancer in Jamaica has not yet been explored. We sought to determine the prevalence of germline mutations in BRCA1, BRCA2, and PALB2 in 179 unselected Jamaican women with breast cancer.

Methods

We sequenced the entire coding regions of BRCA1, BRCA2, and PALB2 for all the study subjects.

Results

Overall, 8 of 179 patients (4.5%) had a mutation in one of the three genes: one in BRCA1, two in BRCA2, and five in PALB2.

Conclusions

These data suggest that in addition to BRCA1 and BRCA2, PALB2 should be included in genetic testing for breast cancer patients in Jamaica.

     

Relationship between expression of CEA,E-cadherin and liver metastasis in colorectal cancer

OBJECTIVE To investigate the expression of E-cadherin and CEA in serum in colorectal carcinoma and their relationship with liver metastasis.
METHODS CEA level was measured post-operatively by radioimmunoassay of 60 patients with colorectal cancer. Immunohistochemical analysis was used to evaluate the expression of E-cadherin.
RESULTS In liver metastasis group, 24 patients （24/26, 92.3%） were high level of CEA, but only 9 patients in non-liver metastasis group. The difference is significant （P = 0.004）. Expression of E-cadherin significantly correlated with differentiation, but was not associated with T stage or N stage. Liver metastatic rate in negative expression was higher than that in positive expression. And the survival analysis showed that time of liver metastasis was significant different in two groups （P 〈 0.05）.
CONCLUSION The expression of CEA in serum can be used to predict liver mestatasis of colorectal cancer after operation. E-cadherin, associated with tumor differentiation, is also a hopeful indicator for the prediction of liver metastasis in patients with colorectal cancer.     

Candidate predisposing germline copy number variants in early onset colorectal cancer patients

Purpose

A great proportion of the heritability of colorectal cancer (CRC) still remains unexplained, and rare variants, as well as copy number changes, have been proposed as potential candidates to explain the so-called ‘missing heritability’. We aimed to identify rare high-to-moderately penetrant copy number variants (CNVs) in patients suspected of having hereditary CRC due to an early onset.

Methods/patients

We have selected for genome-wide copy number analysis, 27 MMR-proficient early onset CRC patients (<50 years) without identifiable germline mutations in Mendelian genes related to this phenotype. Rare CNVs were selected by removing all CNVs detected at MAF >1% in the in-house control CNV database (n = 629 healthy controls). Copy number assignment was checked by duplex real-time quantitative PCR or multiplex ligation probe amplification. Somatic mutation analysis in candidate genes included: loss of heterozygosity studies, point mutation screening, and methylation status of the promoter.

Results

We have identified two rare germline deletions involving the AK3 and SLIT2 genes in two patients. The search for a second somatic mutational event in the corresponding CRC tumors showed loss of heterozygosity in AK3, and promoter hypermethylation in SLIT2. Both genes have been previously related to colorectal carcinogenesis.

Conclusions

These findings suggest that AK3 and SLIT2 may be potential candidates involved in genetic susceptibility to CRC.

     

Targeted next-generation sequencing identifies clinically relevant mutations in patients with chronic neutrophilic leukemia at diagnosis and blast crisis

Purpose

Chronic neutrophilic leukemia is a rare form of myeloproliferative neoplasm characterized by mature neutrophil hyperleukocytosis. The majority of patients harbor somatic mutations of CSF3R gene and are potentially amenable to targeted therapy with JAK inhibitors. The incidence and clinical significance of additional mutations requires clarification.

Materials and methods

A next-generation sequencing approach for myeloid malignancy-associated mutations was applied to diagnostic and matched blast crisis samples from four chronic neutrophilic leukemia patients.

Results

Next-generation sequencing confirmed the CSF3R T618I in all patients with identification of concurrent SRSF2, SETBP1, NRAS and CBL mutations at diagnosis. At blast crisis, clonal evolution was evidenced by an increased CSF3R T618I allele frequency and by loss or acquisition of CBL and NRAS mutations.

Conclusion

The diagnostic utility of a targeted next-generation sequencing approach was clearly demonstrated with the identification of additional mutations providing the potential for therapeutic stratification of chronic neutrophilic leukemia patients.

