Pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) is strongly associated with favorable outcome. We examined the utility of serial circulating tumor DNA (ctDNA) testing for ...predicting pCR and risk of metastatic recurrence.
Cell-free DNA (cfDNA) was isolated from 291 plasma samples of 84 high-risk early breast cancer patients treated in the neoadjuvant I-SPY 2 TRIAL with standard NAC alone or combined with MK-2206 (AKT inhibitor) treatment. Blood was collected at pretreatment (T0), 3 weeks after initiation of paclitaxel (T1), between paclitaxel and anthracycline regimens (T2), or prior to surgery (T3). A personalized ctDNA test was designed to detect up to 16 patient-specific mutations (from whole-exome sequencing of pretreatment tumor) in cfDNA by ultra-deep sequencing. The median follow-up time for survival analysis was 4.8 years.
At T0, 61 of 84 (73%) patients were ctDNA positive, which decreased over time (T1: 35%; T2: 14%; and T3: 9%). Patients who remained ctDNA positive at T1 were significantly more likely to have residual disease after NAC (83% non-pCR) compared with those who cleared ctDNA (52% non-pCR; odds ratio 4.33, P = 0.012). After NAC, all patients who achieved pCR were ctDNA negative (n = 17, 100%). For those who did not achieve pCR (n = 43), ctDNA-positive patients (14%) had a significantly increased risk of metastatic recurrence hazard ratio (HR) 10.4; 95% confidence interval (CI) 2.3-46.6; interestingly, patients who did not achieve pCR but were ctDNA negative (86%) had excellent outcome, similar to those who achieved pCR (HR 1.4; 95% CI 0.15-13.5).
Lack of ctDNA clearance was a significant predictor of poor response and metastatic recurrence, while clearance was associated with improved survival even in patients who did not achieve pCR. Personalized monitoring of ctDNA during NAC of high-risk early breast cancer may aid in real-time assessment of treatment response and help fine-tune pCR as a surrogate endpoint of survival.
•Lack of ctDNA clearance early during NAC portends poor response.•Detectable ctDNA during NAC is associated with poor outcomes.•Failure to clear ctDNA after NAC is associated with inferior distant disease-free recurrence survival.•Clearance of ctDNA is associated with improved survival even in patients who did not achieve pCR.
Aim Sacrococcygeal pilonidal disease is a common condition afflicting the young male working and student population, resulting in considerable pain, embarrassment and loss of work days. Controversy ...surrounds the most appropriate surgical approach to achieve low recurrence rates whilst minimizing morbidity and permitting an early return to work. This study aims to review the published literature comparing excision followed by either primary suture or rhomboid flap repair.
Methods PubMed, EMBASE, MEDLINE and The Cochrane Library were systematically reviewed, by two independent investigators, for relevant randomized controlled trials. Keywords and MeSH terms included ‘pilonidal disease’, ‘primary suture/repair’, ‘rhomboid flap’ and ‘limberg/modified Limberg flap’. ‘Related study’ function and manuscript bibliographies were searched for further relevant studies. Study quality was assessed using the Jadad score. Meta‐analysis was performed on pooled data, utilizing a random effects model when heterogeneity was high and a fixed effects model when heterogeneity was low. The primary end‐point assessed was disease recurrence. Secondary end‐points included wound dehiscence, pain scores, hospital stay and return to work.
Results Six studies were eventually included for pooled analysis following exclusion of randomized controlled trials with poor methodology. Two studies compared ‘off‐midline’ (Karydakis) primary suture with the Limberg flap repair. Six hundred and forty‐one patients were included (331 flap repairs). Rhomboid flap excision demonstrated a trend towards less disease recurrence (P = 0.07), lower wound infection (P = 0.001) and dehiscence (P = 0.01). However, no significant difference was found for pain scores, hospital stay or return to work.
Conclusion The current published literature supports the use of the rhomboid flap excision and the Limberg flap‐repair procedures over primary midline suture techniques for the elective management of primary pilonidal disease. Further high‐quality studies are necessary to compare flap with off‐midline repairs.
Integrins are a ubiquitous family of non-covalently associated alpha/beta transmembrane heterodimers linking extracellular ligands to intracellular signaling pathways 1 Cell, 2002; 110: 673. ...Platelets contain five integrins, three beta1 integrins that mediate platelet adhesion to the matrix proteins collagen, fibronectin and laminin, and the beta3 integrins alphavbeta3 and alphaIIbbeta3 2 J Clin Invest, 2005; 115: 3363. While there are only several hundred alphavbeta3 molecules per platelet, alphavbeta3 mediates platelet adhesion to osteopontin and vitronectin in vitro 3 J Biol Chem, 1997; 272: 8137; whether this occurs in vivo remains unknown. By contrast, the 80,000 alphaIIbbeta3 molecules on agonist-stimulated platelets bind fibrinogen, von Willebrand factor, and fibronectin, mediating platelet aggregation when the bound proteins crosslink adjacent platelets 2 J Clin Invest, 2005; 115: 3363. Although platelet integrins are poised to shift from resting to active conformations, tight regulation of their activity is essential to prevent the formation of intravascular thrombi. This review focuses on the structure and function of the intensively studied beta3 integrins, in particular alphaIIbbeta3, but reference will be made to other integrins where relevant.
Based on the results of randomized control trials, screening for lung cancer using computed tomography (CT) is now widely recommended. However, adherence to screening remains an issue outside the ...clinical trial setting. This study examines the utility of biomarker-based risk assessment on uptake and subsequent adherence in a community screening study.
In a single arm pilot study, current or former smokers > 50 years old with 20 + pack year history were recruited following local advertising. One hundred and fifty seven participants volunteered to participate in the study that offered an optional gene-based lung cancer risk assessment followed by low-dose CT according to a standardised screening protocol.
All 157 volunteers who attended visit 1 underwent the gene-based risk assessment comprising of a clinical questionnaire and buccal swab. Of this group, 154 subsequently attended for CT screening (98%) and were followed prospectively for a median of 2.7 years. A participant’s adherence to screening was influenced by their baseline lung cancer risk category, with overall adherence in those with a positive scan being significantly greater in the “very high” risk group compared to “moderate” and “high” risk categories (71% vs 52%, Odds ratio = 2.27, 95% confidence interval of 1.02–5.05, P = 0.047). Those in the “moderate” risk group were not different to those in the “high” risk group (52% and 52%, P > 0.05).
In this proof-of-concept study, personalised gene-based lung cancer risk assessment was well accepted, associated with a 98% uptake for screening and increased adherence for those in the highest risk group.
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