Fluoropyrimidine type, patient age, tumour sidedness and mutation status as determinants of benefit in patients with metastatic colorectal cancer treated with EGFR monoclonal antibodies: individual patient data pooled analysis of randomised trials from the ARCAD database.

BACKGROUND: KRAS mutations in metastatic colorectal cancer (mCRC) are used as predictive biomarkers to select therapy with EGFR monoclonal antibodies (mAbs). Other factors may be significant determinants of benefit. METHODS: Individual patient data from randomised trials with a head-to-head comparison between EGFR mAb versus no EGFR mAb (chemotherapy alone or best supportive care) in mCRC, across all lines of therapy, were pooled. Overall survival (OS) and progression-free survival (PFS) were compared between groups. Treatment effects within the predefined KRAS biomarker subsets were estimated by adjusted hazard ratio (HRadj) and 95% confidence interval (CI). EGFR mAb efficacy was measured within the KRAS wild-type subgroup according to BRAF and NRAS mutation status. In both KRAS wild-type and mutant subgroups, additional factors that could impact EGFR mAb efficacy were explored including the type of chemotherapy, line of therapy, age, sex, tumour sidedness and site of metastasis. RESULTS: 5675 patients from 8 studies were included, all with known mCRC KRAS mutation status. OS (HRadj 0.90, 95% CI 0.84-0.98, p = 0.01) and PFS benefit (HRadj 0.73, 95% CI 0.68-0.79, p < 0.001) from EGFR mAbs was observed in the KRAS wild-type group. PFS benefit was seen in patients treated with fluorouracil (HRadj 0.75, 95% CI 0.68-0.82) but not with capecitabine-containing regimens (HRadj 1.04, 95% CI 0.86-1.26) (pinteraction = 0.002). Sidedness also interacted with EGFR mAb efficacy, with survival benefit restricted to left-sided disease (pinteraction = 0.038). PFS benefits differed according to age, with benefits greater in those under 70 (pinteraction = 0.001). The survival benefit was not demonstrated in those patients with mutations found in the KRAS, NRAS or BRAF genes. The presence of liver metastases interacted with EGFR mAb efficacy in patients with KRAS mutant mCRC (pinteraction = 0.004). CONCLUSION: The benefit provided by EGFR mAbs in KRAS WT mCRC is associated with left-sided primary tumour location, younger patient age and absence of NRAS or BRAF mutations. Survival benefit is observed with fluorouracil but not capecitabine. Exploratory results support further research in KRAS mutant mCRC without liver metastases.

The effect of renal impairment and obesity on anti-Xa peak and trough levels in patients receiving therapeutic doses of nadroparin: a comparison with control patients.

PURPOSE: Anti-Xa peak level monitoring is recommended during LMWH treatment in renal impairment or obesity. The trough level has been proposed as marker for bleeding. We studied the influence of renal impairment and obesity on anti-Xa levels. METHODS: Peak and trough levels were collected during therapeutic nadroparin treatment in patients with renal impairment, obese patients, and controls. 27 patients (n = 68 samples) were evaluated and combined with published data (n = 319 samples from 35 patients) using population pharmacokinetic (popPK) modelling. RESULTS: Median peak level was 0.44 and 0.95 IU/mL in renal impairment with and without dose reduction and 0.60 and 0.43 IU/mL in obesity and controls, respectively. Trough levels were < 0.5 IU/mL in all patients with renal impairment with dose reduction and in 5/6 control patients. In the popPK model, total body weight and eGFR were covariates for clearance and lean body weight for distribution volume. Model-based evaluations demonstrated peak levels below the therapeutic window in controls and increased levels in renal impairment. Dose reductions resulted in a different effect on peak and trough levels. Obese patients (BMI up to 32 kg/m2) had similar levels upon weight-based dosing. CONCLUSION: In renal impairment, anti-Xa peak levels after dose reduction are comparable to those in controls. Weight-based dosing is suitable for obese patients. Aiming for peak levels between 0.6 and 1.0 IU/mL in these patients would result in overexposure compared to controls. Considering the association of trough levels and bleeding risk and our findings, trough monitoring seems to be a suitable parameter to identify nadroparin accumulation.

Added value of repeat sentinel lymph node biopsy in FDG-PET/CT node-negative patients with ipsilateral breast cancer recurrence.

