Nab-paclitaxel weekly versus dose-dense solvent-based paclitaxel followed by dose-dense epirubicin plus cyclophosphamide in high-risk HR+/HER2- early breast cancer: results from the neoadjuvant part of the WSG-ADAPT-HR+/HER2- trial.

BACKGROUND: In high-risk hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) early breast cancer (EBC), nanoparticle albumin-bound (nab)-paclitaxel showed promising efficacy versus solvent-based (sb)-paclitaxel in neoadjuvant trials; however, optimal patient and therapy selection remains a topic of ongoing research. Here, we investigate the potential of Oncotype DX® recurrence score (RS) and endocrine therapy (ET) response (low post-endocrine Ki67) for therapy selection. PATIENTS AND METHODS: Within the WSG-ADAPT trial (NCT01779206), high-risk HR+/HER2- EBC patients were randomized to (neo)adjuvant 4× sb-paclitaxel 175 mg/m2 q2w or 8× nab-paclitaxel 125 mg/m2 q1w, followed by 4× epirubicin + cyclophosphamide (90 mg + 600 mg) q2w; inclusion criteria: (i) cN0-1, RS 12-25, and post-ET Ki67 >10%; (ii) cN0-1 with RS >25. Patients with cN2-3 or (G3, baseline Ki67 ≥40%, and tumor size >1 cm) were allowed to be included without RS and/or ET response testing. Associations of key factors with pathological complete response (pCR) (primary) and survival (secondary) endpoints were analyzed using statistical mediation and moderation models. RESULTS: Eight hundred and sixty-four patients received neoadjuvant nab-paclitaxel (n= 437) or sb-paclitaxel (n = 427); nab-paclitaxel was superior for pCR (20.8% versus 12.9%, P = 0.002). pCR was higher for RS >25 versus RS ≤25 (16.0% versus 8.4%, P = 0.021) and for ET non-response versus ET response (15.1% versus 6.0%, P = 0.027); no factors were predictive for the relative efficacy of nab-paclitaxel versus sb-paclitaxel. Patients with pCR had longer distant disease-free survival [dDFS; hazard ratio 0.42, 95% confidence interval (CI) 0.20-0.91, P = 0.024]. Despite favorable prognostic association of RS >25 versus RS ≤25 with pCR (odds ratio 3.11, 95% CI 1.71-5.63, P ≤ 0.001), higher RS was unfavorably associated with dDFS (hazard ratio 1.03, 95% CI 1.01-1.05, P = 0.010). CONCLUSIONS: In high-risk HR+/HER2- EBC, neoadjuvant nab-paclitaxel q1w appears superior to sb-paclitaxel q2w regarding pCR. Combining RS and ET response assessment appears to select patients with highest pCR rates. The disadvantage of higher RS for dDFS is reduced in patients with pCR. These are the first results from a large neoadjuvant randomized trial supporting the use of RS to help select patients for neoadjuvant chemotherapy in high-risk HR+/HER2- EBC.

A scoping review of statistical methods in studies of biomarker-related treatment heterogeneity for breast cancer.

BACKGROUND: Many scientific papers are published each year and substantial resources are spent to develop biomarker-based tests for precision oncology. However, only a handful of tests is currently used in daily clinical practice, since development is challenging. In this situation, the application of adequate statistical methods is essential, but little is known about the scope of methods used. METHODS: A PubMed search identified clinical studies among women with breast cancer comparing at least two different treatment groups, one of which chemotherapy or endocrine treatment, by levels of at least one biomarker. Studies presenting original data published in 2019 in one of 15 selected journals were eligible for this review. Clinical and statistical characteristics were extracted by three reviewers and a selection of characteristics for each study was reported. RESULTS: Of 164 studies identified by the query, 31 were eligible. Over 70 different biomarkers were evaluated. Twenty-two studies (71%) evaluated multiplicative interaction between treatment and biomarker. Twenty-eight studies (90%) evaluated either the treatment effect in biomarker subgroups or the biomarker effect in treatment subgroups. Eight studies (26%) reported results for one predictive biomarker analysis, while the majority performed multiple evaluations, either for several biomarkers, outcomes and/or subpopulations. Twenty-one studies (68%) claimed to have found significant differences in treatment effects by biomarker level. Fourteen studies (45%) mentioned that the study was not designed to evaluate treatment effect heterogeneity. CONCLUSIONS: Most studies evaluated treatment heterogeneity via separate analyses of biomarker-specific treatment effects and/or multiplicative interaction analysis. There is a need for the application of more efficient statistical methods to evaluate treatment heterogeneity in clinical studies.

