Awareness, attitudes, and beliefs about palliative care: Results from a representative survey of the Italian-speaking Swiss population.

OBJECTIVE: To understand the knowledge and awareness of palliative care in the Italian-speaking Swiss general population, describing main misconceptions or false beliefs and their relationship with attitudes towards palliative care. METHODS: Cross-sectional representative population survey (N = 313). RESULTS: We observed a high awareness of «palliative care,¼ although it is mainly associated with pain management and the very last days of life. While false beliefs are relatively rare, there is low awareness of goals, targets, and services offered by palliative care. Overall the Italian-speaking Swiss population has a good predisposition towards palliative care, but negative attitudes are more common among those who lack knowledge. More than one-third of respondents are interested in receiving more information about palliative care, especially from their healthcare providers or through dedicated information points. CONCLUSION AND PRACTICE IMPLICATIONS: Health communication interventions to promote palliative care are needed because there is still significant unclarity about the goals of palliative care, which negatively affects its acceptance. This study instructs on how to intervene specifically in the Italian-speaking part of Switzerland, including what to communicate and how. Further, our findings can inspire similar studies in other Swiss regions or countries that can optimize recognition, knowledge, and understanding and contribute to filling gaps in populations' health service demand and utilization.

Recent and Future Strategies to Overcome Resistance to Targeted Therapies and Immunotherapies in Metastatic Colorectal Cancer.

Colorectal cancer (CRC) is the third most common cause of cancer-related deaths worldwide, and 20% of patients with CRC present at diagnosis with metastases. The treatment of metastatic CRC is based on a fluoropyrimidine-based chemotherapy plus additional agents such as oxaliplatin and irinotecan. To date, on the basis of the molecular background, targeted therapies (e.g., monoclonal antibodies against epidermal growth factor receptor or inhibiting angiogenesis) are administered to improve the treatment of metastatic CRC. In addition, more recently, immunological agents emerged as effective in patients with a defective mismatch repair system. The administration of targeted therapies and immunotherapy lead to a significant increase in the survival of patients; however these drugs do not always prove effective. In most cases the lack of effectiveness is due to the development of primary resistance, either a resistance-inducing factor is already present before treatment or resistance is acquired when it occurs after treatment initiation. In this review we describe the most relevant targeted therapies and immunotherapies and expand on the reasons for resistance to the different approved or under development targeted drugs. Then we showed the possible mechanisms and drugs that may lead to overcoming the primary or acquired resistance in metastatic CRC.

A Pilot, Prospective, Observational Study to Investigate the Value of NGS in Liquid Biopsies to Predict Tumor Response After Neoadjuvant Chemo-Radiotherapy in Patients With Locally Advanced Rectal Cancer: The LiBReCa Study.

Introduction: Circulating tumor DNA (ctDNA) correlates with the response to therapy in different types of cancer. However, in patients with locally advanced rectal cancer (LARC), little is known about how ctDNA levels change with neoadjuvant chemoradiation (Na-ChRT) and how they correlate with treatment response. This work aimed to explore the value of serial liquid biopsies in monitoring response after Na-ChRT with the hypothesis that this could become a reliable biomarker to identify patients with a complete response, candidates for non-operative management. Materials and Methods: Twenty-five consecutive LARC patients undergoing long-term Na-ChRT therapy were included. Applying next-generation sequencing (NGS), we characterized DNA extracted from formalin-fixed paraffin embedded diagnostic biopsy and resection tissue and plasma ctDNA collected at the following time points: the first and last days of radiotherapy (T0, Tend), at 4 (T4), 7 (T7) weeks after radiotherapy, on the day of surgery (Top), and 3-7 days after surgery (Tpost-op). On the day of surgery, a mesenteric vein sample was also collected (TIMV). The relationship between the ctDNA at those time-points and the tumor regression grade (TRG) of the surgical specimen was statistically explored. Results: We found no association between the disappearance of ctDNA mutations in plasma samples and pathological complete response (TRG1) as ctDNA was undetectable in the majority of patients from Tend on. However, we observed that the poor (TRG 4) response to Na-ChRT was significantly associated with a positive liquid biopsy at the Top. Conclusions: ctDNA evaluation by NGS technology may identify LARC patients with poor response to Na-ChRT. In contrast, this technique does not seem useful for identifying patients prone to developing a complete response.