PURPOSE: Repeat sentinel lymph node biopsy (rSLNB) has been suggested for axillary staging in clinically node-negative (cN0) patients with ipsilateral breast tumor recurrence (IBTR). Although rSLNB is technically feasible in this group of patients, the clinical value has not been established. We aimed to assess the added value of rSLNB in cN0 patients with IBTR who underwent optimal clinical staging with FDG-PET/CT. METHODS: This retrospective single-center cohort study included 119 patients with IBTR-staged cT1-4N0M0 with FDG-PET/CT who underwent rSLNB between 2006 and 2020. Overall recurrence-free survival (RFS) and overall survival (OS) were calculated for subgroups with tumor-positive, tumor negative, and unsuccessful rSLNB. RESULTS: rSLNB was successful in 79 (66%) of the 119 included patients, of whom 70 (59%) had a tumor negative and 9 (8%) a tumor-positive rSLNB; rSLNB was unsuccessful in the remaining 40 (34%) patients. Patients with a tumor-positive rSLNB had poorer overall 5-year RFS compared to patients with a tumor negative or unsuccessful rSLNB (44% vs. 86% vs. 90%, p = 0.004). Although patients with a tumor-positive rSLNB had worse RFS, the 10-year OS was comparable to a tumor negative or unsuccessful rSLNB (89% vs. 89% vs. 95%, p = 0.701). CONCLUSION: The incidence of a tumor-positive rSLNB in patients with a negative FDG-PET/CT is low and does not change survival. Therefore, in cN0 patients with IBTR who underwent optimal clinical staging with FDG-PET/CT, we support a patient- and tumor-tailored treatment strategy in which rSLNB may be omitted.

Toward omitting sentinel lymph node biopsy after neoadjuvant chemotherapy in patients with clinically node-negative breast cancer.

BACKGROUND: The nodal positivity rate after neoadjuvant chemotherapy (ypN+) in patients with clinically node-negative (cN0) breast cancer is low, especially in those with a pathological complete response of the breast. The aim of this study was to identify characteristics known before surgery that are associated with achieving ypN0 in patients with cN0 disease. These characteristics could be used to select patients in whom sentinel lymph node biopsy may be omitted after neoadjuvant chemotherapy. METHODS: This cohort study included patients with cT1-3 cN0 breast cancer treated with neoadjuvant chemotherapy followed by breast surgery and sentinel node biopsy between 2013 and 2018. cN0 was defined by the absence of suspicious nodes on ultrasound imaging and PET/CT, or absence of tumour cells at fine-needle aspiration. Univariable and multivariable logistic regression analyses were performed to determine predictors of ypN0. RESULTS: Overall, 259 of 303 patients (85.5 per cent) achieved ypN0, with high rates among those with a radiological complete response (rCR) on breast MRI (95·5 per cent). Some 82 per cent of patients with hormone receptor-positive disease, 98 per cent of those with triple-negative breast cancer (TNBC) and all patients with human epidermal growth factor receptor 2 (HER2)-positive disease who had a rCR achieved ypN0. Multivariable regression analysis showed that HER2-positive (odds ratio (OR) 5·77, 95 per cent c.i. 1·91 to 23·13) and TNBC subtype (OR 11·65, 2·86 to 106·89) were associated with ypN0 status. In addition, there was a trend toward ypN0 in patients with a breast rCR (OR 2·39, 0·95 to 6·77). CONCLUSION: The probability of nodal positivity after neoadjuvant chemotherapy was less than 3 per cent in patients with TNBC or HER2-positive disease who achieved a breast rCR on MRI. These patients could be included in trials investigating the omission of sentinel node biopsy after neoadjuvant chemotherapy.

Differences in Adolescents' Alcohol Use and Smoking Behavior between Educational Tracks: Do Popularity Norms Matter?

Explanations about differences in drinking and smoking rates between educational tracks have so far mainly focused on factors outside the classroom. The extent to which these behaviors are rewarded with popularity within a classroom-so called popularity norms-and their interaction with individual characteristics could explain the observed differences in risk behavior. 1860 adolescents (Mage = 13.04; 50% girls) from 81 different classrooms reported three times during one academic year about their own and their classmates behavior. Overall, in vocational tracks popularity norms for alcohol and smoking were more positive and predicted classroom differences in alcohol and smoking. Knowledge about classroom processes can advance the field in unraveling the functional aspects of risk behavior in adolescence. Preregistration: The hypotheses and the analytical plan of this study were preregistered under number #39136 ( https://aspredicted.org/blind.php?x=gx77p6 ).

Eliminating the breast cancer surgery paradigm after neoadjuvant systemic therapy: current evidence and future challenges.

In patients with operable early breast cancer, neoadjuvant systemic treatment (NST) is a standard approach. Indications have expanded from downstaging of locally advanced breast cancer to facilitate breast conservation, to in vivo drug-sensitivity testing. The pattern of response to NST is used to tailor systemic and locoregional treatment, that is, to escalate treatment in nonresponders and de-escalate treatment in responders. Here we discuss four questions that guide our current thinking about 'response-adjusted' surgery of the breast after NST. (i) What critical diagnostic outcome measures should be used when analyzing diagnostic tools to identify patients with pathologic complete response (pCR) after NST? (ii) How can we assess response with the least morbidity and best accuracy possible? (iii) What oncological consequences may ensue if we rely on a nonsurgical-generated diagnosis of, for example, minimally invasive biopsy proven pCR, knowing that we may miss minimal residual disease in some cases? (iv) How should we design clinical trials on de-escalation of surgical treatment after NST?

Regorafenib after failure of gemcitabine and platinum-based chemotherapy for locally advanced/metastatic biliary tumors: REACHIN, a randomized, double-blind, phase II trial.

