RAD51 foci as a functional biomarker of homologous recombination repair and PARP inhibitor resistance in germline BRCA mutated breast cancer

Abstract

Background

BRCA1 and BRCA2 (BRCA1/2)-deficient tumors display impaired homologous recombination repair (HRR) and enhanced sensitivity to DNA damaging agents or to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi). Their efficacy in germline BRCA1/2 (gBRCA1/2)-mutated metastatic breast cancers has been recently confirmed in clinical trials. Numerous mechanisms of PARPi resistance have been described, whose clinical relevance in gBRCA-mutated breast cancer is unknown. This highlights the need to identify functional biomarkers to better predict PARPi sensitivity.

Patients and Methods

We investigated the in vivo mechanisms of PARPi resistance in gBRCA1 patient-derived tumor xenografts (PDXs) exhibiting differential response to PARPi. Analysis included exome sequencing and immunostaining of DNA damage response proteins to functionally evaluate HRR. Findings were validated in a retrospective sample set from gBRCA1/2-cancer patients treated with PARPi.

Results

RAD51 nuclear foci, a surrogate marker of HRR functionality, was the only common feature in PDX and patient samples with primary or acquired PARPi resistance. Consistently, low RAD51 was associated with objective response to PARPi. Evaluation of the RAD51 biomarker in untreated tumors was feasible due to endogenous DNA damage. In PARPi-resistant gBRCA1 PDXs, genetic analysis found no in-frame secondary mutations, but BRCA1 hypomorphic proteins in 60% of the models, TP53BP1-loss in 20% and RAD51-amplification in one sample, none mutually exclusive. Conversely, one of three PARPi-resistant gBRCA2 tumors displayed BRCA2 restoration by exome sequencing. In PDXs, PARPi resistance could be reverted upon combination of a PARPi with an ATM inhibitor.

Conclusion

Detection of RAD51 foci in gBRCA tumors correlates with PARPi resistance regardless of the underlying mechanism restoring HRR function. This is a promising biomarker to be used in the clinic to better select patients for PARPi therapy. Our study also supports the clinical development of PARPi combinations such as those with ATM inhibitors.

Induction Chemotherapy in Locally Advanced Squamous Cell Carcinoma of the Head and Neck: Role, Controversy, and Future Directions

Abstract

Background

The value of induction chemotherapy (ICT) remains under investigation despite decades of research. New advancements in the field, specifically regarding the induction regimen of choice, have reignited interest in this approach for patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN). Sufficient evidence has accumulated regarding the benefits and superiority of TPF (docetaxel, cisplatin, and fluorouracil) over the chemotherapy doublet PF (cisplatin and fluorouracil). We therefore sought to collate and interpret the available data and further discuss the considerations for delivering ICT safely and optimally selecting suitable post-ICT regimens.

Design

We nonsystematically reviewed published phase 3 clinical trials on TPF ICT in a variety of LA SCCHN patient populations conducted between 1990 and 2017.

Results

TPF may confer survival and organ preservation benefits in a subgroup of patients with functionally inoperable or poor-prognosis LA SCCHN. Additionally, patients with operable disease or good prognosis (who are not candidates for organ preservation) may benefit from TPF induction in terms of reducing local and distant failure rates and facilitating treatment deintensification in selected populations. The safe administration of TPF requires treatment by a multidisciplinary team at an experienced institution. The management of adverse events associated with TPF and post-ICT radiotherapy-based treatment is crucial. Finally, post-ICT chemotherapy alternatives to cisplatin concurrent with radiotherapy (ie, cetuximab or carboplatin plus radiotherapy) appear promising and must be investigated further.

Conclusions

TPF is an evidence-based ICT regimen of choice in LA SCCHN and confers benefits in suitable patients when it is administered safely by an experienced multidisciplinary team and paired with the optimal post-ICT regimen, for which, however, no consensus currently exists.