Health-related quality of life of long-term advanced melanoma survivors treated with anti-CTLA-4 immune checkpoint inhibition compared to matched controls.

BACKGROUND: Checkpoint inhibitors have changed overall survival for patients with advanced melanoma. However, there is a lack of data on health-related quality of life (HRQoL) of long-term advanced melanoma survivors, years after treatment. Therefore, we evaluated HRQoL in long-term advanced melanoma survivors and compared the study outcomes with matched controls without cancer. MATERIAL AND METHODS: Ipilimumab-treated advanced melanoma survivors without evidence of disease and without subsequent systemic therapy for a minimum of two years following last administration of ipilimumab were eligible for this study. The European Organization for Research and Treatment of Cancer quality of life questionnaire Core 30 (EORTC QLQ-C30), the Multidimensional Fatigue Inventory (MFI), the Hospital Anxiety and Depression Scale (HADS), and the Functional Assessment of Cancer Therapy-Melanoma questionnaire (FACT-M) were administered. Controls were individually matched for age, gender, and educational status. Outcomes of survivors and controls were compared using generalized estimating equations, and differences were interpreted as clinically relevant according to published guidelines. RESULTS: A total of 89 survivors and 265 controls were analyzed in this study. After a median follow-up of 39 (range, 17-121) months, survivors scored significantly lower on physical (83.7 vs. 89.8, difference (diff) = -5.80, p=.005), role (83.5 vs. 90, diff = -5.97, p=.02), cognitive (83.7 vs. 91.9, diff = -8.05, p=.001), and social functioning (86.5 vs. 95.1, diff = -8.49, p= <.001) and had a higher symptom burden of fatigue (23.0 vs. 15.5, diff = 7.48, p=.004), dyspnea (13.3 vs. 6.7, diff = 6.47 p=.02), diarrhea (7.9 vs. 4.0, diff = 3.78, p=.04), and financial impact (10.5 vs. 2.5, diff = 8.07, p=.001) than matched controls. Group differences were indicated as clinically relevant. DISCUSSION: Compared to matched controls, long-term advanced melanoma survivors had overall worse functioning scores, more physical symptoms, and financial difficulties. These data may contribute to the development of appropriate survivorship care.

One-stop-shop with confocal microscopy imaging vs. standard care for surgical treatment of basal cell carcinoma: an open-label, noninferiority, randomized controlled multicentre trial.

BACKGROUND: Routine punch biopsies are considered to be standard care for diagnosing and subtyping basal cell carcinoma (BCC) when clinically suspected. OBJECTIVES: We assessed the efficacy of a one-stop-shop concept using in vivo reflectance confocal microscopy (RCM) imaging as a diagnostic tool vs. standard care for surgical treatment in patients with clinically suspected BCC. METHODS: In this open-label, parallel-group, noninferiority, randomized controlled multicentre trial we enrolled patients with clinically suspected BCC at two tertiary referral centres in Amsterdam, the Netherlands. Patients were randomly assigned to the RCM one-stop-shop (diagnosing and subtyping using RCM followed by direct surgical excision) or standard care (planned excision based on the histological diagnosis and subtype of a punch biopsy). The primary outcome was the proportion of patients with tumour-free margins after surgical excision of BCC. RESULTS: Of the 95 patients included, 73 (77%) had a BCC histologically confirmed using a surgical excision specimen. All patients (40 of 40, 100%) in the one-stop-shop group had tumour-free margins. In the standard-care group tumour-free margins were found in all but two patients (31 of 33, 94%). The difference in the proportion of patients with tumour-free margins after BCC excision between the one-stop-shop group and the standard-care group was -0·06 (90% confidence interval -0·17-0·01), establishing noninferiority. CONCLUSIONS: The proposed new treatment strategy seems suitable in facilitating early diagnosis and direct treatment for patients with BCC, depending on factors such as availability of RCM, size and site of the lesion, patient preference and whether direct surgical excision is feasible.