BACKGROUND: There is a high unmet clinical need for treatments of advanced/metastatic biliary tract cancers after progression on first-line chemotherapy. Regorafenib has demonstrated efficacy in some gastrointestinal tumors that progress on standard therapies. PATIENTS AND METHODS: REACHIN was a multicenter, double-blind, placebo-controlled, randomized phase II study designed to evaluate the safety and efficacy of regorafenib in patients with nonresectable/metastatic biliary tract cancer that progressed after gemcitabine/platinum chemotherapy. Patients were randomly assigned 1 : 1 to best supportive care plus either regorafenib 160 mg once daily 3 weeks on/1 week off or placebo until progression or unacceptable toxicity. No crossover was allowed. The primary objective was progression-free survival (PFS). Secondary objectives were response rate, overall survival, and translational analysis. RESULTS: Sixty-six patients with intrahepatic (n = 42), perihilar (n = 6), or extrahepatic (n = 9) cholangiocarcinoma, or gallbladder carcinoma (n = 9) were randomized, 33 to each treatment group (33 per group). At a median follow-up of 24 months, all patients had progressed and six patients were alive. Median treatment duration was 11.0 weeks [95% confidence interval (CI): 6.0-15.9] in the regorafenib group and 6.3 weeks (95% CI: 3.9-7.0) in the placebo group (P = 0.002). Fourteen of 33 patients (42%) in the regorafenib group had a dose reduction. Stable disease rates were 74% (95% CI: 59-90) in the regorafenib group and 34% with placebo (95% CI: 18-51; P = 0.002). Median PFS in the regorafenib group was 3.0 months (95% CI: 2.3-4.9) and 1.5 months (95% CI: 1.2-2.0) in the placebo group (hazard ratio 0.49; 95% CI: 0.29-0.81; P = 0.004) and median overall survival was 5.3 months (95% CI: 2.7-10.5) and 5.1 months (95% CI: 3.0-6.4), respectively (P = 0.28). There were no unexpected/new safety signals. CONCLUSION: Regorafenib significantly improved PFS and tumor control in patients with previously treated metastatic/unresectable biliary tract cancer in the second- or third-line setting. CLINICAL TRIAL REGISTRATION: The trial is registered in the European Clinical Trials Register database (EudraCT 2012-005626-30) and at ClinicalTrials.gov (NCT02162914).

Neutropenia and survival outcomes in metastatic colorectal cancer patients treated with trifluridine/tipiracil in the RECOURSE and J003 trials.

BACKGROUND: The phase II J003 (N = 169) and phase III RECOURSE (N = 800) trials demonstrated a significant improvement in survival with trifluridine (FTD)/tipiracil (TPI) versus placebo in patients with refractory metastatic colorectal cancer. This post hoc analysis investigated pharmacokinetic data of FTD/TPI exposure and pharmacodynamic markers, such as chemotherapy-induced neutropenia (CIN) and clinical outcomes. PATIENTS AND METHODS: A total of 210 patients from RECOURSE were enrolled in this substudy. A limited sampling approach was used, with three pharmacokinetic samples drawn on day 12 of cycle 1. Patients were categorized as being above or below the median area under the plasma concentration-time curve (AUC) for FTD and TPI. We conducted a post hoc analysis using the entire RECOURSE population to determine the correlations between CIN and clinical outcome. We then carried out a similar analysis on the J003 trial to validate the results. RESULTS: In the RECOURSE subset, patients in the high FTD AUC group had a significantly increased CIN risk. Analyses of the entire population demonstrated that FTD/TPI-treated patients with CIN of any grade in cycles 1 and 2 had significantly longer median overall survival (OS) and progression-free survival (PFS) than patients who did not develop CIN and patients in the placebo group. Patients who required an FTD/TPI treatment delay had increased OS and PFS versus those in the placebo group and those who did not develop CIN. Similar results were obtained in the J003 cohort. CONCLUSIONS: In RECOURSE, patients with higher FTD drug exposure had an increased CIN risk. FTD/TPI-treated patients who developed CIN had improved OS and PFS versus those in the placebo group and those who did not develop CIN. Similar findings were reported in the J003 cohort, thus validating the RECOURSE results. The occurrence of CIN may be a useful predictor of treatment outcomes for FTD/TPI-treated patients. CLINICALTRIALS. GOV IDENTIFIER: NCT01607957 (RECOURSE). JAPAN PHARMACEUTICAL INFORMATION CENTER NUMBER: JapicCTI-090880 (J003).

Breast-contour preserving procedures for early-stage breast cancer: a population-based study of the trends, variation in practice and predictive characteristics in Denmark and the Netherlands.