     

CpG island methylator phenotype is associated with the efficacy of sequential oxaliplatin- and irinotecan-based chemotherapy and EGFR-related gene mutation in Japanese patients with metastatic colorectal cancer

Background

The CpG island methylator phenotype (CIMP) with multiple promoter methylated loci has been observed in a subset of human colorectal cancer (CRC) cases. CIMP status, which is closely associated with specific clinicopathological and molecular characteristics, is considered a potential predictive biomarker for efficacy of cancer treatment. However, the relationship between the effect of standard chemotherapy, including cytotoxic drugs and anti-epidermal growth factor receptor (EGFR) antibodies, and CIMP status has not been elucidated.

Methods

In 125 metastatic colorectal cancer (mCRC) patients, we investigated how clinical outcome of chemotherapy was related to CIMP status as detected by methylation-specific PCR (MSP) and to genetic status in five EGFR-related genes (KRAS, BRAF, PIK3CA, NRAS, and AKT1) as detected by direct sequencing.

Results

CIMP-positive status was significantly associated with proximal tumor location and peritoneum metastasis (all P values <0.05). The progression-free survival of patients with CIMP-positive tumors receiving sequential therapy with FOLFOX as the first-line treatment followed by irinotecan-based therapy as the second-line treatment (median = 6.6 months) was inferior to that of such patients receiving the reverse sequence (median = 15.2 months; P = 0.043). Furthermore, CIMP-positive tumors showed higher mutation frequencies for the five EGFR-related genes (74.1 %) than the CIMP-negative tumors did (50.0 %). Among the KRAS wild-type tumors, CIMP-positive tumors were associated with a worse clinical outcome than CIMP-negative tumors following anti-EGFR antibody therapy.

Conclusion

Sequential FOLFOX followed by an irinotecan-based regimen is unfavorable in patients with CIMP-positive tumors. High frequencies of mutation in EGFR-related genes in CIMP-positive tumors may cause the lower response to anti-EGFR antibody therapy seen in patients with wild-type KRAS and CIMP-positive tumors.

     

Alteration of tumor suppressor BMP5 in sporadic colorectal cancer: a genomic and transcriptomic profiling based study

Background

Although the genetic spectrum of human colorectal cancer (CRC) is mainly characterized by APC, KRAS and TP53 mutations, driver genes in tumor initiation have not been conclusively demonstrated. In this study, we aimed to identify novel markers for CRC.

Methods

We performed exome analysis of sporadic colorectal cancer (sCRC) coding regions to screen loss of function (LoF) mutation genes, and carried out systems-level approaches to confirm top rank gene in this study.

Results

We identified loss of BMP5 is an early event in CRC. Deep sequencing identified BMP5 was mutated in 7.7% (8/104) of sCRC samples, with 37.5% truncating mutation frequency. Notably, BMP5 negative expression and its prognostic value is uniquely significant in sCRC but not in other tumor types. Furthermore, BMP5 expression was positively correlated with E-cadherin in CRC patients and its dysregulation play a vital role in epithelial-mesenchymal transition (EMT), thus triggering tumor initiation and development. RNA sequencing identified, independent of BMP/Smads pathway, BMP5 signaled though Jak-Stat pathways to inhibit the activation of oncogene EPSTI1.

Conclusions

Our result support a novel concept that the importance of BMP5 in sCRC. The tumor suppressor role of BMP5 highlights its crucial role in CRC initiation and development.

     

Germline promoter hypermethylation in <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> genes is not present in hereditary breast cancer patients

Purpose

Germline promoter hypermethylation of BRCA1 and BRCA2 genes is an alternative event of gene silencing that has not been widely investigated in hereditary breast and ovarian cancer (HBOC) syndrome.

Methods

We analyzed germline BRCA promoter hypermethylation in HBOC patients with and without BRCA mutations and control subjects, using a recently developed BRCA methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) assay.

Results

Neither the patients tested nor the control subjects showed germline hypermethylation of the BRCA1 and BRCA2 promoter regions analyzed.

Conclusions

Despite the results achieved at somatic levels by other researchers, these were not confirmed in our study at the germline level. Our results show the need to establish more predictive CpG sites in the BRCA promoter regions to optimize the MS-MLPA assayfor the detection of germline hypermethylation as an effective pre-screening tool for whole-BRCA genetic analysis in HBOC, because we can not rule out the existence of germline promoter hypermethylation in BRCA.

