Efficacy of subsequent treatments in patients with hormone-positive advanced breast cancer who had disease progression under CDK 4/6 inhibitor therapy

Background: There is no standard treatment recommended at category 1 level in international guidelines for subsequent therapy after cyclin-dependent kinase 4/6 inhibitor (CDK4/6) based therapy. We aimed to evaluate which subsequent treatment oncologists prefer in patients with disease progression under CDKi. In addition, we aimed to show the effectiveness of systemic treatments after CDKi and whether there is a survival difference between hormonal treatments (monotherapy vs. mTOR-based). Methods: A total of 609 patients from 53 centers were included in the study. Progression-free-survivals (PFS) of subsequent treatments (chemotherapy (CT, n:434) or endocrine therapy (ET, n:175)) after CDKi were calculated. Patients were evaluated in three groups as those who received CDKi in first-line (group A, n:202), second-line (group B, n: 153) and ≥ 3rd-line (group C, n: 254). PFS was compared according to the use of ET and CT. In addition, ET was compared as monotherapy versus everolimus-based combination therapy. Results: The median duration of CDKi in the ET arms of Group A, B, and C was 17.0, 11.0, and 8.5 months in respectively; it was 9.0, 7.0, and 5.0 months in the CT arm. Median PFS after CDKi was 9.5 (5.0–14.0) months in the ET arm of group A, and 5.3 (3.9–6.8) months in the CT arm (p = 0.073). It was 6.7 (5.8–7.7) months in the ET arm of group B, and 5.7 (4.6–6.7) months in the CT arm (p = 0.311). It was 5.3 (2.5–8.0) months in the ET arm of group C and 4.0 (3.5–4.6) months in the CT arm (p = 0.434). Patients who received ET after CDKi were compared as those who received everolimus-based combination therapy versus those who received monotherapy ET: the median PFS in group A, B, and C was 11.0 vs. 5.9 (p = 0.047), 6.7 vs. 5.0 (p = 0.164), 6.7 vs. 3.9 (p = 0.763) months. Conclusion: Physicians preferred CT rather than ET in patients with early progression under CDKi. It has been shown that subsequent ET after CDKi can be as effective as CT. It was also observed that better PFS could be achieved with the subsequent everolimus-based treatments after first-line CDKi compared to monotherapy ET.Breast Cancer Consortiu

MOBYL: MOdel-driven BYpassing of middleware Layers

The Layered architectural style presents a quandary for software architects. On the one hand, the style provides important advantages: separation of concerns, abstraction, ease of evolution, etc. Each layer can build on lower layers to add specific abstractions or services. On the other hand, the layers can become opaque, rigid barriers that inhibit the ability to adapt to new application needs. Consider, for example that some application functions may not need the services of all the layers; it may be more efficient to implement them in a lower layer. We refer to these as bypassing functions. In such situations, where changes to lower layers are needed, developers must resort to writing tricky, intricate, low-level code, which is time-consuming, error prone, and not portable. We address this phenomenon in the context of middleware, and extend the middleware notion of model-driven development with new modeling syntax, code generation tools, and development processes to make it easier to build bypassing implementations. We will describe our approach and provide several illustrative examples and performance data. We will use this data to argue that bypassing implementations can provide more efficient use of a server’s resources, leading to overall better client experience. Our core contribution is this idea: model-driven code generation can enable application developers to conveniently bypass middleware layers when they are not needed, thus improving the server’s performance

An aspect-oriented approach to bypassing middleware layers

The layered architecture of middleware platforms (such as CORBA, SOAP, J2EE) is a mixed blessing. On the one hand, layers provide services such as demarshaling, session management, request despatching, quality-of-service (QoS) etc. In a typical middleware platform, every request passes through each layer, whether or not the services provided by that layer are needed for that specific request. This rigid layer processing can lower overall system throughput, and reduce availability and/or increase vulnerability to denial-of-service attacks. For use cases where the response is a simple function of the request input parameters, bypassing middleware layers may be permissible and highly advantageous. Unfortunately, if an application developer desires to selectively bypass the middleware, and process some requests in the lower layer, she has to write platform-specific, intricate low-level code. To evade this trap, we propose to extend the middleware platform with new aspect-oriented modeling syntax, code generation tools, and a development process for building bypassing implementations. Bypassing implementations provide better use of server's resources, leading to better overall client experience. Our core contribution is this idea: aspect-oriented extensions to IDL, additional code generation, along with an enhanced run-time, can enable application developers to conveniently bypass middleware layers when they are not needed, thus improving the server's performance and providing more "operational headroom"

Optimizing Layered Middleware

Abstract. Middleware is often built using a layered architectural style. Layered design provides good separation of the different concerns of middleware, such as communication, marshaling, request dispatching, thread management, etc. Layered architecture helps in the development and evolution of the middleware. It also provides tactical side-benefits: layers provide convenient protection boundaries for enforcing security policies. However, the benefits of this layered structure come at a cost. Layered designs can hinder performance-related optimizations, and actually make it more difficult to adapt systems to conveniently address late-bound requirements such as dependability, access control, virus protection, and so on. We present some examples of this issue, and outline a new approach, under investigation at UC Davis, which includes ideas in middleware, architectures, and programming models.