Should decisions on adding adjuvant chemotherapy in early stage ER positive breast cancer be based on gene expression testing or clinicopathologic factors or both?

Neo-adjuvant chemotherapy followed by chemoradiation and surgery with and without cetuximab in patients with resectable esophageal cancer: a randomized, open-label, phase III trial (SAKK 75/08)

Abstract

Background

This open-label, phase lll trial compared chemoradiation followed by surgery with or without neoadjuvant and adjuvant cetuximab in patients with resectable esophageal carcinoma.

Patients and Methods

Patients were randomly assigned (1:1) to 2 cycles of chemotherapy (docetaxel 75 mg/m², cisplatin 75 mg/m²) followed by chemoradiation (45 Gy, docetaxel 20 mg/m² and cisplatin 25 mg/m², weekly for 5 weeks) and surgery, with or without neoadjuvant cetuximab 250 mg/m² weekly and adjuvant cetuximab 500 mg/m² fortnightly for 3 months. The primary endpoint was progression-free survival (PFS).

Results

In total, 300 patients (median age, 61 years; 88% male; 63% adenocarcinoma; 85% cT3/4a, 90% cN+) were assigned to cetuximab (n = 149) or control (n = 151). The R0-resection rate was 95% for cetuximab versus 97% for control. Postoperative treatment-related mortality was 6% in both arms. Median PFS was 2.9 years (95% CI, 2.0 to not reached) with cetuximab and 2.0 years (95% CI, 1.5 to 2.8) with control (HR, 0.79; 95% CI, 0.58 to 1.07; P = .13). Median overall survival (OS) time was 5.1 years (95% CI, 3.7 to not reached) versus 3.0 years (95% CI, 2.2 to 4.2) for cetuximab and control, respectively (HR, 0.73; 95% CI, 0.52 to 1.01; P = .055). Time to loco-regional failure after R0-resection was significantly longer for cetuximab (HR 0.53; 95% CI, 0.31 to 0.90; P = .017); time to distant failure did not differ between arms (HR, 1.01; 95% CI, 0.64 to 1.59, P = .97). Cetuximab did not increase adverse events in neoadjuvant or postoperative settings.

Conclusion

Adding cetuximab to multimodal therapy significantly improved loco-regional control, and led to clinically relevant, but not-significant improvements in PFS and OS in resectable esophageal carcinoma.

Clinical trial information

NCT01107639

Circulating tumor DNA detection in hepatocellular carcinoma

Eribulin in BRAF V600E mutant metastatic colorectal cancer: Case series and potential rationale

Cutis laxa in a patient with 1p36 deletion syndrome

The Journal of Dermatology, EarlyView.

Herpes vegetans accompanied by Good's syndrome

The Journal of Dermatology, EarlyView.

Pigmented dermatofibrosarcoma protuberans associated with dermal melanocytosis

The Journal of Dermatology, EarlyView.

Relationship between environmental factors, age of onset and familial history in Japanese patients with psoriasis

The Journal of Dermatology, EarlyView.

Review on applications of artificial intelligence methods for dam and reservoir-hydro-environment models

Abstract

Efficacious operation for dam and reservoir system could guarantee not only a defenselessness policy against natural hazard but also identify rule to meet the water demand. Successful operation of dam and reservoir systems to ensure optimal use of water resources could be unattainable without accurate and reliable simulation models. According to the highly stochastic nature of hydrologic parameters, developing accurate predictive model that efficiently mimic such a complex pattern is an increasing domain of research. During the last two decades, artificial intelligence (AI) techniques have been significantly utilized for attaining a robust modeling to handle different stochastic hydrological parameters. AI techniques have also shown considerable progress in finding optimal rules for reservoir operation. This review research explores the history of developing AI in reservoir inflow forecasting and prediction of evaporation from a reservoir as the major components of the reservoir simulation. In addition, critical assessment of the advantages and disadvantages of integrated AI simulation methods with optimization methods has been reported. Future research on the potential of utilizing new innovative methods based AI techniques for reservoir simulation and optimization models have also been discussed. Finally, proposal for the new mathematical procedure to accomplish the realistic evaluation of the whole optimization model performance (reliability, resilience, and vulnerability indices) has been recommended.