PURPOSE: Breast-contour preservation (BCP) is possible for most women treated for early-stage breast cancer. BCP can be defined as primary breast-conserving treatment (BCT), neoadjuvant chemotherapy (NAC) followed by BCT and immediate postmastectomy breast reconstruction (IBR). This study provides insight in current BCP strategies in Denmark and the Netherlands and aims to identify opportunities for improvement within both countries. METHODS: A total of 92,881 patients with early-stage breast cancer who were operated in Denmark and the Netherlands between 2012 and 2017 were selected from the Danish Breast Cancer Group and the Dutch National Breast Cancer Audit databases. BCP procedures and predictive factors were analyzed within and between both countries. RESULTS: BCP was achieved in 76.7% (n = 16,355) of the Danish and in 74.5% (n = 53,328) of the Dutch patients. While BCP rate did not change significantly over time in Denmark (p = 0.250), a significant increase in BCP rate from 69.5% in 2012 to 78.5% in 2017 (p < 0.001) was observed in the Netherlands. In both countries, variation in BCP rates between hospitals decreased over time. NAC followed by BCT and postmastectomy IBR was substantially more often used in the Netherlands compared to Denmark, specifically in patients younger than 50 years. CONCLUSIONS: In more than 75% of all Danish and Dutch patients, surgically treated for early-stage breast cancer, the breast-contour was preserved. The different use of BCP strategies within Denmark and the Netherlands and the differences observed between hospitals in both countries emphasize the need for more (inter)national consensus on treatment modalities.

Thermistors coated with molecularly imprinted nanoparticles for the electrical detection of peptides and proteins.

In this communication, molecularly imprinted nanoparticles (nanoMIPs) that are produced by solid-phase synthesis are functionalised onto thermistors via dip-coating. These thermistors are soldered onto a printed-circuit board to facilitate electrical detection. Subsequently, these are inserted into a home-made thermal device that can measure the selective binding of biomolecules to the nanoMIP layer via monitoring the thermal resistance (Rth) at the solid-liquid interface. This thermal analysis technique, referred to as the Heat-Transfer Method, has previously been used for detection of proteins with MIP-based binders. While offering the advantages of low-cost and label free analysis, this method is limited by the high noise on the feedback loop and not being commercially available. These disadvantages can be overcome by the use of thermistors, which offer superior temperature sensitivity compared to thermocouples, and its electrical read-out can be easily integrated into portable devices. To our knowledge, this is the first report where MIPs are directly integrated onto thermistors for detection purposes. Measurements were conducted with an epitope of epidermal growth factor receptor (EGFR) and trypsin, where the electrical resistance was correlated to the biomolecule concentration. For both EGFR and trypsin, an enhanced signal to noise ratio for the electrical measurements was observed compared to previous analysis that was based on thermal resistance. The sensitivity of the sensors in buffered solution was in the nanomolar range, which is compatible with physiologically relevant concentrations. Upon exposure of the nanoMIP for EGFR towards pepsin no significant change in the resistance was yielded, establishing the selectivity of the developed sensor platform. Besides the enhanced sensitivity, the use of thermistors will enable miniaturisation of the device and has potential for in vivo measurements since specified electrochemical measurements are compatible with human use. To highlight the versatility of the nanoMIPs, this work should be extended to a set of biomolecules with various structures, with the possibility of extending this to an array format.

Impact of Second Opinions in Breast Cancer Diagnostics and Treatment: A Retrospective Analysis.

BACKGROUND: Breast cancer care is becoming increasingly complex, and patients with breast cancer are increasingly aware of the different treatment options, resulting in requests for second opinions (SOs). The current study investigates the impact of breast cancer SOs on final diagnosis and treatment in the Netherlands Cancer Institute (NCI) using a newly designed Breast Cancer Second Opinion (BCSO) classification system. METHODS: Patients who visited the NCI for an SO between October 2015 and September 2016 were included. Demographics, diagnostics, and treatment proposals were compared between first and SO. Discrepancy was categorized using our BCSO classification system, categorizing SOs into (1) noncomparable, (2) identical, and (3) minor or (4) major discrepancy. RESULTS: The majority of SOs (n = 591) were patient initiated (90.7%). A total of 121 patients underwent treatment prior to their SO, leaving 470 patients for assessment of discrepancies according to our BCSO classification system. More than 45% of these SOs resulted in at least one discrepancy, with comparable rates for physician- and patient-initiated SOs (42.5% vs. 45.6%, p = 0.708). Significantly more discrepancies were observed in patients with additional imaging (51.3% vs. 37.2%, p = 0.002) and biopsies (53.7% vs. 40.3%, p = 0.005). Almost 60% of all discrepancies were categorized as major (neoadjuvant systemic treatment instead of primary surgery, breast-conserving surgery instead of mastectomy, and proposing postmastectomy immediate breast reconstruction). CONCLUSIONS: Our findings show substantial differences in diagnostic and treatment options in breast cancer patients visiting the Netherlands Cancer Institute for an SO, thereby emphasizing more consensus for the indications of these treatment modalities.

Nationwide population-based study of the impact of immediate breast reconstruction after mastectomy on the timing of adjuvant chemotherapy.