Cox proportional hazards regression in small studies of predictive biomarkers.

Predictive biomarkers are essential for personalized medicine since they select the best treatment for a specific patient. However, of all biomarkers that are evaluated, only few are eventually used in clinical practice. Many promising biomarkers may be erroneously abandoned because they are investigated in small studies using standard statistical techniques which can cause small sample bias or lack of power. The standard technique for failure time endpoints is Cox proportional hazards regression with a multiplicative interaction term between binary variables of biomarker and treatment. Properties of this model in small studies have not been evaluated so far, therefore we performed a simulation study to understand its small sample behavior. As a remedy, we applied a Firth correction to the score function of the Cox model and obtained confidence intervals (CI) using a profile likelihood (PL) approach. These methods are generally recommended for small studies of different design. Our results show that a Cox model estimates the biomarker-treatment interaction term and the treatment effect in one of the biomarker subgroups with bias, and overestimates their standard errors. Bias is however reduced and power is increased with Firth correction and PL CIs. Hence, the modified Cox model and PL CI should be used instead of a standard Cox model with Wald based CI in small studies of predictive biomarkers.

Prognostic value of histopathologic traits independent of stromal tumor-infiltrating lymphocyte levels in chemotherapy-naïve patients with triple-negative breast cancer.

BACKGROUND: In the absence of prognostic biomarkers, most patients with early-stage triple-negative breast cancer (eTNBC) are treated with combination chemotherapy. The identification of biomarkers to select patients for whom treatment de-escalation or escalation could be considered remains an unmet need. We evaluated the prognostic value of histopathologic traits in a unique cohort of young, (neo)adjuvant chemotherapy-naïve patients with early-stage (stage I or II), node-negative TNBC and long-term follow-up, in relation to stromal tumor-infiltrating lymphocytes (sTILs) for which the prognostic value was recently reported. MATERIALS AND METHODS: We studied all 485 patients with node-negative eTNBC from the population-based PARADIGM cohort which selected women aged <40 years diagnosed between 1989 and 2000. None of the patients had received (neo)adjuvant chemotherapy according to standard practice at the time. Associations between histopathologic traits and breast cancer-specific survival (BCSS) were analyzed with Cox proportional hazard models. RESULTS: With a median follow-up of 20.0 years, an independent prognostic value for BCSS was observed for lymphovascular invasion (LVI) [adjusted (adj.) hazard ratio (HR) 2.35, 95% confidence interval (CI) 1.49-3.69], fibrotic focus (adj. HR 1.61, 95% CI 1.09-2.37) and sTILs (per 10% increment adj. HR 0.75, 95% CI 0.69-0.82). In the sTILs <30% subgroup, the presence of LVI resulted in a higher cumulative incidence of breast cancer death (at 20 years, 58%; 95% CI 41% to 72%) compared with when LVI was absent (at 20 years, 32%; 95% CI 26% to 39%). In the ≥75% sTILs subgroup, the presence of LVI might be associated with poor survival (HR 11.45, 95% CI 0.71-182.36, two deaths). We confirm the lack of prognostic value of androgen receptor expression and human epidermal growth factor receptor 2 -low status. CONCLUSIONS: sTILs, LVI and fibrotic focus provide independent prognostic information in young women with node-negative eTNBC. Our results are of importance for the selection of patients for de-escalation and escalation trials.

{Beta}2-adrenergic receptor agonists inhibit the proliferation of 1321N1 astrocytoma cells.