A qualitative analysis of educational, professional and socio-cultural issues affecting interprofessional collaboration in oncology palliative care.

OBJECTIVES: Oncology palliative care (PC) services seek to improve quality of life in patients with cancer. PC providers face significant systemic obstacles, stemming from insufficient collaboration between healthcare providers. This study explores these obstacles and strategies to help facilitate successful collaboration amongst healthcare providers at a systemic level. METHODS: A multicenter qualitative study was conducted via interviews and focus groups. Fifty employees in Italian-speaking Switzerland were interviewed, along with ten relatives of oncology patients. Framework analysis was used to identify and categorize the most prominent themes. RESULTS: Three main themes were identified: knowledge of and connection to other healthcare approaches; beliefs, attitudes and behavior regarding collaboration; and values, attitudes and beliefs towards life, end-of-life and optimal care approaches for oncology patients. CONCLUSIONS: Strategies that promote interprofessional collaboration and oncology PC services should foster a cultural shift towards perceiving these services as a medical specialty, thereby contributing to quality patient care. IMPLICATIONS: An overview of potential limitations is provided, in addition to a timeline of interprofessional collaboration which would help to optimize oncology PC services.

A qualitative exploration of interactional and organizational determinants of collaboration in cancer palliative care settings: Family members', health care professionals' and key informants' perspectives.

As life expectancy has increased, a growing number of people experience conditions, including cancers, that carry complex health and social needs. Palliative care services have the potential to address these needs but face significant obstacles. One major obstacle is suboptimal interprofessional collaboration. This study's goal was an in-depth exploration of interactional and organizational barriers and supports of collaboration in palliative care in Switzerland. We sought the perspectives of health care professionals, patients' family members and leaders and experts in oncology/palliative care delivery (key informants) through interviews and focus groups with fifty HPs and key informants and ten patients' family members. Qualitative analyses of interviews and focus groups used framework analysis. We identified three major themes of interaction: personal characteristics, communication, and connectedness with other health care professionals; and three major organizational themes: service characteristics, standardized communication and processes, and service coordination and promotion. Based on our findings, we recommend that health care professionals consider strategies to increase their collaboration and communication skills and opportunities to interact. We advocate the implementation of methods for coordinating services, standardization of consultation/referral procedures and communication between health care professionals, and the promotion of underutilized services to foster successful, sustainable collaboration.

Occurence of RAS reversion in metastatic colorectal cancer patients treated with bevacizumab.

BACKGROUND: A disappearance of RAS mutations in the plasma of about 50% of mCRCs (metastatic colorectal cancers) treated with bevacizumab-based chemotherapy has been reported. Our aim was to evaluate the same issue at tissue level. MATERIALS AND METHODS: Using next-generation sequencing and real-time PCR approaches, we characterized the primary tumor (PT) and paired liver metastases in 28 RAS mutant mCRCs. Patients were subdivided into 3 treatment groups: 1) bevacizumab plus chemotherapy; 2) chemotherapy alone; 3) any systemic therapy (control group). In groups 1 and 2, liver metastases were resected after removal of PT and subsequent neoadjuvant systemic therapy. RESULTS: RAS mutant alleles are at the same percentage in PT and liver metastases in the control group, while a significant reduction of the level of RAS mutations was detected in 57.1% of cases in group 1 and in 8.3% of cases in group 2. Differences among groups are statistically significant (p = 0.038). CONCLUSIONS: Most of mCRC patients treated with bevacizumab-containing regimens experience a strong reduction of RAS mutant cells, suggesting bevacizumab as particularly active against RAS mutant cells. This finding might have potential therapeutic implications, as anti-EGFR could be reconsidered in primarily RAS mutant patients reverted to a wild-type status after bevacizumab exposure.