BACKGROUND: Initiation of adjuvant chemotherapy within 6-12 weeks after mastectomy is recommended by guidelines. The aim of this population-based study was to investigate whether immediate breast reconstruction (IBR) after mastectomy reduces the likelihood of timely initiation of adjuvant chemotherapy. METHODS: All patients with breast cancer who had undergone mastectomy and adjuvant chemotherapy between 2012 and 2016 in the Netherlands were identified. Time from surgery to adjuvant chemotherapy was categorized as within 6 weeks or after more than 6 weeks, within 9 weeks or after more than 9 weeks, and within 12 weeks or after more than 12 weeks. The impact of IBR on the initiation of adjuvant chemotherapy for these three scenarios was estimated using propensity score matching to adjust for treatment by indication bias. RESULTS: A total of 6300 patients had undergone primary mastectomy and adjuvant chemotherapy, of whom 1700 (27·0 per cent) had received IBR. Multivariable analysis revealed that IBR reduced the likelihood of receiving adjuvant chemotherapy within 6 weeks (odds ratio (OR) 0·76, 95 per cent c.i. 0·66 to 0·87) and 9 weeks (0·69, 0·54 to 0·87), but not within 12 weeks (OR 0·75, 0·48 to 1·17). Following propensity score matching, IBR only reduced the likelihood of receiving adjuvant chemotherapy within 6 weeks (OR 0·95, 0·90 to 0·99), but not within 9 weeks (OR 0·97, 0·95 to 1·00) or 12 weeks (OR 1·00, 0·99 to 1·01). CONCLUSION: Postmastectomy IBR marginally reduced the likelihood of receiving adjuvant chemotherapy within 6 weeks, but not within 9 or 12 weeks. Thus, IBR is not contraindicated in patients who need adjuvant chemotherapy after mastectomy.

ANTECEDENTES: Las guías clínicas recomiendan iniciar la quimioterapia adyuvante entre las 6 y las 12 semanas después de la mastectomía. El objetivo de este estudio de base poblacional fue investigar si la reconstrucción inmediata de la mama (immediate breast reconstruction, IBR) tras mastectomía reduce la posibilidad de iniciar la quimioterapia adyuvante en el momento adecuado. MÉTODOS: Se identificaron todas las pacientes con cáncer de mama a las que se había realizado mastectomía y quimioterapia adyuvante entre el 2012 y el 2016 en los Países Bajos. El tiempo transcurrido entre la cirugía y la quimioterapia adyuvante se clasificó en tres grupos: ≤ 6 versus > 6 semanas, ≤ 9 versus > 9 semanas y ≤ 12 versus > 12 semanas. El impacto de la IBR en el inicio de la quimioterapia adyuvante en estos tres escenarios se estimó mediante un análisis de emparejamiento por puntaje de propensión para ajustar el tratamiento por sesgo de indicación. RESULTADOS: Se realizó una mastectomía primaria y quimioterapia adyuvante en 6.300 pacientes, de las que a 1.700 (27%) se hizo una IBR. El análisis multivariable demostró que la IBR redujo la probabilidad de recibir quimioterapia adyuvante dentro de las 6 y 9 semanas (razón de oportunidades, odds ratio, OR 0,76; i.c. del 95% 0,66-0,87 y OR 0,69; i.c. del 95% 0,54-0,87, respectivamente), pero no dentro de las 12 semanas (OR 0,75, i.c. del 95% 0,48-1,17). Al emparejar mediante el análisis de puntaje de propensión, la IBR solo redujo la probabilidad de recibir quimioterapia adyuvante dentro de las 6 semanas (OR 0,95; i.c. del 95%: 0,90 a 0,99), pero no dentro de las 9 ó 12 semanas (OR 0,97; i.c. del 95%: 0,95 a 1,00 y OR 1,00, i.c. del 95% 0,99-1,01). CONCLUSIÓN: La IBR postmastectomía disminuyó marginalmente la probabilidad de recibir quimioterapia adyuvante dentro de las 6 semanas, pero no más allá de las 9 ó 12 semanas. Por lo tanto, la IBR postmastectomía no está contraindicada en pacientes que necesitan tratamiento con quimioterapia adyuvante.

Trends on Axillary Surgery in Nondistant Metastatic Breast Cancer Patients Treated Between 2011 and 2015: A Dutch Population-based Study in the ACOSOG-Z0011 and AMAROS Era.

OBJECTIVES: To evaluate patterns of care in axillary surgery for Dutch clinical T1-4N0M0 (cT1-4N0M0) breast cancer patients and to assess the effect of the American College for Surgeons Oncology Group (ACOSOG)-Z0011 and After Mapping of the Axilla: Radiotherapy Or Surgery (AMAROS) trial on axillary surgery patterns in Dutch cT1-2N0M0 sentinel node positive breast cancer patients. BACKGROUND: Since publication of the ACOSOG-Z0011 and AMAROS trial, omitting a completion axillary lymph node dissection (cALND) in sentinel node positive breast cancer patients is proposed in selected patients. METHODS: Data were obtained from the nationwide Nationaal Borstkanker Overleg Nederland breast cancer audit. Descriptive analyses were used to demonstrate trends in axillary surgery. Multivariable logistic regression analyses were used to identify factors associated with the omission of cALND in cT1-2N0M0 sentinel node-positive breast cancer patients. RESULTS: Between 2011 and 2015 in cT1-4N0M0 breast cancer patients, the use of sentinel lymph node biopsy as definitive axillary staging increased from 72% to 93%, and (c)ALND as definitive axillary staging decreased from 24% to 6% (P < 0.001). The use of cALND decreased from 75% to 17% in cT1-2N0 sentinel node-positive patients (P < 0.001). Earlier year of diagnosis, lower age, primary mastectomy, invasive lobular subtype, increasing tumor grade, and treatment in a nonteaching hospital were associated with a lower probability of omitting cALND (P < 0.001). CONCLUSIONS: This study shows a trend towards less extensive axillary surgery in Dutch cT1-T4N0M0 breast cancer patients; illustrated by an overall increase of sentinel lymph node biopsy and decrease in cALND. Despite this trend, particularly noticed in cT1-2N0 sentinel node-positive patients after publication of the ACOSOG-Z0011 and AMAROS trial, variations in patterns of care in axillary surgery are still present.