The role of the water footprint in the context of green marketing

Abstract

The environmental degradation, because of various factors, such as climate change, human activities, increase of population globally, etc. have brought on pressures on the fresh water supplies that vary on time and space. Consequently, economic, environmental, and social tools have emerged known as footprints, in an effort to examine and measure the needs and consequences of humanity on the Earth's life support systems and take measures towards sustainable development. Furthermore, the constantly worsening environmental conditions have resulted in the cultivation of a green culture among society stakeholders that brought on terms such as green marketing and green products. This paper deals with the water footprint (WF) concept and an effort is performed, to explore through a literature review, in which ways it can contribute to the sustainable development of water use, in the context of green marketing (GM) strategies. The approach of the analysis is based on the discrimination to the following aspects: international scale, national and subnational scale, farmers, business, and consumers, in order to track the affection of each part in water issues. The main findings of the literature review showed that the aforementioned factors are playing a key role in protecting water recourses, by the way they formulate their water use and they are interrelated and interdependent. WFs can be useful in the context of GM, by providing helpful information about direct and indirect water consumption, to every contributor factor in supply chains, to consumers, governments, and water managers.

Official control of plant protection products in Poland: detection of illegal products

Abstract

Market presence of illegal and counterfeit pesticides is now a global problem. According to data published in 2012 by the European Crop Protection Association (ECPA), illegal products represent over 10% of the global market of plant protection products. Financial benefits are the main reason for the prevalence of this practice. Counterfeit and illegal pesticides may contain substances that may pose a threat to the environment, crops, animals, and humans, inconsistent with the label and registration dossier. In Poland, action against illegal and counterfeit plant protection products is undertaken by the Main Inspectorate of Plant Health and Seed Inspection (PIORiN), the police, the prosecution, and the pesticide producers. Results of chemical analyses carried out by the Institute of Plant Protection - National Research Institute Sośnicowice Branch, Pesticide Quality Testing Laboratory (PQTL IPP-NRI Sosnicowice Branch) indicate that a majority of illegal pesticides in Poland are detected in the group of herbicides. Products from parallel trade tend to have the most irregularities. This article describes the official quality control system of plant protection products in Poland and presents the analytical methods for testing pesticides suspected of adulteration and recent test results.

Does biologic treatment of psoriasis lower the risk of cardiovascular events and mortality? A critical question that we are only just beginning to answer

Modernizing Regulation of Cosmetic Products: Reintroduction of the Personal Care Products Safety Act

Can We Perform CT of the Appendix with Less Than 1 mSv? A De-escalating Dose-simulation Study

Abstract

Objectives

To systematically explore the lowest reasonably achievable radiation dose for appendiceal CT using an iterative reconstruction (IR) in young adults.

Methods

We prospectively included 30 patients who underwent 2.0-mSv CT for suspected appendicitis. From the helical projection data, 1.5-, 1.0- and 0.5-mSv CTs were generated using a low-dose simulation tool and the knowledge-based IR. We performed step-wise non-inferiority tests sequentially comparing 2.0-mSv CT with each of 1.5-, 1.0- and 0.5-mSv CT, with a predetermined non-inferiority margin of 0.06. The primary end point was the pooled area under the receiver-operating-characteristic curve (AUC) for three abdominal and three non-abdominal radiologists.