Palliative care utilization in oncology and hemato-oncology: a systematic review of cognitive barriers and facilitators from the perspective of healthcare professionals, adult patients, and their families.

BACKGROUND: Despite the high potential to improve the quality of life of patients and families, palliative care services face significant obstacles to their use. In countries with high-resource health systems, the nonfinancial and nonstructural obstacles to palliative care services are particularly prominent. These are the cognitive barriers -knowledge and communication barriers- to the use of palliative care. To date no systematic review has given the deserved attention to the cognitive barriers and facilitators to palliative care services utilization. This study aims to synthesize knowledge on cognitive barriers and facilitators to palliative care use in oncology and hemato-oncology from the experiences of health professionals, patients, and their families. METHODS: A systematic review was conducted. PubMed, PsycINFO, International Association for Hospice and Palliative Care/Cumulative Index of Nursing and Allied Health Literature (IAHPC/CINAHL), and Communication & Mass Media Complete (CMMC) were systematically searched for the main core concepts: palliative care, barriers, facilitators, perspectives, points of view, and related terms and synonyms. After screening of titles, abstracts, and full-texts, 52 studies were included in the qualitative thematic analysis. RESULTS: Four themes were identified: awareness of palliative care, collaboration and communication in palliative care-related settings, attitudes and beliefs towards palliative care, and emotions involved in disease pathways. The results showed that cognitive barriers and facilitators are involved in the educational, social, emotional, and cultural dimensions of palliative care provision and utilization. In particular, these barriers and facilitators exist both at the healthcare professional level (e.g. a barrier is lack of understanding of palliative care applicability, and a facilitator is strategic visibility of the palliative care team in patient floors and hospital-wide events) and at the patient and families level (e.g. a barrier is having misconceptions about palliative care, and a facilitator is patients' openness to their own needs). CONCLUSIONS: To optimize palliative care services utilization, awareness of palliative care, and healthcare professionals' communication and emotion management skills should be enhanced. Additionally, a cultural shift, concerning attitudes and beliefs towards palliative care, should be encouraged.

Detection rate of unknown primary tumour by using somatostatin receptor PET/CT in patients with metastatic neuroendocrine tumours: a meta-analysis.

PURPOSE: The high diagnostic performance of somatostatin receptor positron emission tomography with computed tomography (PET/CT) in neuroendocrine tumours (NETs) was demonstrated by several articles. However, only some studies evaluated the detection rate (DR) of this imaging method in patients with metastatic NETs and unknown primary tumours (CUP-NETs). Therefore, we aimed to perform a meta-analysis to add evidence-based data in this setting. METHODS: A comprehensive computer literature search of studies listed in PubMed/MEDLINE, EMBASE, and Cochrane library databases through December 2018 and regarding the use of somatostatin receptor PET/CT in patients with CUP-NETs was carried out. Pooled DR of CUP-NETs by using somatostatin receptor PET/CT was calculated. A pooled analysis evaluating the percentage of change of management by using somatostatin receptor PET/CT in these patients was also performed. RESULTS: Twelve studies on the use of somatostatin receptor PET/CT in detecting CUP-NETs in 383 metastatic patients were included. The meta-analysis of all these studies provided the following DR on a per patient-based analysis: 56% (95% confidence interval (95% CI): 48-63%). Moderate heterogeneity among the selected studies was found (I2 = 50%), whereas a significant publication bias was excluded by Egger's test (p = 0.45). The most common primary tumour sites were the bowel and the pancreas. A change of management by using somatostatin receptor PET/CT was demonstrated in 20% (95% CI: 10-33%) of patients with CUP-NET. CONCLUSIONS: Somatostatin receptor PET/CT is very useful in detecting CUP-NETs in patients with metastatic disease. More studies on the change of management by using this imaging method in this setting are needed.