Early changes in the extracellular matrix of the degenerating intervertebral disc, assessed by Fourier transform infrared imaging.

OBJECTIVE: Mechanical overloading induces a degenerative cell response in the intervertebral disc. However, early changes in the extracellular matrix (ECM) are challenging to assess with conventional techniques. Fourier Transform Infrared (FTIR) imaging allows visualization and quantification of the ECM. We aim to identify markers for disc degeneration and apply these to investigate early degenerative changes due to overloading and katabolic cell activity. DESIGN: Three experiments were conducted; Exp 1.: In vivo, lumbar spines of seven goats were operated: one disc was injected with chondroitinase ABC [cABC (mild degeneration)] and compared to the adjacent disc (control) after 24 weeks. Exp 2a: Ex vivo, caprine discs received physiological loading (n = 10) or overloading (n = 10) in a bioreactor. Exp 2b: Cell activity was diminished prior to testing by freeze-thaw cycles, 18 discs were then tested as in Exp 2a. In all experiments, FTIR images (spectral region: 1000-1300 cm-1) of mid-sagittal slices were analyzed using multivariate curve resolution. RESULTS: In vivo, FTIR was more sensitive than biochemical and histological analysis in identifying reduced proteoglycan content (P = 0.046) and increased collagen content in degenerated discs (P < 0.01). Notably, FTIR analysis additionally showed disorganization of the ECM, indicated by increased collagen entropy (P = 0.011). Ex vivo, the proteoglycan/collagen ratio decreased due to overloading (P = 0.047) and collagen entropy increased (P = 0.047). Cell activity affected collagen content only (P = 0.044). CONCLUSION: FTIR imaging allows a more detailed investigation of early disc degeneration than traditional measures. Changes due to mild overloading could be assessed and quantified. Matrix remodeling is the first detectable step towards intervertebral disc degeneration.

Major Reduction in Axillary Lymph Node Dissections After Neoadjuvant Systemic Therapy for Node-Positive Breast Cancer by combining PET/CT and the MARI Procedure.

BACKGROUND: Axillary lymph node dissection (ALND) is frequently performed for node-positive (cN+) breast cancer patients. Combining positron emission tomography/computed tomography (PET/CT) before-NST and the MARI (marking axillary lymph nodes with radioactive iodine seeds) procedure after neoadjuvant systemic therapy (NST) has the potential for avoiding unnecessary ALNDs. This report presents the results from implementation of this strategy. METHODS: All breast cancer patients treated with NST at the Netherlands Cancer Institute who underwent a PET/CT and the MARI procedure from July 2014 to July 2017 were included in the study. All the patients underwent tailored axillary treatment according to a protocol based on the combined results of PET/CT before NST and the MARI procedure after NST. With this protocol, patients showing one to three FDG-avid axillary lymph nodes (ALNs) on PET/CT (cN<4) and a tumor-negative MARI node receive no further axillary treatment. All cN (<4) patients with a tumor-positive MARI node receive locoregional radiotherapy, as well as patients with four or more FDG-avid ALNs [cN(4+)] and a tumor-negative MARI node after NST. An ALND is performed only for cN(4+) patients with a tumor-positive MARI node. RESULTS: The data of 159 patients who received a PET/CT before NST and a MARI procedure after NST were analyzed. Of these patients, 110 had one to three FDG-avid ALNs and 49 patients showed four or more FDG-avid ALNs on PET/CT before NST. For 130 patients (82%), ALND was omitted. Locoregional radiotherapy was administered to 91 patients (57%), and 39 patients (25%) received no further axillary treatment. CONCLUSION: Combining pre-NST axillary staging with PET/CT and post-NST staging with the MARI procedure resulted in an 82% reduction of ALNDs for cN + breast cancer patients.

Engineering molecularly imprinted polymers (MIPs) for the selective extraction and quantification of the novel psychoactive substance (NPS) methoxphenidine and its regioisomers.

In this communication, we present the first developed Molecularly Imprinted Polymers (MIPs) for the specific detection of a New Psychoactive Substance (NPS); namely, methoxphenidine (MXP) and its regioisomers. Selectivity of the MIP towards MXP is studied by analysing mixtures and an acquired street sample with High Performance Liquid Chromatography coupled to UV detection. The study demonstrates that the engineered polymers selectively extract MXP from heterogeneous samples, which makes for a very powerful diagnostic tool that can detect traces of MXP in complicated NPS samples.