Results

For the abdominal radiologists, the non-inferiorities of 1.5-, 1.0- and 0.5-mSv CT to 2.0-mSv CT were sequentially accepted [pooled AUC difference: 2.0 vs. 0.5 mSv, 0.017 (95% CI: -0.016, 0.050)]. For the non-abdominal radiologists, the non-inferiorities of 1.5- and 1.0-mSv CT were accepted; however, the non-inferiority of 0.5-mSv CT could not be proved [pooled AUC difference: 2.0 vs. 1.0 mSv, -0.017 (-0.070, 0.035) and 2.0 vs. 0.5 mSv, 0.045 (-0.071, 0.161)].

Conclusion

The 1.0-mSv appendiceal CT was non-inferior to 2.0-mSv CT in terms of diagnostic performance for both abdominal and non-abdominal radiologists; 0.5-mSv appendiceal CT was non-inferior only for abdominal radiologists.

Key points

• For both abdominal and non-abdominal radiologists, 1.0-mSv appendiceal CT could be feasible.

• The 0.5-mSv CT was non-inferior to 2.0-mSv CT only for expert abdominal radiologists.

• Reader experience is an important factor affecting diagnostic impairment by low-dose CT.

Cervical ultrasonography has no additional value over negative 18 F-FDG PET/CT scans for diagnosing cervical lymph node metastases in patients with oesophageal cancer

Abstract

Objectives

To investigate the additional value of cervical ultrasonography over ¹⁸F-FDG PET/CT for diagnosing cervical lymph node metastases in patients with newly diagnosed oesophageal cancer.

Methods

Between January 2013 and January 2016, 163 patients with newly diagnosed oesophageal cancer underwent both cervical ultrasonography and ¹⁸F-FDG PET/CT at a tertiary referral centre in the Netherlands. Retrospective clinical data analysis was performed to assess the diagnostic value of cervical ultrasonography and ¹⁸F-FDG PET/CT for the detection of cervical lymph node metastases. Fine needle aspiration or clinical follow-up was used as reference standard.

Results

The overall incidence of patients with cervical lymph node metastases was 14%. The sensitivity of ¹⁸F-FDG PET/CT to detect cervical lymph node metastases was 82% (95% CI 59–94%) and specificity was 91% (95% CI 85–95%). The sensitivity and specificity of cervical ultrasonography were 73% (95% CI 50–88%) and 84% (95% CI 77–90%), respectively. In patients with a negative ¹⁸F-FDG PET/CT, 12 of 133 (9%) patients had suspicious nodes on cervical ultrasonography. In all these 12 patients the nodes were confirmed benign.

Conclusions

Cervical ultrasonography has no additional diagnostic value to a negative integrated ¹⁸F-FDG PET/CT for the detection of cervical lymph node metastases in patients with newly diagnosed oesophageal cancer.

Key Points

• Cervical ultrasonography has no value over PET/CT in evaluating cervical node metastases.

• PET/CT provides greater diagnostic confidence compared to cervical ultrasonography.

• Cervical ultrasonography during standard diagnostic work-up may be considered unnecessary.

• Cervical lesions on PET/CT require cytopathological confirmation by FNA.

Round-the-clock performance of coronary CT angiography for suspected acute coronary syndrome: Results from the BEACON trial

Abstract

Objective

To assess the image quality of coronary CT angiography (CCTA) for suspected acute coronary syndrome (ACS) outside office hours.

Methods

Patients with symptoms suggestive of an ACS underwent CCTA at the emergency department 24 hours, 7 days a week. A total of 118 patients, of whom 89 (75 %) presented during office hours (weekdays between 07:00 and 17:00) and 29 (25 %) outside office hours (weekdays between 17:00 and 07:00, weekends and holidays) underwent CCTA. Image quality was evaluated per coronary segment by two experienced readers and graded on an ordinal scale ranging from 1 to 3.

Results

There were no significant differences in acquisition parameters, beta-blocker administration or heart rate between patients presenting during office hours and outside office hours. The median quality score per patient was 30.5 [interquartile range 26.0–33.5] for patients presenting during office hours in comparison to 27.5 [19.75–32.0] for patients presenting outside office hours (p=0.043). The number of non-evaluable segments was lower for patients presenting during office hours (0 [0–1.0] vs. 1.0 [0–4.0], p=0.009).