Cetuximab monotherapy and cetuximab plus capecitabine as first-line treatment in older patients with RAS- and BRAF wild-type metastatic colorectal cancer. Results of the multicenter phase II trial SAKK 41/10.

INTRODUCTION: While the anti-VEGF antibody bevacizumab was studied repeatedly as part of low-intensity regimens in less fit elderly patients with metastatic colorectal cancer (mCRC), anti-EGFR antibodies as upfront treatment modality have been scarcely investigated. MATERIAL AND METHODS: In SAKK 41/10, the benefit of cetuximab, either alone or in combination with capecitabine, was evaluated in vulnerable elderly patients with RAS/BRAF-wild-type mCRC. RESULTS AND DISCUSSION: The trial was stopped prematurely due to slow accrual after the inclusion of 24 patients (11 in the monotherapy arm, 13 in the combination arm). Median patient age was 80 years (range 71-89), median CIRS-G score 7 (range 2-13), and median IADL score 7 (range 3-8). At week 12, 6 of 11 patients (55%) were progression-free in the cetuximab monotherapy arm and 9 of 13 patients (69%) in the combination arm. Response rate was 9% in the monotherapy arm and 38% combination arm. The 6 patients with right-sided primary tumors were not responsive to cetuximab. NGS revealed additional mutations affecting the RAS/RAF/MAP kinase pathway in 5 patients; 4 of these patients showed early disease progression. Cetuximab was generally well tolerated and a trend toward an improvement of symptom-related QoL was observed. In the combination arm, a higher incidence of toxicities and treatment stoppings was observed. In conclusion, trial recruitment - requiring both geriatric as well as molecular eligibility criteria - proved more difficult than expected. Bearing in mind the very small sample size, upfront cetuximab treatment appeared tolerable and showed promising activity in left-sided tumors in both treatment arms.

Choosing wisely in oncology: necessity and obstacles.

In the last decades, the survival of many patients with cancer improved thanks to modern diagnostic methods and progresses in therapy. Still for several tumours, especially when diagnosed at an advanced stage, the benefits of treatment in terms of increased survival or quality of life are at best modest when not marginal, and should be weighed against the potential discomfort caused by medical procedures. As in other specialties, in oncology as well the dialogue between doctor and patient should be encouraged about the potential overuse of diagnostic procedures or treatments. Several oncological societies produced recommendations similar to those proposed by other medical disciplines adhering to the Choosing Wisely (CW) campaign. In this review, we describe what was reported in the medical literature concerning adequacy of screening, diagnostic, treatment and follow-up procedures and the potential impact on them of the CW. We only marginally touch on the more complex topic of treatment appropriateness, for which several evaluation methods have been developed (including the European Society for Medical Oncology-magnitude of clinical benefit scale). Finally, we review the possible obstacles for the development of CW in the oncological setting and focus on the strategies which could allow CW to evolve in the cancer field, so as to enhance the therapeutic relationship between medical professionals and patients and promote more appropriate management.

Second-line therapy in advanced upper gastrointestinal cancers: current status and new prospects.

The prognosis of patients with advanced upper gastrointestinal cancers (UGC) remains poor. Current available systemic armamentarium is limited, and little progress has been made over the last decades. Main achievements have been obtained in first-line setting, however an increasingly proportion of patients are considered for second-line therapy, although data from randomized trials are scarce or even lacking. In this comprehensive review we examine the literature to summarize the efficacy and limitations of second-line systemic options in patients with advanced UGC, with a glimpse into the innovations.

Neoadjuvant radiotherapy combined with capecitabine and sorafenib in patients with advanced KRAS-mutated rectal cancer: A phase I/II trial (SAKK 41/08).