     

Bevacizumab improves survival in patients with synchronous colorectal liver metastases provided the primary tumor is resected first

Background

Multimodal strategy including chemotherapy and hepatectomy is advocated for the management of colorectal liver metastases (CRLM). The aim of this study was to evaluate the impact of neoadjuvant Bevacizumab-based chemotherapy on survival in patients with resected stage IVA colorectal cancer and liver metastases.

Methods

Data from 120 consecutive patients who received neoadjuvant chemotherapy and underwent curative-intent hepatectomy for synchronous CRLM were retrospectively reviewed. Overall survival (OS) was stratified according to administration of Bevacizumab before liver resection and surgical strategy, i.e., classical strategy (primary tumor resection first) versus reverse strategy (liver metastases resection first).

Results

Patients who received Bevacizumab (n?=?37; 30%) had a higher number of CRLM (p?=?0.003) and underwent more often reverse strategy (p?=?0.005), as compared to those who did not (n?=?83; 70%). Bevacizumab was associated with an improved OS compared with conventional chemotherapy (p?=?0.04). After stratifying by the surgical strategy, Bevacizumab was associated with improved OS in patients who had classical strategy (p?=?0.03). In contrast, Bevacizumab had no impact on OS among patients who had liver metastases resection first (p?=?0.89).

Conclusions

Neoadjuvant Bevacizumab-based chemotherapy was associated with improved OS in patients who underwent liver resection of synchronous CRLM, especially in those who underwent primary tumor resection first.

     

Initial validation of the Danish version of the Fear of Cancer Recurrence Inventory (FCRI) in colorectal cancer patients

Purpose

The Fear of Cancer Recurrence Inventory (FCRI) is a multidimensional measure for fear of cancer recurrence (FCR). The aim of this study was to assess the psychometric properties of the translated Danish version of the FCRI in a population of colorectal cancer patients.

Methods

The English version of the FCRI was forward–backward translated into Danish and pilot tested in a gynaecological cancer population. The psychometric properties of the FCRI were assessed in terms of responsiveness, test–retest reliability and discriminative and convergent validity in a population of colorectal cancer patients by asking them to complete questionnaires at three time points during follow-up. Clinical FCR was defined as ≥?16 at the FCRI short form.

Results

The participation rate was 57%. A low association was found between higher scores on the FCRI and younger age (r?=???0.29, p?=?0.02). A moderate correlation was found between the FCRI score and a measure for worry traits (r?=?0.49, p?<?0.001). Mean difference in total FCRI score was statistically significant between ‘pre-scan’ and ‘postscan’ (p?<?0.001), thus indicating that the FCRI was responsive to change. The FCRI score showed good test–retest reliability (intraclass correlation?=?0.84).

Conclusion

The Danish version of the FCRI is a reliable and responsive measure for FCR in colorectal cancer patients and shows acceptable discriminative and convergent validity.

Implications for Cancer Survivors

A valid measure for FCR is crucial in order to identify patients with a need for special attention or interventions for high levels of FCR and to improve future research into FCR among cancer survivors.

     

Colorectal obstruction is a potential prognostic factor for stage II colorectal cancer

Background

Obstructive colorectal cancer (CRC) is an emergency situation with high morbidity and mortality, but long-term outcomes of stage II/III obstructive CRC remain unclear. The aim of this study was to evaluate prognostic factors, including colorectal obstruction.

Methods

Data were retrospectively reviewed from consecutive patients with stage II/III CRC who underwent curative surgery between January 2007 and December 2011 at two Japanese institutions. We analyzed overall survival (OS) and relapse-free survival (RFS), according to various prognostic factors including colorectal obstruction.

Results

In total, 979 patients with stage II/III CRC were identified for this study. Among these 979 patients, 94 patients showed colorectal obstruction (9.6%). In both stage II and stage III CRCs, colorectal obstruction showed significantly poorer OS and RFS compared to non-obstruction (5-year OS, obstruction vs. non-obstruction, stage II: 65.9 vs. 86.5%, P?=?0.002; stage III: 55.9 vs. 73.6%, P?=?0.007) (5-year RFS, obstruction vs. non-obstruction, stage II: 59.2 vs. 77.8%, P?=?0.008; stage III 31.3 vs. 56.3%, P?=?0.001). Multivariate analysis demonstrated colorectal obstruction as a significant independent and poor prognostic factor in terms of both OS (hazard ratio (HR) 2.469; 95% CI 1.339–4.545; P?=?0.004) and RFS (HR 1.992; 95% CI 1.160–3.425; P?=?0.012) for stage II CRC, as well as pT4 stage. On multivariate analysis for stage III CRC, colorectal obstruction was a significant predictor of poor RFS (HR 1.626; 95% CI 1.070–2.469; P?=?0.023), but not poor OS.