Astrocytomas and glioblastomas have been particularly difficult to treat and refractory to chemotherapy. However, significant evidence has been presented that demonstrates a decrease in astrocytoma cell proliferation subsequent to an increase in cAMP levels. The 1321N1 astrocytoma cell line, as well as other astrocytomas and glioblastomas, expresses ß(2)-adrenergic receptors (ß(2)-ARs) that are coupled to G(s) activation and consequent cAMP production. Experiments were conducted to determine whether the ß(2)-AR agonist (R,R')-fenoterol and other ß(2)-AR agonists could attenuate mitogenesis and, if so, by what mechanism. Receptor binding studies were conducted to characterize ß(2)-AR found in 1321N1 and U118 cell membranes. In addition, cells were incubated with (R,R')-fenoterol and analogs to determine their ability to stimulate intracellular cAMP accumulation and inhibit [(3)H]thymidine incorporation into the cells. 1321N1 cells contain significant levels of ß(2)-AR as determined by receptor binding. (R,R')-fenoterol and other ß(2)-AR agonists, as well as forskolin, stimulated cAMP accumulation in a dose-dependent manner. Accumulation of cAMP induced a decrease in [(3)H]thymidine incorporation. There was a correlation between concentration required to stimulate cAMP accumulation and inhibit [(3)H]thymidine incorporation. U118 cells have a reduced number of ß(2)-ARs and a concomitant reduction in the ability of ß(2)-AR agonists to inhibit cell proliferation. These studies demonstrate the efficacy of ß(2)-AR agonists for inhibition of growth of the astrocytoma cell lines. Because a significant portion of brain tumors contain ß(2)-ARs to a greater extent than whole brain, (R,R')-fenoterol, or some analog, may be useful in the treatment of brain tumors after biopsy to determine ß(2)-AR expression.

Comparison of the Peritoneal Cancer Index and Dutch region count as tools to stage patients with peritoneal metastases of colorectal cancer.

BACKGROUND: Extent of peritoneal metastases (PM) is among the most powerful prognostic factors for survival after cytoreductive surgery (CRS). This study aimed to compare the Peritoneal Cancer Index (PCI) and the Dutch region count as tools for staging PM of colorectal cancer. The Dutch region count is a simpler classification that distinguishes seven rather than 13 abdominal regions. Presence or absence of PM is recorded. METHODS: This was a retrospective cohort study in two tertiary referral centres in the Netherlands. Consecutive patients with colorectal PM who were intentionally treated with CRS and subsequent hyperthermic intraperitoneal chemotherapy in 2016 and 2017 were included. The PCI and Dutch region count were both recorded during laparotomy. Correlation between scoring tools was calculated using Spearman's rank correlation coefficient. Diagnostic values were calculated for different cut-off values of the PCI, alongside the Dutch region count. The correlation of both scores was determined for the exploration and validation cohorts separately. RESULTS: In the exploration and validation cohorts, 73 and 85 patients respectively were included. Spearman's correlation coefficients of 0·897 and 0·961 were observed for continuous scores of the Dutch region count and PCI in the exploration and validation group respectively. A cut-off value of 20 for the PCI score and 5 for the Dutch region count showed 91·9 and 94·5 per cent sensitivity, and 81·8 and 91·7 per cent specificity, respectively. CONCLUSION: The Dutch region count correlated well with the PCI score, and may help to simplify reporting of the extent of peritoneal disease.

ANTECEDENTES: La extensión de las metástasis peritoneales (peritoneal metastases, PM) es uno de los factores pronósticos más importantes para la supervivencia después de la cirugía citorreductora (cytoreductive surgery, CRS). El objetivo de este estudio fue comparar el índice de carcinomatosis peritoneal (Peritoneal Cancer Index, PCI) y el recuento holandés por regiones como herramientas para la estadificación de las PM del cáncer colorrectal. El recuento holandés por regiones es una clasificación más simple que distingue 7 regiones abdominales en lugar de 13. En dichas regiones abdominales se registró la presencia o ausencia de PM. MÉTODOS: Se llevó a cabo un estudio de cohortes retrospectivo en dos centros de referencia terciarios en los Países Bajos. Se incluyeron pacientes consecutivos con PM de origen colorrectal que fueron tratados con CRS seguida de quimioterapia intraperitoneal hipertérmica (hyperthermic intraperitoneal chemotherapy, HIPEC) en 2016 y 2017. Durante la laparotomía se recogieron datos del índice PCI y de la clasificación de las regiones abdominales. Se utilizó el coeficiente de correlación de Spearman para analizar la correlación entre estas dos herramientas de puntuación. Se calculó la precisión diagnóstica en función de diferentes umbrales del índice PCI junto con los datos del recuento por regiones. Asimismo, se calcularon las correlaciones entre ambas puntuaciones en las cohortes de exploración y validación por separado. RESULTADOS: Se incluyeron 73 pacientes en la cohorte de exploración y 85 en la de validación. Los coeficientes de correlación de Spearman eran de 0,987 para puntuaciones continuas del recuento holandés por regiones abdominales y del PCI en la cohorte de exploración y de 0,961 en la cohorte de validación. Los umbrales de corte de 20 para el índice PCI y de 5 para el recuento por regiones demostraron sensibilidades de 91,9% y 94,5%, y especificidades de 81,8% y 91,7%, respectivamente. CONCLUSIÓN: El recuento holandés por regiones abdominales se correlacionó bien con el PCI y puede ser útil para simplificar la extensión de la enfermedad peritoneal.