BACKGROUND: KRAS mutation occurs in ∼40% of locally advanced rectal cancers (LARCs). The multitarget tyrosine kinase inhibitor sorafenib has radiosensitising effects and might improve outcomes for standard preoperative chemoradiotherapy in patients with KRAS-mutated LARC. METHODS: Adult patients with KRAS-mutated T3/4 and/or N1/2M0 LARC were included in this phase I/II study. The phase I dose-escalation study of capecitabine plus sorafenib and radiotherapy was followed by a phase II study assessing efficacy and safety. Primary end-points were to: establish the maximum tolerated dose of the regimen in phase I; determine the pathologic complete response (pCR) rate in phase II defined as Dworak regression grade 3 and 4. RESULTS: Fifty-four patients were treated at 18 centres in Switzerland and Hungary; 40 patients were included in the single-arm phase II study. Recommended doses from phase I comprised radiotherapy (45 Gy in 25 fractions over 5 weeks) with capecitabine 825 mg/m2 twice daily × 33 plus sorafenib 400 mg/d. Median daily dose intensity in phase II was radiotherapy 100%, capecitabine 98.6%, and sorafenib 100%. The pCR rate (Dworak 3/4) was 60% (95% CI, 43.3-75.1%) by central independent pathologic review. Sphincter preservation was achieved in 89.5%, R0 resection in 94.7%, and downstaging in 81.6%. The most common grade 3 toxicities during phase II included diarrhoea (15.0%), skin toxicity outside radiotherapy field (12.5%), pain (7.5%), skin toxicity in radiotherapy field, proctitis, fatigue and cardiac ischaemia (each 5%). CONCLUSIONS: Combining sorafenib and standard chemoradiotherapy with capecitabine is highly active in patients with KRAS-mutated LARC with acceptable toxicity and deserves further investigation. www.clinicaltrials.gov: NCT00869570.

Neoadjuvant chemotherapy in borderline resectable pancreatic cancer: A case report.

Pancreatic cancer is the fourth leading cause of cancer mortality and is associated with a poor overall survival even when diagnosed early and considered resectable. Complete surgical removal with negative histological margins is an independent predictor of survival and remains the only potential curative treatment. In borderline resectable pancreatic adenocarcinoma (BRPAC), preoperative systemic therapy may increase resectability and margin-negative resection rate. There is no current consensus on the optimal chemotherapy regimen for BRPAC. The present case describes a patient with BRPAC who achieved a pathological complete response to neoadjuvant FOLFIRINOX (folinic acid, fluorouracil, irinotecan and oxaliplatin), but early relapse following a pancreaticoduodenectomy without vascular resection, with an uneventful postoperative course, except for a pulmonary embolism.

EGFR, KRAS, BRAF, and PIK3CA characterization in squamous cell anal cancer.

BACKGROUND: Combined chemoradiation therapy is the gold standard in the treatment of squamous cell anal cancer (SCAC). However, even if the response rate is very high, many patients eventually relapse or experience a reccurrence, thus requiring an invasive surgical procedure that has severe side effects. Most SCAC tumors overexpress epidermal growth factor receptor (EGFR); therefore, it is reasonable to consider anti-EGFR drugs as a new treatment option, as demonstrated by anecdotal reports. Promising results obtained in other solid tumors, both squamous and non-squamous, have revealed that an increase in the EGFR gene copy number may predict the efficacy of anti-EGFR therapies, while the presence of mutations in downstream members of the EGFR pathway may confer resistance. These markers have been only sporadically considered in SCAC. METHODS: We investigated the status of the EGFR gene using FISH and examined KRAS, BRAF, and PIK3CA hot-spots mutations using sequencing analysis in a cohort of 84 patients affected by SCAC. RESULTS: Twenty-eight patients (34%) showed an increase in EGFR gene copy number due to amplification (4%) or to polysomy (30%). KRAS and PIK3CA gene mutations were found in 4 (5%) and 13 patients (16%), respectively. No mutations were found in the BRAF gene. CONCLUSIONS: The characterization of the EGFR pathway may help in identifying different subgroups of SCAC that have specific molecular features, which may have implications in what targeted therapies are used to treat each patient.