Conclusion

Image quality of CCTA outside office hours in the diagnosis of suspected ACS is diminished.

Key Points

• Quality scores were higher for coronary-CTA during office hours.

• There were no differences in acquisition parameters.

• There was a non-significant trend towards higher heart rates outside office hours.

• Coronary-CTA on the ED requires state-of-the-art scanner technology and sufficiently trained staff.

• Coronary-CTA on the ED needs preparation time and optimisation of the procedure.

The impact of injector-based contrast agent administration in time-resolved MRA

Abstract

Objectives

Time-resolved contrast-enhanced MR angiography (4D-MRA), which allows the simultaneous visualization of the vasculature and blood-flow dynamics, is widely used in clinical routine. In this study, the impact of two different contrast agent injection methods on 4D-MRA was examined in a controlled, standardized setting in an animal model.

Methods

Six anesthetized Goettingen minipigs underwent two identical 4D-MRA examinations at 1.5 T in a single session. The contrast agent (0.1 mmol/kg body weight gadobutrol, followed by 20 ml saline) was injected using either manual injection or an automated injection system. A quantitative comparison of vascular signal enhancement and quantitative renal perfusion analyses were performed.

Results

Analysis of signal enhancement revealed higher peak enhancements and shorter time to peak intervals for the automated injection. Significantly different bolus shapes were found: automated injection resulted in a compact first-pass bolus shape clearly separated from the recirculation while manual injection resulted in a disrupted first-pass bolus with two peaks. In the quantitative perfusion analyses, statistically significant differences in plasma flow values were found between the injection methods.

Conclusions

The results of both qualitative and quantitative 4D-MRA depend on the contrast agent injection method, with automated injection providing more defined bolus shapes and more standardized examination protocols.

Key points

• Automated and manual contrast agent injection result in different bolus shapes in 4D-MRA.

• Manual injection results in an undefined and interrupted bolus with two peaks.

• Automated injection provides more defined bolus shapes.

• Automated injection can lead to more standardized examination protocols.

Evaluation of an adaptive detector collimation for prospectively ECG-triggered coronary CT angiography with third-generation dual-source CT

Abstract

Objectives

To investigate the impact of an adaptive detector collimation on the dose parameters and accurateness of scan length adaption at prospectively ECG-triggered sequential cardiac CT with a wide-detector third-generation dual-source CT.

Methods

Ideal scan lengths for human hearts were retrospectively derived from 103 triple-rule-out examinations. These measures were entered into the new scanner operated in prospectively ECG-triggered sequential cardiac scan mode with three different detector settings: (1) adaptive collimation, (2) fixed 64 × 0.6-mm collimation, and (3) fixed 96 × 0.6-mm collimation. Differences in effective scan length and deviation from the ideal scan length and dose parameters (CTDIvol, DLP) were documented.

Results

The ideal cardiac scan length could be matched by the adaptive collimation in every case while the mean scanned length was longer by 15.4% with the 64 × 0.6 mm and by 27.2% with the fixed 96 × 0.6-mm collimation. While the DLP was almost identical between the adaptive and the 64 × 0.6-mm collimation (83 vs. 89 mGycm at 120 kV), it was 62.7% higher with the 96 × 0.6-mm collimation (135 mGycm), p < 0.001.

Conclusion

The adaptive detector collimation for prospectively ECG-triggered sequential acquisition allows for adjusting the scan length as accurate as this can only be achieved with a spiral acquisition. This technique allows keeping patient exposure low where patient dose would significantly increase with the traditional step-and-shoot mode.

Key points

• Adaptive detector collimation allows keeping patient exposure low in cardiac CT.

• With novel detectors the desired scan length can be accurately matched.

• Differences in detector settings may cause 62.7% of excessive dose.