Factors influencing long-term survival after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for pseudomyxoma peritonei originating from appendiceal neoplasms.

Background: Pseudomyxoma peritonei (PMP) is a rare disease, most commonly of appendiceal origin. Treatment consists of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). The aim of this study was to identify prognostic factors for recurrence and survival. Methods: This was an observational study using a prospectively designed database containing consecutive patients with PMP originating from the appendix, undergoing CRS-HIPEC at a tertiary referral centre between 1996 and 2015. Histopathological slides were reassessed. Cox regression was used for multivariable analyses. Results: Of 225 patients identified, 36 (16·0 per cent) were diagnosed with acellular mucin, 149 (66·2 per cent) had disseminated peritoneal adenomucinosis (DPAM) and 40 (17·8 per cent) had peritoneal mucinous carcinomatosis (PMCA). The 5-year overall survival (OS) rates were 93, 69·8 and 55 per cent respectively. Recurrence was observed in 120 patients (53·3 per cent), 39 of whom (17·3 per cent) were treated with a second CRS-HIPEC procedure. Factors independently associated with poor disease-free survival were six or seven affected regions (hazard ratio (HR) 6·01, 95 per cent c.i. 2·04 to 17·73), incomplete cytoreduction (R2a resection: HR 1·67, 1·05 to 2·65; R2b resection: HR 2·00, 1·07 to 3·73), and more than threefold raised carcinoembryonic antigen (CEA) and/or carbohydrate antigen (CA) 19-9 level (HR 2·31, 1·30 to 4·11). Factors independently associated with poorer OS were male sex (HR 1·74, 1·09 to 2·77), incomplete cytoreduction (R2a resection: HR 1·87, 1·14 to 3·08; R2b resection: HR 2·28, 1·19 to 4·34), and more than threefold raised CEA and/or CA19-9 level (HR 2·89, 1·36 to 6·16). Conclusion: CEA and CA19-9 levels raised more than threefold above the upper limit identify patients with PMP of appendiceal origin and poorer survival.

Determination and modelling of stereoselective interactions of ligands with drug transporters: a key dimension in the understanding of drug disposition.

1. Stereochemistry is an important dimension in pharmacology and plays a role in every aspect of the pharmacological fate of chiral xenobiotics. This includes small molecule-drug transporter binding. 2. This paper reviews the reported stereoselectivities of substrate and inhibitor interactions with P-glycoprotein and the organic cation transporter obtained using standard functional and binding studies, as well as data obtained from online cellular membrane affinity chromatography studies. 3. The use of stereochemical data in quantitative structure-activity relationship (QSAR) and pharmacophore modelling is also addressed as is the effect of ignoring the fact that small molecule-drug transporter interactions take place in three-dimensional and asymmetric space.

Novel peptide inhibitor of dipeptidyl peptidase IV (Tyr-Pro-D-Ala-NH2) with anti-inflammatory activity in the mouse models of colitis.

Protease inhibition has become a new possible approach in the inflammatory bowel disease (IBD) therapy. A serine exopeptidase, dipeptidyl peptidase IV (DPP IV) is responsible for inactivation of incretin hormone, glucagon-like peptide 2 (GLP-2), a potent stimulator of intestinal epithelium regeneration and growth. Recently we showed that the novel peptide analog of endomorphin-2, EMDB-1 (Tyr-Pro-D-ClPhe-Phe-NH2) is a potent blocker of DPP IV and exhibits an anti-inflammatory activity in vivo. The aim of this study was to design, synthesize and characterize the therapeutic activity and mechanism of action of a series of novel EMDB-1 analogs. The inhibitory potential of all peptides was evaluated using the fluorometric screening assay employing Gly-Pro-Aminomethylcoumarin (AMC) to measure DPP IV activity. Consequently, one compound, namely DI-1 was selected and its therapeutic activity evaluated using mouse models of experimental colitis (induced by TNBS and DSS). Macro- and microscopic score, ulcer score, colonic wall thickness as well as myeloperoxidase activity were measured. We showed that DI-1 blocks DPP IV in vitro (IC50 = 0.76 ± 0.04 nM) and attenuates acute, semichronic and relapsing TNBS- as well as DSS-induced colitis in mice after topical administration. Its anti-inflammatory action is associated with the increase of colonic GLP-2 but not GLP2 receptor or DPP IV expression. Our results validate DPP IV as a pharmacological target for the anti-IBD drugs and its inhibitors, such as DI-1, have the potential to become valuable anti-inflammatory therapeutics.

