Abemaciclib plus a nonsteroidal aromatase inhibitor as initial therapy for HR+, HER2- advanced breast cancer: Final overall survival results of MONARCH 3.

BACKGROUND: In MONARCH 2, the addition of abemaciclib to fulvestrant significantly improved both progression-free survival (PFS) and overall survival (OS) in patients with HR+, HER2- advanced breast cancer (ABC) with disease progression on prior endocrine therapy (ET). In MONARCH 3, the addition of abemaciclib to a nonsteroidal aromatase inhibitor (NSAI) as initial therapy for HR+, HER2- ABC significantly improved PFS. Here, we present the prespecified final OS results for MONARCH 3. PATIENTS AND METHODS: MONARCH 3 is a randomized, double-blind, phase 3 study of abemaciclib plus NSAI (anastrozole or letrozole) versus placebo plus NSAI in postmenopausal women with HR+, HER2- ABC without prior systemic therapy in the advanced setting. The primary objective was investigator-assessed PFS; OS was a gated secondary endpoint, and chemotherapy-free survival (CFS) was an exploratory endpoint. RESULTS: A total of 493 women were randomized 2:1 to receive abemaciclib plus NSAI (n = 328) or placebo plus NSAI (n = 165). After a median follow-up of 8.1 years, there were 198 OS events (60.4%) in the abemaciclib arm and 116 (70.3%) in the placebo arm (hazard ratio, 0.804; 95% confidence interval [CI], 0.637-1.015; P = 0.0664, non-significant). Median OS was 66.8 versus 53.7 months for abemaciclib versus placebo. In the subgroup with visceral disease (sVD), there were 113 OS events (65.3%) in the abemaciclib arm and 65 (72.2%) in the placebo arm (hazard ratio, 0.758; 95% CI, 0.558-1.030; P = 0.0757, non-significant). Median OS was 63.7 months versus 48.8 months for abemaciclib versus placebo. The previously demonstrated PFS benefit was sustained, and CFS numerically improved with the addition of abemaciclib. No new safety signals were observed. CONCLUSION: Abemaciclib combined with an NSAI resulted in clinically meaningful improvement in median OS (ITT: 13.1 months; sVD: 14.9 months) in patients with HR+ HER2- ABC; however, statistical significance was not reached.

A pleiotropy scan to discover new susceptibility loci for pancreatic ductal adenocarcinoma.

Pleiotropic variants (i.e., genetic polymorphisms influencing more than one phenotype) are often associated with cancer risk. A scan of pleiotropic variants was successfully conducted ten years ago in relation to pancreatic ductal adenocarcinoma susceptibility. However, in the last decade, genetic association studies performed on several human traits have greatly increased the number of known pleiotropic variants. Based on the hypothesis that variants already associated with a least one trait have a higher probability of association with other traits, 61,052 variants reported to be associated by at least one genome wide association study (GWAS) with at least one human trait were tested in the present study consisting of two phases (discovery and validation), comprising a total of 16,055 pancreatic ductal adenocarcinoma (PDAC) cases and 212,149 controls. The meta-analysis of the two phases showed two loci (10q21.1-rs4948550 (P=6.52×10-5) and 7q36.3-rs288762 (P=3.03×10-5) potentially associated with PDAC risk. 10q21.1-rs4948550 shows a high degree of pleiotropy and it is also associated with colorectal cancer risk while 7q36.3-rs288762 is situated 28,558 base pairs upstream of the Sonic Hedgehog (SHH) gene, which is involved in the cell differentiation process and PDAC etiopathogenesis. In conclusion, none of the single nucleotide polymorphisms (SNPs) showed a formally statistically significant association after correction for multiple testing. However, given their pleiotropic nature and association with various human traits including colorectal cancer, the two SNPs showing the best associations with PDAC risk merit further investigation through fine mapping and ad hoc functional studies.

Open-label, phase II, multicenter study of lasofoxifene plus abemaciclib for treating women with metastatic ER+/HER2- breast cancer and an ESR1 mutation after disease progression on prior therapies: ELAINE 2.