ERCC1 predicts outcome in patients with gastric cancer treated with adjuvant cisplatin-based chemotherapy.

BACKGROUND: Adjuvant chemotherapy is gaining an increasing role in resectable gastric cancer. Customizing chemotherapy on the basis of chemosensitivity may improve outcome, and putative predictive molecular markers have been mostly evaluated in Asian patients. We profiled key DNA and damage signaling factors and correlated them with outcome, in a European cohort. METHODS: Formalin-fixed tumor samples obtained from surgical specimens of patients treated with adjuvant cisplatin-based chemotherapy for gastric cancer were analyzed. Immunohistochemistry (IHC) was performed to analyze excision repair cross-complementing gene 1 (ERCC1) and thymidylate synthase (TS) expression, and p53 mutations were detected with direct sequencing. RESULTS: Among the 68 patient recruited, the median age was 69 (range 30-74), and UICC stage was III in 44 patients (65 %). With a median follow-up of 40.5 months, disease-free and overall survival were 18.0 (95 % CI 13.4-22.76) and 56 months (95 % CI 44.87-67.13), respectively. ERCC1 score was 0 in 14 out 67 (21 %) cases, 1 in 19 (28 %), 2 in 20 (30 %) and 3 in 14 cases (21 %). Longer overall survival (p = 0.04) was found in patients categorized as ERCC1 negative by IHC according to median score. TS score was 0 in 16 out 67 (24 %) cases, 1 in 27 (40 %), 2 in 16 (24 %) and 3 in 8 cases (12 %). Mutations of p53 were found in 21 out 66 (32 %) cases. Neither TS nor p53 were found to correlate with outcome. CONCLUSION: Excision repair cross-complementing gene 1 by IHC might predict patients more likely to benefit from adjuvant cisplatin-based chemotherapy in curatively resected gastric cancer. In patients exhibiting ERCC1 positive tumors, alternative regimens should be evaluated.

The clinical management in familial adenomatous polyposis deserves continuous monitoring for thyroid carcinoma.

Papillary thyroid carcinoma is an extraintestinal manifestation of patients with familial adenomatous polyposis, mainly occurring in young women. Recent publications highlight that familial adenomatous polyposis-associated papillary thyroid carcinoma represents a distinct type of follicular cell neoplasm histologically characterised by cribriform-morular aspects, the incidence of which has probably been underestimated so far. We report a case history of familial adenomatous polyposis-associated papillary thyroid carcinoma occurring in a 55-year-old man with Gardner syndrome, underscoring the importance of careful ultrasound screening examination of the thyroid gland in this condition.

Defining new criteria for selection of cell-based intestinal models using publicly available databases.

BACKGROUND: The criteria for choosing relevant cell lines among a vast panel of available intestinal-derived lines exhibiting a wide range of functional properties are still ill-defined. The objective of this study was, therefore, to establish objective criteria for choosing relevant cell lines to assess their appropriateness as tumor models as well as for drug absorption studies. RESULTS: We made use of publicly available expression signatures and cell based functional assays to delineate differences between various intestinal colon carcinoma cell lines and normal intestinal epithelium. We have compared a panel of intestinal cell lines with patient-derived normal and tumor epithelium and classified them according to traits relating to oncogenic pathway activity, epithelial-mesenchymal transition (EMT) and stemness, migratory properties, proliferative activity, transporter expression profiles and chemosensitivity. For example, SW480 represent an EMT-high, migratory phenotype and scored highest in terms of signatures associated to worse overall survival and higher risk of recurrence based on patient derived databases. On the other hand, differentiated HT29 and T84 cells showed gene expression patterns closest to tumor bulk derived cells. Regarding drug absorption, we confirmed that differentiated Caco-2 cells are the model of choice for active uptake studies in the small intestine. Regarding chemosensitivity we were unable to confirm a recently proposed association of chemo-resistance with EMT traits. However, a novel signature was identified through mining of NCI60 GI50 values that allowed to rank the panel of intestinal cell lines according to their drug responsiveness to commonly used chemotherapeutics. CONCLUSIONS: This study presents a straightforward strategy to exploit publicly available gene expression data to guide the choice of cell-based models. While this approach does not overcome the major limitations of such models, introducing a rank order of selected features may allow selecting model cell lines that are more adapted and pertinent to the addressed biological question.