Optimal adjuvant endocrine treatment of ER+/HER2+ breast cancer patients by age at diagnosis: A population-based cohort study.

BACKGROUND: Prior randomised controlled trials on adjuvant hormonal therapy included HER2any patients; however, a differential effect of aromatase inhibitors (AIs) versus tamoxifen (TAM) may have been missed in ER+/HER2+ patients that comprise 7-15% of all breast cancer patients. In addition, a woman's hormonal microenvironment may influence sensitivity to TAM and AIs in the adjuvant setting, which changes during menopausal transition, a process that takes years. We studied the efficacy of AIs versus TAM in ER+/HER2+ breast cancer patients grouped by age at diagnosis as a proxy for menopausal status using treatment and outcome data from the nationwide population-based Netherlands Cancer Registry (NCR). PATIENTS AND METHODS: All women diagnosed between 2005 and 2007 with endocrine-treated, TanyNanyM0, ER+/HER2+ breast cancer were identified through the NCR (n = 1155). Patients were divided by age at diagnosis: premenopausal (≤45 years; n = 326), perimenopausal (4555 years; n = 525). A time-dependent variable, indicating whether AI or TAM was received for >50% of endocrine treatment duration, was applied to subdivide groups by predominant treatment received. Recurrence-free survival (RFS) and overall survival (OS) were assessed using Kaplan-Meier survival estimation and Cox regression. Hazard ratios (HRs) were adjusted for chemotherapy, trastuzumab, age at diagnosis, N-status, grade, pT-stage and ovarian ablation. RESULTS: During follow-up, 237 recurrences and 182 deaths occurred. Perimenopausal women derived significant RFS and OS benefit from AI compared with TAM, HR 0.47 (95% CI 0.25-0.91; P = 0.03) and HR 0.37 (95% CI 0.18-0.79; P = 0.01), respectively, whereas premenopausal women derived no benefit from AI compared with TAM. Treatment effects differed significantly between these age groups (interaction P = 0.03 and P = 0.02, respectively). Among postmenopausal women a small but non-significant AI benefit was observed. CONCLUSION: AI treatment, preferably without any TAM treatment, was associated with the best RFS and OS outcome in ER+/HER2+ perimenopausal breast cancer patients.

Intraoperative ultrasound guidance in breast-conserving surgery shows superiority in oncological outcome, long-term cosmetic and patient-reported outcomes: Final outcomes of a randomized controlled trial (COBALT).

BACKGROUND: The multicenter randomized controlled COBALT trial demonstrated that ultrasound-guided breast-conserving surgery (USS) results in a significant reduction of margin involvement (3.1% vs. 13%) and excision volumes compared to palpation-guided surgery (PGS). The aim of the present study was to determine long term oncological and patient-reported outcomes including quality of life (QoL), together with their progress over time. METHODS: 134 patients with T1-T2 breast cancer were randomized to USS (N = 65) or PGS (N = 69). Cosmetic outcomes were assessed with the Breast Cancer Conservative Treatment cosmetic results (BCCT.core) software, panel-evaluation and patient self-evaluation on a 4-point Likert-scale. QoL was measured using the EORTC QLQ-C30/-BR23 questionnaire. RESULTS: No locoregional recurrences were reported after mean follow-up of 41 months. Seven patients (5%) developed distant metastatic disease (USS 6.3%, PGS 4.4%, p = 0.466), of whom six died of disease (95.5% overall survival). USS achieved better cosmetic outcomes compared to PGS, with poor outcomes of 11% and 21% respectively, a result mainly attributable to mastectomies due to involved margins following PGS. There was no difference after 1 and 3 years in cosmetic outcome. Dissatisfied patients included those with larger excision volumes, additional local therapies and worse QoL. Patients with poor/fair cosmetic outcomes scored significantly lower on aspects of QoL, including breast-symptoms, body image and sexual enjoyment. CONCLUSION: By significantly reducing positive margin status and lowering resection volumes, USS improves the rate of good cosmetic outcomes and increases patient-satisfaction. Considering the large impact of cosmetic outcome on QoL, USS has great potential to improve QoL following breast-conserving therapy.