Long extensive transverse myelitis associated with aquaporin-4 antibody and breast cancer: Favorable response to cancer treatment

CONTEXT: Long extensive transverse myelitis (LETM) seldom develops in patients with breast cancer who are aquaporin-4 antibody (Aqp-4 Ab)-positive. Whether this association is coincidental is not well understood. FINDINGS: A 62-year-old woman presented with treatment-resistant LETM and Aqp-4 Ab. Two months later, a stage 3 invasive ductal carcinoma was detected in her right breast. Following tumor resection and chemotherapy, her neurologic symptoms and magnetic resonance imaging findings significantly improved and serum Aqp-4 Ab disappeared. The breast tumor samples of this patient and neurologically normal patients showed inflammatory infiltrates and Aqp-4 expressing cells. CONCLUSION/CLINICAL RELEVANCE: The temporal association between tumor treatment, amelioration of clinical findings, and seroreversion suggest that coexistence of cancer and LETM is not coincidental. Cancer screening should be considered at least in treatment-resistant LETM cases

Dual-phase F-18 FDG PET-CT in staging and lymphoscintigraphy for detection of sentinel lymph nodes in oral cavity cancers

Aim: Our objective was to evaluate the diagnostic role of dual-phase fluor-18 fluorodeoxyglucose (F-18 FOG) positron emission tomography-computed tomography (PET-CT) and planar lymphoscintigraphy in patients with oral cavity cancer (OCC). We also investigated the combined impact of F-18 FOG PET-CT and sentinel lymph node biopsy (SLNB) in decision making for patients with OCC

Are pretreatment inflammation-based prognostic scores useful in predicting the outcomes of patients with ALK-positive NSCLC?

Background: Approximately 5% of all diagnosed non-small cell lung cancer (NSCLC) patients harbor a genetic rearrangement between the ALK and EML4 genes, representing a specific molecular and clinical subgroup (ALK+ NSCLC). To date, upfront treatment with ALK-tyrosine-kinase inhibitors (ALK-TKIs) has replaced chemotherapy in the first line setting for this subset of patients with excellent results, but reliable prognostic markers are lacking. An increased systemic inflammatory response has been shown to be associated with a poor prognosis, and some of the parameters used to characterize this response can easily be measured in clinical practice in several tumor types, but have not been analyzed extensively in ALK+ lung cancer in the era of crizotinib. Method: We reviewed the medical records of all patients with previously treated advanced ALK-positive NSCLC who received crizotinib between January 2013 and March 2018 outside of a clinical trial. Pre-treatment modified Glasgow prognostic score (mGPS), Prognostic Nutritional Index (PNI) and Systemic immune-inflammation index (SII) were calculated. Multivariable logistic regression and Cox proportional hazards models were used to assess the impact of pretreatment mGPS, PNI and SII on overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). Result: 82 patients were treated. Median age was 52.5 years (range; 20e77 years); 42.7% were female. Eighty-four point two percent of patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) 1; 17.1% had received 2 prior systemic therapies. The objective response rate was 77.2% (CR+PR). The optimal cutoff levels were 0.09 for mGPS and PNI, 934.7 for SII by ROC curves analysis. Patients in the SII 934.7 grous was significantly correlated with worse PFS and OS by univariate analysis (Figure 1). In multivariate analyses, pretreatment prognostic nutritional index (PNI) 0.09 was independently associated with inferior OS (1 year OS rates, 90.2% vs. 73.7%; HR 2.46, 95% CI 0.88- 4.85; p ¼ 0.035). Additionally, we evaluated the effects of these markers on response prediction. The logistic regression analysis of the predictive factors for the response to crizotinib demonstrated that the mGPS and PNI were associated with inferior ORR (OR: 0.1, 95% CI 0.16-1.04; p ¼ 0.009 and OR: 0.16, 95% CI 0.02-0.55; p ¼ 0.035, respectively). Conclusion: In a cohort of patients with ALK positive NSCLC treated with crizotinib in routine practice, elevated pre-treatment SII was associated with shorter OS and PFS in univariate analysis and PNI was associated with shorter OS in multivariate analyses. Moreover the mGPS and PNI were associated with lower response rates

Systemic inflammatory markers as a predictors of response to crizotinib in patients with ALK-positive non-small-cell lung cancer

The significance of the presence of a systemic inflammatory response (SIR) in predicting survival has been demonstrated in patients with cancer. Moreover, neutrophil-to-lymphocyte ratio (NLR), lymphocyteratio (NLR), lymphocyte-to-monocyte ratio (LMR) and platelet-to-lymphocyte ratio (PLR) have been also investigated in patients with both early and advanced non-small-cell lung cancer (NSCLC). However, determination of SIR predicting outcomes of patients who are likely to response to crizotinib in ALK-positive NSCLC patients has not been clearly demonstrated