Gastrointestinal stromal tumors (GISTs) may be defined as morphologically spindle cell, epithelioid, or occasionally pleomorphic mesenchymal tumours of the gastrointestinal tract that usually express ...the KIT protein and harbour mutation of a gene that encodes for a type III receptor tyrosine kinase (either KIT or PDGFRA). In Caucasian populations their annual incidence is 10 to 15 cases per million. Approximately 80% of GISTs have mutated KIT and 5% mutated PDGFRA. Most KIT mutations occur in untreated GISTs in the juxtamembrane exon 11 and only rarely in the kinase domain, whereas in imatinib-treated patients secondary mutations are frequent in exons encoding for the ATP/imatinib binding pocket or the kinase activation loop. Surgery is the standard treatment of local GIST. Tyrosine kinase inhibitor imatinib is the standard treatment for metastatic disease with few exceptions. A majority (80–90%) of patients with metastatic disease respond to imatinib or achieve durable tumour growth stabilisation with continuous therapy using a daily dose of 400 mg to 600 mg. Treatment with imatinib increases survival of patients with advanced disease with a few years and is associated with only moderate toxicity. Imatinib is being evaluated as adjuvant treatment following surgery, and other tyrosine kinase inhibitors as treatments of advanced GIST.
We have previously shown the prognostic importance of tumor-infiltrating lymphocytes (TILs) in newly diagnosed triple-negative breast cancer (TNBC) using tumor samples from a large clinical trial ...cohort. In this study, we aimed to validate these findings and also investigate associations with trastuzumab benefit in HER2-overexpressing disease (HER2+).
A prospective–retrospective study was conducted using samples from the FinHER adjuvant, phase III trial that enrolled 1010 early-stage BC patients, 778 of whom were HER2-nonamplified. Those with HER2+ disease (n = 232) were randomized to 9 weeks of trastuzumab or no trastuzumab in addition to chemotherapy. Two pathologists independently quantified stromal TILs in 935 (92.6%) available slides. The primary end point of distant disease-free survival (DDFS) and interactions with trastuzumab were studied in Cox regression models.
Confirming our previous findings, in TNBC (n = 134) each 10% increase in TILs was significantly associated with decreased distant recurrence in TNBC; for DDFS the hazard ratio adjusted for clinicopathological factors: 0.77; 95% confidence interval (CI) 0.61–0.98, P = 0.02. In HER2+ BC (n = 209), each 10% increase in lymphocytic infiltration was significantly associated with decreased distant recurrence in patients randomized to the trastuzumab arm (DDFS Pinteraction = 0.025).
Higher levels of TILs present at diagnosis were significantly associated with decreased distant recurrence rates in primary TNBC. These results confirm our previous data and further support that TILs should be considered as a robust prognostic factor in this BC subtype. We also report for the first time an association between higher levels of TILs and increased trastuzumab benefit in HER2+ disease. Further research into why some TN and HER2+ BCs can or cannot generate a host antitumor immune response and how trastuzumab can favorably alter the immune microenvironment is warranted.
Conventional chemotherapy is the mainstay of adjuvant systemic treatment for most patients with early triple-negative breast cancer (TNBC). At present, comparisons between adjuvant chemotherapy ...regimens are retrospective in nature, and so the optimal drugs or drug combinations have not been established for patients with early TNBC. In retrospective subgroup analyses, taxanes are more effective than 5-fluorouracil in combination with cyclophosphamide and doxorubicin. Classical CMF (cyclophosphamide, methotrexate and 5-fluorouracil) has shown efficacy, whereas few data on the role of anthracyclines are available. An unplanned subgroup analysis of one randomised study suggests that capecitabine adds efficacy to a taxane-anthracycline regimen, but this observation requires confirmation. High-dose adjuvant chemotherapy is considered experimental. Ongoing trials are comparing standard adjuvant regimens with regimens that integrate an anti-angiogenic agent, a platin or maintenance capecitabine. Inhibitors of DNA repair or specific tyrosine kinases have not yet been addressed in the adjuvant setting. In the absence of data from prospective trials that focus on adjuvant therapy of early TNBC, several regimens, such as a taxane and an anthracycline-containing regimen or classical CMF may be considered reasonable choices.