Subchronic administration of (R,S)-ketamine induces ketamine ring hydroxylation in Wistar rats.

Subchronic administration of (R,S)-ketamine, (R,S)-Ket, is used in the treatment of neuropathic pain, in particular Complex Regional Pain Syndrome, but the effect of this protocol on the metabolism of (R,S)-Ket is unknown. In this study, daily administration of a low dose of (R,S)-Ket for 14-days to Wistar rats was conducted to determine the impact of sub-chronic dosing on the pharmacokinetics of (R,S)-Ket and its major metabolites. The data indicate that, relative to a single administration of (R,S)-Ket, subchronic administration resulted in increased clearance of (R,S)-Ket and the N-demethylated metabolite norketamine measured as elimination half-life (t1/2) and decreased plasma concentrations of these compounds. Subchronic administration produced a slight decrease in t1/2 and an increase in plasma concentration of the major metabolite, (2S,6S;2R,6R)-hydroxynorketamine, and produced significant increases in the plasma concentrations of the (2S,6R;2R,6S)-hydroxynorketamine and (2S,4R;2R,4S)-hydroxynorketamine metabolites. The metabolism of (R,S)-Ket predominately occurs via two microsomal enzyme-mediated pathways: (R,S)-Ket⇒(R,S)-norketamine⇒(2S,6S;2R,6R)-hydroxynorketamine and (2S,4R;2R,4S)-hydroxynorketamine and the (R,S)-Ket⇒(2S,6R;2R,6S)-hydroxyketamine⇒(2S,6R;2R,6S)-hydroxynorketamine and (2S,6S;2R,6R)-hydroxynorketamine. The results indicate that the activity of both metabolic pathways are increased by subchronic administration of (R,S)-Ket producing new metabolite patterns and potential differences in clinical effects.

Neoadjuvant chemotherapy in breast-conserving surgery - Consequences on margin status and excision volumes: A nationwide pathology study.

BACKGROUND: Neoadjuvant chemotherapy (NACT) is increasingly used in patients with operable disease due to the potential of converting patients requiring mastectomy to breast conserving surgery (BCS) or lowering resection volumes to improve cosmetic outcome. This nationwide retrospective study aims to determine margin status and specimen volume in patients with invasive breast cancer who underwent BCS after NACT. METHODS: All patients who underwent BCS in 2012-2013 for invasive breast cancer were selected from a nationwide network and registry of histology and cytopathology in the Netherlands (PALGA). RESULTS: Of the 9901 patients, 626 (6.3%) received NACT. After primary surgery 949 (10.2%) patients had tumour-involved margins compared to 152 (24.3%) after NACT. Close margins (≤1 mm) were seen in another 111 (17.7%) patients after NACT. The adjusted odds ratio for involved margins after NACT was 2.94, meaning a three times higher risk of involved margins compared with primary surgery. In patients with lobular carcinoma (54.9%) and no response to NACT (42.1%) higher tumour-involved margins were seen. High resection volumes >60 cc were observed in 224 (36%) patients after NACT of which 37 (16.5%) had tumour involved margins and 32 (14.3%) close margins ≤1 mm. CONCLUSION: The primary goal of the surgeon performing BCS after NACT, to reach tumour-free margins, is not accomplished in one out of four patients. Patients especially at risk are patients with ILC and no pathological tumour response. Excessive resection volumes after NACT do not guarantee tumour-free margins. Further research is necessary to analyze whether we are counterproductive when NACT is given in order to lower resection volumes.

A nationwide pathology study on surgical margins and excision volumes after breast-conserving surgery: There is still much to be gained.