Efficacy of everolimus plus octreotide LAR in patients with advanced neuroendocrine tumor and carcinoid syndrome: final overall survival from the randomized, placebo-controlled phase 3 RADIANT-2 study.

Background: In the phase 3 RADIANT-2 study, everolimus plus octreotide long-acting repeatable (LAR) showed improvement of 5.1 months in median progression-free survival versus placebo plus octreotide LAR among patients with advanced neuroendocrine tumors associated with carcinoid syndrome. The progression-free survival P-value was marginally above the prespecified threshold for statistical significance. Here, we report final overall survival (OS) and key safety update from RADIANT-2. Patients and methods: The RADIANT-2 trial compared everolimus (10 mg/day, orally; n = 216) versus placebo (n = 213), both in conjunction with octreotide LAR (30 mg, intramuscularly, every 28 days). Patients, unblinded at the time of progression or after end of double-blind core phase following primary analysis, were offered open-label everolimus with octreotide LAR (open-label phase). In the open-label phase, patients had similar safety and efficacy assessments as those in the core phase. For OS, hazard ratios (HRs) with 95% CIs using unadjusted Cox model and a Cox model adjusted for prespecified baseline covariates were calculated. Results: A total of 170 patients received open-label everolimus (143 crossed over from the placebo arm; 27 in the everolimus arm continued to receive the same treatment after unblinding). The median OS (95% CI) after 271 events was 29.2 months (23.8-35.9) for the everolimus arm and 35.2 months (30.0-44.7) for the placebo arm (HR, 1.17; 95% CI, 0.92-1.49). HR adjusted for baseline covariates was 1.08 (95% CI, 0.84-1.38). The most frequent drug-related grade 3 or 4 AEs reported during the open-label phase were diarrhea (5.3%), fatigue (4.7%), and stomatitis (4.1%). Deaths related to pulmonary or cardiac failure were observed more frequently in the everolimus arm. Conclusion: No significant difference in OS was observed for the everolimus plus octreotide LAR and placebo plus octreotide LAR arms of the RADIANT-2 study, even after adjusting for imbalances in the baseline covariates. Clinical Trial Number: NCT00412061, www.clinicaltrials.gov.

Primary tumor sidedness has an impact on prognosis and treatment outcome in metastatic colorectal cancer: results from two randomized first-line panitumumab studies.

BACKGROUND: Previous studies have reported the prognostic impact of primary tumor sidedness in metastatic colorectal cancer (mCRC) and its influence on cetuximab efficacy. The present retrospective analysis of two panitumumab trials investigated a possible association between tumor sidedness and treatment efficacy in first-line mCRC patients with RAS wild-type (WT) primary tumors. MATERIALS AND METHODS: Data from two randomized first-line panitumumab trials were analyzed for treatment outcomes by primary tumor sidedness for RAS WT patients. PRIME (phase 3; NCT00364013) compared panitumumab plus FOLFOX versus FOLFOX alone; PEAK (phase 2; NCT00819780) compared panitumumab plus FOLFOX versus bevacizumab plus FOLFOX. Primary tumors located in the cecum to transverse colon were coded as right-sided, while tumors located from the splenic flexure to rectum were considered left-sided. RESULTS: Tumor sidedness ascertainment (RAS WT population) was 83% (n = 559/675); 78% of patients (n = 435) had left-sided and 22% (n = 124) had right-sided tumors. Patients with right-sided tumors did worse for all efficacy parameters compared with patients with left-sided disease in the RAS WT population and also in the RAS/BRAF WT subgroup. In patients with left-sided tumors, panitumumab provided better outcomes than the comparator treatment, including on median overall survival (PRIME: 30.3 versus 23.6 months, adjusted hazard ratio = 0.73, P = 0.0112; PEAK: 43.4 versus 32.0 months, adjusted hazard ratio = 0.77, P = 0.3125). CONCLUSION: The results of these retrospective analyses confirm that in RAS WT patients, right-sided primary tumors are associated with worse prognosis than left-sided tumors, regardless of first-line treatment received. RAS WT patients with left-sided tumors derive greater benefit from panitumumab-containing treatment than chemotherapy alone or combined with bevacizumab, including an overall survival advantage (treatment difference: PRIME 6.7 months; PEAK 11.4 months). No final conclusions regarding optimal treatment could be drawn for RAS WT patients with right-sided mCRC due to the relatively low number of paxtients. Further research in this field is warranted. TRIAL REGISTRATION (CLINICALTRIALS.GOV): PRIME (NCT00364013), PEAK (NCT00819780).

Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomized trials.