Abstract Background Patients with gastrointestinal stromal tumour (GIST) are often followed up after surgery with longitudinally repeated imaging examinations to detect recurrence early. Studies on ...follow-up of GIST patients are few, the optimal follow-up methods are unknown and the recommendations for follow-up vary in guidelines. Methods We reviewed the current evidence for follow-up of patients treated with surgery alone and of patients who were treated with adjuvant or neoadjuvant imatinib. Results Imaging of the abdomen and the pelvis with computerised tomography (CT) or magnetic resonance imaging (MRI) usually suffices, since metastases are uncommon at other sites. The frequency of imaging may be adjusted with the risk of recurrence with time. Very low risk GISTs are very frequently cured with surgery and usually require no regular follow-up after complete surgery, and annual CT of the abdomen and the pelvis for 5 years suffices for most patients with a low to intermediate risk for recurrence. Most high-risk patients are treated with imatinib for at least 3 years after surgery. CT or MRI may be carried out 6-monthly during adjuvant imatinib, 3 to 4-monthly during the 2 years that follow discontinuation of imatinib when the risk of recurrence is high, and then at 6–12 month intervals to complete 10 years of follow-up. Recurrence after the first 10 years of follow-up is infrequent. Conclusions The follow-up schedules are best tailored with the risk of recurrence. The risk of recurrence should be estimated with the prognostic tools that consider the most relevant prognostic factors.
5-Fluorouracil (5-FU)-based chemotherapy is frequently associated with diarrhoea. We compared two 5-FU-based regimens and the effect of Lactobacillus and fibre supplementation on treatment ...tolerability. Patients diagnosed with colorectal cancer (n=150) were randomly allocated to receive monthly 5-FU and leucovorin bolus injections (the Mayo regimen) or a bimonthly 5-FU bolus plus continuous infusion (the simplified de Gramont regimen) for 24 weeks as postoperative adjuvant therapy. On the basis of random allocation, the study participants did or did not receive Lactobacillus rhamnosus GG supplementation (1-2 x 10(10) per day) and fibre (11 g guar gum per day) during chemotherapy. Patients who received Lactobacillus had less grade 3 or 4 diarrhoea (22 vs 37%, P=0.027), reported less abdominal discomfort, needed less hospital care and had fewer chemotherapy dose reductions due to bowel toxicity. No Lactobacillus-related toxicity was detected. Guar gum supplementation had no influence on chemotherapy tolerability. The simplified de Gramont regimen was associated with fewer grade 3 or 4 adverse effects than the Mayo regimen (45 vs 89%), and with less diarrhoea. We conclude that Lactobacillus GG supplementation is well tolerated and may reduce the frequency of severe diarrhoea and abdominal discomfort related to 5-FU-based chemotherapy.
Background and purpose
Cancer is a frequent finding in ischaemic stroke patients. The frequency of cancer amongst participants in the NAVIGATE ESUS randomized trial and the distribution of outcome ...events during treatment with aspirin and rivaroxaban were investigated.
Methods
Trial participation required a recent embolic stroke of undetermined source. Patients’ history of cancer was recorded at the time of study entry. During a mean follow‐up of 11 months, the effects of aspirin and rivaroxaban treatment on recurrent ischaemic stroke, major bleeding and all‐cause mortality were compared between patients with cancer and patients without cancer.
Results
Amongst 7213 randomized patients, 543 (7.5%) had cancer. Of all patients, 3609 were randomized to rivaroxaban 254 (7.0%) with cancer and 3604 patients to aspirin 289 (8.0%) with cancer. The annual rate of recurrent ischaemic stroke was 4.5% in non‐cancer patients in the rivaroxaban arm and 4.6% in the aspirin arm hazard ratio (HR) 0.98, 95% confidence interval (CI) 0.78–1.24. In cancer patients, the rate of recurrent ischaemic stroke was 7.7% in the rivaroxaban arm and 5.4% in the aspirin arm (HR 1.43, 95% CI 0.71–2.87). Amongst cancer patients, the annual rate of major bleeds was non‐significantly higher for rivaroxaban than aspirin (2.9% vs. 1.1%; HR 2.57, 95% CI 0.67–9.96; P for interaction 0.95). All‐cause mortality was similar in both groups.
Conclusions
Our exploratory analyses show that patients with embolic stroke of undetermined source and a history of cancer had similar rates of recurrent ischaemic strokes and all‐cause mortality during aspirin and rivaroxaban treatments and that aspirin appeared safer than rivaroxaban in cancer patients regarding major bleeds. www.clinicaltrials.gov (NCT02313909).
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