AIM OF THE STUDY: The current study aims to assess margin status in relation to amount of healthy breast tissue resected in breast-conserving surgery (BCS) on a nationwide scale. METHODS: Using PALGA (a nationwide network and registry of histology and cytopathology in the Netherlands), all patients who underwent BCS for primary invasive carcinoma in 2012-13 were selected (10,058 excerpts). 9276 pathology excerpts were analyzed for a range of criteria including oncological margin status and distance to closest margin, specimen weight/volume, greatest tumor diameter, and with or without localization method. Calculated resection ratios (CRR) were assessed to determine excess healthy breast tissue resection. RESULTS: Margins for invasive carcinoma and in situ carcinoma combined were tumor-involved in 498 (5.4%) and focally involved in 1021 cases (11.0%) of cases. Unsatisfactory resections including (focally) involved margins and margins ≤ 1 mm were reported in 33.8% of patients. The median lumpectomy volume was 46 cc (range 1-807 cc; SD 49.18) and median CRR 2.32 (range 0.10-104.17; SD 3.23), indicating the excision of 2.3 the optimal resection volume. CONCLUSION: The unacceptable rate of tumor-involved margins as well as margins ≤ 1 mm in one third of all patients is also achieved at the expense of healthy breast tissue resection, which may carry the drawback of high rates of cosmetic failure. These data clearly suggest the need for improvement in current breast conserving surgical procedures to decrease tumor-involved margin rates while reducing the amount of healthy breast tissue resected.

Use of reversed-phase high-performance liquid chromatography in QSAR analysis of 2,4-dihydroxythiobenzanilide analogues.

Thiobenzanilides are found to show strong biological activity as antimicrobial, antimycotic, and tuberculostatic agents. In addition, they are relatively weakly toxic to higher organisms. A large set of new (N-phenyl-)-2,4-dihydroxybenzenecarbothioamide derivatives was obtained. Preliminary studies showed high microbiological action of some of them. In the process of chromatographic analysis, several different chromatographic parameters were obtained. In case of RP-HPLC, these parameters correspond to hydrophobicity of the solute. Obtained chromatographic parameters exhibited moderate correlation with calculated log P parameter. Linear dependence of bacteriostatic or fungostatic activity on lipophilicity was observed. The degree of correlation of different parameters was compared. The lipophilicity of analysed tioamides was the most important factor responsible for fungostatic and bacteriostatic activity. In comparison to methanol eluent system, chromatographic parameters obtained in acetonitrile system were better correlated with bioactivity. Conversely with the calculated log P values, the experimentally derived parameters exhibited significant higher correlation to fungostatic activity determined on dermatophytes. While in case of other tested microorganisms log P was comparably or sometimes slightly better correlated.

Correlation of fungostatic activity with log P and sigma parameters in the group of thiobenzanilides.

2,4-Dihydroxythiobenzanilide and its analogues were recently found to show strong biological activity. Earlier works exhibited that their biological activity depends strongly on their lipophilicity determined by means of RP-HPLC. Among others, fungostatic activity against tested yeast and mould strains appeared to be comparatively poorer modelled by chromatographic lipophilicity parameters. Very high correlation (r approximately 0.85-0.9) with these activities was obtained by means of multiparameter regression analysis where calculated log P and Hammet sigma values were involved as the independent variables. Analysed data show that activity against yeast and mould fungi is a superposition of two basic properties of thiobenzanilides: their lipophilicity and electronic properties.

Recent progress in understanding of structure, ligand interactions and the mechanism of activation of the ß2-adrenergic receptor.

The understanding of ß2-adrenergic receptor (ß2AR) interactions with ligands as well as the mechanism of receptor activation changed radically from 2007, when the first crystallographic structure of the receptor was reported. Since then numerous crystallographic studies described interactions with all main classes of ß2AR ligands and with G proteins, which provided a great insight into the molecular structure of the receptor. However, molecular mechanisms of receptor activations remain to be determined. Functional research supported the concept of ligand-directed signaling at ß-adrenoceptors. Agonist can activate alternative signaling pathways with different capacities and trigger cellular effects. It indicates that agonists nominally belonging to the same class may bind to and/or stabilize different active conformations of the receptor which are selectively recognized by signaling proteins in the allosteric manner.