Adjuvant PEFG (cisplatin, epirubicin, 5-fluorouracil, gemcitabine) or gemcitabine followed by chemoradiation in pancreatic cancer: a randomized phase II trial.

BACKGROUND: Information from randomized trials on the role of combination chemotherapy in the adjuvant treatment of pancreatic adenocarcinoma is limited. This randomized phase II trial aimed to identify the most promising regimen warranting phase III evaluation. METHODS: Therapy-naive patients, age 18-75 years, Karnofsky Performance Status (KPS)>60, gross total resection of stage IB-III pancreatic adenocarcinoma, stratified for center and surgical margins, were randomly assigned to receive either gemcitabine 1 g/m2 weekly on days 1, 8, and 15 (arm A) or the PEFG regimen (cisplatin and epirubicin 40 mg/m2, day 1; gemcitabine 600 mg/m2, days 1, 8; 5-fluorouracil 200 mg/m2 daily, days 1-28) (arm B). Chemotherapy was administered every 4 weeks for 3 months and followed by irradiation concurrent to continuous infusion of 5-fluorouracil 250 mg/m2 daily. Primary endpoint was the probability of being disease-free at 1 year from surgery. Assuming P0=35% and P1=55%, α=.05 and ß=.10, the study was to enroll 51 patients per arm. RESULTS: A total of 102 patients were randomized; 100 were eligible (arm A: 51; arm B: 49). Baseline characteristic (A/B) were: Median age was 61/60 years; 75% had KPS>80 75/76%; 36% grade 3 tumor 29/43%, 79% stage IIB/III 75/84%, 31% R1 resection 35/29%. Survival figures (A/B) were: Median disease-free survival was 11.7 and 15.2 months; 1-year disease-free survival 49.0% (95% confidence interval [95% CI] 35-63%) and 69.4% (95% CI 56-83%); median survival 24.8 and 28.9 months. Combination chemotherapy produced more hematological toxicity without relevant differences in nonhematological toxicities. CONCLUSIONS: The 4-drug regimen deserves further assessment in resectable pancreatic cancer.

KRAS and BRAF mutations predict primary resistance to imatinib in gastrointestinal stromal tumors.

PURPOSE: Gastrointestinal stromal tumors (GIST) are characterized by gain-of-function mutations in KIT/PDGFRA genes leading to a constitutive receptor activation which is well counteracted by imatinib. However, cases in which imatinib as first-line treatment has no effects are reported (primary resistance). Our purpose is to investigate alterations in downstream effectors, not reported so far in mutated GIST, possibly explaining the primary resistance to targeted treatments. EXPERIMENTAL DESIGN: Two independent naive GIST cohorts have been analyzed for KIT, PDGFRA, KRAS, and BRAF mutations by direct sequencing. Cell lines expressing a constitutively activated and imatinib-responding KIT, alone or in combination with activated KRAS and BRAF, were produced and treated with imatinib. KIT receptor and its downstream effectors were analyzed by direct Western blotting. RESULTS: In naive GISTs carrying activating mutations in KIT or PDGFRA a concomitant activating mutation was detected in KRAS (5%) or BRAF (about 2%) genes. In vitro experiments showed that imatinib was able to switch off the mutated receptor KIT but not the downstream signaling triggered by RAS-RAF effectors. CONCLUSIONS: These data suggest the activation of mitogen-activated protein kinase pathway as a possible novel mechanism of primary resistance to imatinib in GISTs and could explain the survival curves obtained from several clinical studies where 2% to 4% of patients with GIST treated with imatinib, despite carrying KIT-sensitive mutations, do not respond to the treatment.