Conclusions

Colorectal obstruction is an independent poor prognostic factor for stage II CRC. Adjuvant chemotherapy might be feasible for stage II CRC with colorectal obstruction.

     

Phosphodiesterases in non-neoplastic appearing colonic mucosa from patients with colorectal neoplasia

Background

Intracellular signaling through cyclic nucleotides, both cyclic AMP and cyclic GMP, is altered in colorectal cancer. Accordingly, it is hypothesized that an underlying mechanism for colorectal neoplasia involves altered function of phosphodiesterases (PDEs), which affects cyclic nucleotide degradation. Here we present an approach to evaluate the function of selected cyclic nucleotide-PDEs in colonic endoscopic biopsies from non-neoplastic appearing mucosa.

Methods

Biopsies were obtained from patients with and without colorectal neoplasia. Activities of PDEs were characterized functionally by measurements of transepithelial ion transport and their expression and localization by employing real-time qPCR and immunohistochemistry.

Results

In functional studies PDE subtype-4 displayed lower activity in colorectal neoplasia patients (p?=?0.006). Furthermore, real-time qPCR analysis showed overexpression of subtype PDE4B (p?=?0.002) and subtype PDE5A (p?=?0.02) in colorectal neoplasia patients. Finally, immunohistochemistry for 7 PDE isozymes demonstrated the presence of all 7 isozymes, albeit with weak reactions, and with no differences in localization between colorectal neoplasia and control patients. Of note, quantification of PDE subtype immunostaining revealed a lower amount of PDE3A (p?=?0.04) and a higher amount of PDE4B (p?=?0.02) in samples from colorectal neoplasia patients.

Conclusion

In conclusion, functional data indicated lower activity of PDE4 subtypes while expressional and abundance data indicated a higher expression of PDE4B in patients with colorectal neoplasia. We suggest that cyclic nucleotide-PDE4B is overexpressed as a malfunctioning protein in non-neoplastic appearing colonic mucosa from patients with colorectal neoplasia. If a predisposition of reduced PDE4B activity in colonic mucosa from colorectal neoplasia patients is substantiated further, this subtype could be a potential novel early diagnostic risk marker and may even be a target for future medical preventive treatment of colorectal cancer.

     

<Emphasis Type="Italic">Helicobacter pylori</Emphasis> infection is an independent risk factor for colonic adenomatous neoplasms

Purpose

Helicobacter pylori infection is considered to have a positive association with colorectal neoplasms. In this study, we evaluated the association between H. pylori infection and colorectal adenomas, based on the characteristics of these adenomas in Korea, where the prevalence of H. pylori infection is high and the incidence of colorectal cancer continues to increase.

Methods

The study cohort consisted of 4,466 subjects who underwent colonoscopy and esophagogastroduodenoscopy during screening (1,245 colorectal adenomas vs. 3,221 polyp-free controls). We compared the rate of H. pylori infection between patients with adenoma and polyp-free control cases, using multivariable logistic regression analysis.

Results

The overall rate of positive H. pylori infection was higher in adenoma cases than in polyp-free control cases (55.0 vs. 48.5%, p < 0.001). The odds ratio (OR) of positive H. pylori infection in patients with adenoma compared to polyp-free controls was 1.28 (95% CI 1.11–1.47). The positive association of H. pylori infection with colorectal adenomas was more prominent in advanced adenomas (OR 1.84, 95% CI 1.25–2.70) and multiple adenomas (OR 1.72, 95% CI 1.26–2.35). Based on the location of these adenomas, the OR was significant only in patients with colonic adenomas (OR 1.31, 95% CI 1.13–1.52) and not in those with rectal adenoma (OR 0.85, 95% CI 0.58–1.24).

Conclusion

Helicobacter pylori infection is an independent risk factor for colonic adenomas, especially in cases of advanced or multiple adenomas, but not for rectal adenomas.