BACKGROUND: There is increasing evidence that metastatic colorectal cancer (mCRC) is a genetically heterogeneous disease and that tumours arising from different sides of the colon (left versus right) have different clinical outcomes. Furthermore, previous analyses comparing the activity of different classes of targeted agents in patients with KRAS wild-type (wt) or RAS wt mCRC suggest that primary tumour location (side), might be both prognostic and predictive for clinical outcome. METHODS: This retrospective analysis investigated the prognostic and predictive influence of the localization of the primary tumour in patients with unresectable RAS wt mCRC included in six randomized trials (CRYSTAL, FIRE-3, CALGB 80405, PRIME, PEAK and 20050181), comparing chemotherapy plus EGFR antibody therapy (experimental arm) with chemotherapy or chemotherapy and bevacizumab (control arms). Hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival (OS) and progression-free survival (PFS) for patients with left-sided versus right-sided tumours, and odds ratios (ORs) for objective response rate (ORR) were estimated by pooling individual study HRs/ORs. The predictive value was evaluated by pooling study interaction between treatment effect and tumour side. RESULTS: Primary tumour location and RAS mutation status were available for 2159 of the 5760 patients (37.5%) randomized across the 6 trials, 515 right-sided and 1644 left-sided. A significantly worse prognosis was observed for patients with right-sided tumours compared with those with left-sided tumours in both the pooled control and experimental arms for OS [HRs = 2.03 (95% CI: 1.69-2.42) and 1.38 (1.17-1.63), respectively], PFS [HRs = 1.59 (1.34-1.88) and 1.25 (1.06-1.47)], and ORR [ORs = 0.38 (0.28-0.50) and 0.56 (0.43-0.73)]. In terms of a predictive effect, a significant benefit for chemotherapy plus EGFR antibody therapy was observed in patients with left-sided tumours [HRs = 0.75 (0.67-0.84) and 0.78 (0.70-0.87) for OS and PFS, respectively] compared with no significant benefit for those with right-sided tumours [HRs = 1.12 (0.87-1.45) and 1.12 (0.87-1.44) for OS and PFS, respectively; P value for interaction <0.001 and 0.002, respectively]. For ORR, there was a trend (P value for interaction = 0.07) towards a greater benefit for chemotherapy plus EGFR antibody therapy in the patients with left-sided tumours [OR = 2.12 (1.77-2.55)] compared with those with right-sided tumours [OR = 1.47 (0.94-2.29)]. Exclusion of the unique phase II trial or the unique second-line trial had no impact on the results. The predictive effect on PFS may depend of the type of EGFR antibody therapy and on the presence or absence of bevacizumab in the control arm. CONCLUSION: This pooled analysis showed a worse prognosis for OS, PFS and ORR for patients with right-sided tumours compared with those with left-sided tumours in patients with RAS wt mCRC and a predictive effect of tumour side, with a greater effect of chemotherapy plus EGFR antibody therapy compared with chemotherapy or chemotherapy and bevacizumab, the effect being greatest in patients with left-sided tumours. These predictive results should be interpreted with caution due to the retrospective nature of the analysis, which was carried out on subpopulations of patients included in these trials, and because none of these studies contemplated a full treatment sequence strategy.

A phase II study of a human anti-PDGFRα monoclonal antibody (olaratumab, IMC-3G3) in previously treated patients with metastatic gastrointestinal stromal tumors.

Background: This study evaluated tumor response to olaratumab (an anti-PDGFRα monoclonal antibody) in previously treated patients with metastatic gastrointestinal stromal tumor (GIST) with or without PDGFRα mutations (cohorts 1 and 2, respectively). Patients and methods: Patients received olaratumab 20 mg/kg intravenously every 14 days until disease progression, death, or intolerable toxicity occurred. Outcome measures were 12-week tumor response, progression-free survival (PFS), overall survival (OS), and safety. Results: Of 30 patients enrolled, 21 patients received ≥1 dose of olaratumab. In the evaluable population (cohort 1, n = 6; cohort 2, n = 14), no complete response (CR) or partial response (PR) was observed. Stable disease (SD) was observed in 3 patients (50.0%) in cohort 1 and 2 patients (14.3%) in cohort 2. Progressive disease (PD) was observed in 3 patients (50.0%) in cohort 1 and 12 patients (85.7%) in cohort 2. The 12-week clinical benefit rate (CR + PR + SD) (90% CI) was 50.0% (15.3-84.7%) in cohort 1 and 14.3% (2.6-38.5%) in cohort 2. SD lasted beyond 12 weeks in 5 patients (cohort 1, n = 3; cohort 2, n = 2). Median PFS (90% CI) was 32.1 (5.0-35.9) weeks in cohort 1 and 6.1 (5.7-6.3) weeks in cohort 2. Median OS was not reached in cohort 1 and was 24.9 (14.4-49.1) weeks in cohort 2. All patients in cohort 1 and 9 (64.3%) in cohort 2 experienced an olaratumab-related adverse event (AE), most commonly fatigue (38.1%), nausea (19.0%), and peripheral edema (14.3%). Two grade ≥3 olaratumab-related events were reported (cohort 1, syncope; cohort 2, hypertension). Conclusions: Olaratumab had an acceptable AE profile in patients with GIST. While there was no apparent effect on PFS in patients without PDGFRα mutations, patients with PDGFRα-mutant GIST (all with D842V mutations) treated with olaratumab had longer disease control compared with historical data for this genotype. ClinicalTrials.gov Identifier: NCT01316263.