     

Genomics of gallbladder cancer: the case for biomarker-driven clinical trial design

Background and aims

Gallbladder carcinoma is a rare, aggressive malignancy of the biliary tract associated with a poor prognosis. Despite the deployment of targeted therapies that have demonstrated marked survival benefits in many tumor types, traditional cytotoxic chemotherapy has remained the mainstay of treatment for unresectable and metastatic gallbladder cancer.

Methods

Systematic review of ongoing and prior clinical studies shows a paucity of biomarker-driven therapeutic trials using targeted agents in gallbladder cancer. In fact, over the past 6 years, of the 38 therapeutic biliary tract protocols listed on clinicaltrials.gov, only 6 (21 %) utilized targeted therapies based upon tumor biomarkers or genomics. Now that we have entered the era of next-generation sequencing and precision medicine, we are beginning to identify common and specific genetic alterations in gallbladder carcinomas.

Results

A review of the literature reveals alterations in ARID1A, BRAF, CDKN2A/B, EGFR, ERBB2-4, HKN-RAS, PIK3CA, PBRM1, and TP53. Given the widespread use of tumor genomic profiling and the fact that most of the aforementioned alterations are pharmacologically tractable, these observations suggest the potential for new therapeutic strategies in this aggressive malignancy.

Conclusions

Taken together, further understanding of the genomic landscape of gallbladder cancer coupled with biomarker-driven clinical trials that match therapies to targets are urgently needed.

     

Rare <Emphasis Type="Italic">RAS</Emphasis> Mutations in Metastatic Colorectal Cancer Detected During Routine <Emphasis Type="Italic">RAS</Emphasis> Genotyping Using Next Generation Sequencing

Background

Overall survival of metastatic colorectal cancer (mCRC) patients has been improved with the addition of targeted therapy such as anti-epithelial growth factor receptor monoclonal antibodies (anti-EGFR mAbs) to standard chemotherapy. Retrospective studies and randomized trials showed that the presence of RAS mutations was linked to the absence of clinical response to anti-EGFR mAbs. Patients harboring KRAS and NRAS mutations on exons 2, 3 or 4 have little or no benefit from anti-EGFR therapies. Polymerase chain reaction (PCR)-based assays are routinely used to assess KRAS and NRAS status, whereas deep sequencing with next generation sequencing (NGS) currently represents an alternative method.

Objective

The objective of our study was to identify KRAS and NRAS non-hotspot mutations using NGS of mCRC tumor samples.

Method

DNA was extracted from 188 consecutive formalin-fixed paraffin embedded samples of histologically proven colorectal cancer tumor tissue from patients with mCRC. Following amplification, DNA was sequenced by ultra-deep pyrosequencing. Non-hotspot mutations identified by NGS (frequency of mutated allele range [1.8–70.6 %]) were confirmed by Sanger direct-sequencing when possible.

Results

NGS procedure was applicable in 94 % of the cases and detected mutations in 62 % of the samples. Nine uncommon mutational profiles were found with a frequency of mutated allele ?>?1 %. Silent mutations were found in 3.6 % of the samples. Mutations at or near functional domains of RAS proteins, other than defined hotspots, were found in 3.6 %. NGS proved to be accurate, sensitive and suitable for routine RAS genotyping.

Conclusion

Clinical responses to anti-EGFR mAbs are potentially impaired in the presence of these uncommon RAS mutations.

     

Reproductive factors and risk of colorectal polyps in a colonoscopy-based study in western Washington State

Background

Oral contraceptives (OC) are associated with a decreased risk of colorectal cancers; however, a recent study reported an increased risk of small colorectal adenomas associated with OC use. To determine if these results were replicable in a different study population, we investigated the relationship between OC use and other reproductive factors and risk of colorectal polyps in a case–control study in western Washington.

Methods

Study participants were 24–79-year-old female enrollees at an integrated health care system in western Washington who were diagnosed as having adenomas (n?=?299), serrated polyps (n?=?337), both types of polyps (n?=?105) or as polyp-free controls (n?=?615) through an index colonoscopy and completed a structured interview to collect reproductive history information. Multivariable polytomous logistic regression was used to compare case groups to controls and to each other; odds ratios (OR) and 95% confidence intervals were estimated.

Results

There was no association between OC use, duration of use, or recency of use and the risk of either adenomas or serrated polyps [adjusted OR for OC ever use (95% CI) 0.85 (0.58–1.23) and 0.96 (0.66–1.40), respectively], and associations did not differ by lesion severity within the adenoma or serrated pathways. Further, no associations were observed between other reproductive factors and risk of colorectal polyp subtypes.

Conclusions

Our results suggest that reproductive factors, including OC use, are not associated with early colorectal cancer precursor lesions.

     

An online randomized controlled trial,with or without problem-solving treatment,for long-term cancer survivors after hematopoietic cell transplantation

Purpose

This randomized controlled trial examines the efficacy of INSPIRE, an INternet-based Survivorship Program with Information and REsources, with or without problem-solving treatment (PST) telehealth calls, for survivors after hematopoietic cell transplantation (HCT).

Methods

All adult survivors who met eligibility criteria were approached for consent. Participants completed patient-reported outcomes at baseline and 6 months. Those with baseline impaired scores on one or more of the outcomes were randomized to INSPIRE, INSPIRE + PST, or control with delayed INSPIRE access. Outcomes included Cancer and Treatment Distress, Symptom Checklist-90-R Depression, and Fatigue Symptom Inventory. Planned analyses compared arms for mean change in aggregated impaired outcomes and for proportion of participants improved on each outcome.

Results

Of 1306 eligible HCT recipients, 755 (58%) participated, and 344 (45%) had one or more impaired scores at baseline. We found no reduction in aggregated outcomes for either intervention (P?>?0.3). In analyses of individual outcomes, participants randomized to INSPIRE + PST were more likely to improve in distress than controls (45 vs. 20%, RR 2.3, CI 1.0, 5.1); those randomized to INSPIRE alone were marginally more likely to improve in distress (40 vs. 20%, RR 2.0, CI 0.9, 4.5).

Conclusions

The INSPIRE online intervention demonstrated a marginal benefit for distress that improved with the addition of telehealth PST, particularly for those who viewed the website or were age 40 or older.

Implications for Cancer Survivors

Online and telehealth programs such as INSPIRE offer opportunities to enhance HCT survivorship outcomes, particularly for mood, though methods would benefit from strategies to improve efficacy.

     

The Role of HER2 Testing in Advanced Colorectal Cancer

Purpose of Review

About 1/3 of all metastatic colorectal cancer (mCRC) patients may harbor a mutation in the KRAS or NRAS gene suggesting inefficacy of EGFR inhibitors cetuximab and panitumumab. In spite of tailoring treatment in RAS wild-type patients to receive EGFR inhibitors, not all show response.

Recent Findings

Studies have shown that HER2-neu amplification/alteration in addition to alteration in BRAF and PI3KA may explain resistance to EGFR inhibitors. Several pre-clinical studies have identified that HER2-neu amplification can result in both de novo and acquired resistance to EGFR inhibitors. Recently, several clinical studies have highlighted the use of single or combination HER2-neu directed therapies in HER2-neu amplified/overexpressed mCRC.

Summary

About 5% mCRC patients will demonstrate HER2-neu overexpression and response to HER2-neu-directed therapies can be in the range of 30–38%. Patients not responding to EGFR-inhibitors warrant testing for HER2-neu testing to explain resistance. In the near future, HER2-neu testing is likely to be integrated into our routine clinical practice for management of metastatic colorectal cancer patients.

     

Molecular Data and the IPSS-R: How Mutational Burden Can Affect Prognostication in MDS

Purpose of Review

The purpose of this study is to review established prognostic models in myelodysplastic syndromes (MDS) and describe how molecular data can be used to improve patient risk stratification.

Recent Findings

Somatic mutations are common in MDS and are associated with disease features including outcomes. Several recurrently mutated genes have prognostic significance independent of risk stratification tools used in practice. However, this prognostic impact can depend on the clinicogenetic context in which mutations occur. Qualitatively, SF3B1 mutations appear favorable only in patients with < 5% bone marrow blasts while mutations of several genes, including ASXL1, SRSF2, U2AF1, NRAS, and IDH2, appear adverse in this context. Mutations of TP53, RUNX1, and EZH2 appear adverse regardless of blast percentage. Consensus on how to best incorporate mutations into risk assessment is still being developed.

Summary

Somatic mutations can refine risk stratification and improve the accuracy of existing prognostic models, often upstaging or downstaging patients across the boundary of higher- and lower-risk MDS.