BACKGROUND: Acquired ESR1 mutations in estrogen receptor-positive (ER+) metastatic breast cancer (mBC) drive treatment resistance and tumor progression; new treatment strategies are needed. Lasofoxifene, a next-generation, oral, endocrine therapy and tissue-specific ER antagonist, provided preclinical antitumor activity, alone or combined with a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) in ESR1-mutated mBC. PATIENTS AND METHODS: In the open-label, phase II, ELAINE 2 trial (NCT04432454), women with ESR1-mutated, ER+/human epidermal growth factor receptor 2-negative (HER2-) mBC who progressed on prior therapies (including CDK4/6i) received lasofoxifene 5 mg/day and abemaciclib 150 mg b.i.d until disease progression/toxicity. The primary endpoint was safety/tolerability. Secondary endpoints included progression-free survival (PFS), clinical benefit rate (CBR), and objective response rate (ORR). RESULTS: Twenty-nine women (median age 60 years) participated; all but one were previously treated with a CDK4/6i (median duration 2 years). The lasofoxifene-abemaciclib combination was well tolerated with primarily grade 1/2 treatment-emergent adverse events (TEAEs), most commonly diarrhea, nausea, fatigue, and vomiting. One patient (with no prior CDK4/6i) discontinued treatment due to grade 2 diarrhea. No deaths occurred during the study. Median PFS was 56.0 weeks [95% confidence interval (CI) 31.9 weeks-not estimable; ∼13 months]; PFS rates at 6, 12, and 18 months were 76.1%, 56.1%, and 38.8%, respectively. CBR at 24 weeks was 65.5% (95% CI 47.3% to 80.1%). In 18 patients with measurable lesions, ORR was 55.6% (95% CI 33.7% to 75.4%). ESR1-mutant circulating tumor DNA (ctDNA) allele fraction decreased from baseline to week 4 in 21/26 (80.8%) patients. CONCLUSIONS: Lasofoxifene plus abemaciclib had an acceptable safety profile, was well tolerated, and exhibited meaningful antitumor activity in women with ESR1-mutated, ER+/HER2- mBC after disease progression on prior CDK4/6i. Observed decreases in ESR1-mutant ctDNA with lasofoxifene concordant with clinical response suggest target engagement. If the ELAINE 2 findings are confirmed in the initiated, phase III, ELAINE 3 trial, these data could be practice-changing and help address a critical unmet need.

Lasofoxifene versus fulvestrant for ER+/HER2- metastatic breast cancer with an ESR1 mutation: results from the randomized, phase II ELAINE 1 trial.

BACKGROUND: Acquired estrogen receptor alpha (ER/ESR1) mutations commonly cause endocrine resistance in ER+ metastatic breast cancer (mBC). Lasofoxifene, a novel selective ER modulator, stabilizes an antagonist conformation of wild-type and ESR1-mutated ER-ligand binding domains, and has antitumor activity in ESR1-mutated xenografts. PATIENTS AND METHODS: In this open-label, randomized, phase II, multicenter, ELAINE 1 study (NCT03781063), we randomized women with ESR1-mutated, ER+/human epidermal growth factor receptor 2 negative (HER2-) mBC that had progressed on an aromatase inhibitor (AI) plus a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) to oral lasofoxifene 5 mg daily or IM fulvestrant 500 mg (days 1, 15, and 29, and then every 4 weeks) until disease progression/toxicity. The primary endpoint was progression-free survival (PFS); secondary endpoints were safety/tolerability. RESULTS: A total of 103 patients received lasofoxifene (n = 52) or fulvestrant (n = 51). The most current efficacy analysis showed that lasofoxifene did not significantly prolong median PFS compared with fulvestrant: 24.2 weeks (∼5.6 months) versus 16.2 weeks (∼3.7 months; P = 0.138); hazard ratio 0.699 (95% confidence interval 0.434-1.125). However, PFS and other clinical endpoints numerically favored lasofoxifene: clinical benefit rate (36.5% versus 21.6%; P = 0.117), objective response rate [13.2% (including a complete response in one lasofoxifene-treated patient) versus 2.9%; P = 0.124], and 6-month (53.4% versus 37.9%) and 12-month (30.7% versus 14.1%) PFS rates. Most common treatment-emergent adverse events with lasofoxifene were nausea, fatigue, arthralgia, and hot flushes. One death occurred in the fulvestrant arm. Circulating tumor DNA ESR1 mutant allele fraction (MAF) decreased from baseline to week 8 in 82.9% of evaluable lasofoxifene-treated versus 61.5% of fulvestrant-treated patients. CONCLUSIONS: Lasofoxifene demonstrated encouraging antitumor activity versus fulvestrant and was well tolerated in patients with ESR1-mutated, endocrine-resistant mBC following progression on AI plus CDK4/6i. Consistent with target engagement, lasofoxifene reduced ESR1 MAF, and to a greater extent than fulvestrant. Lasofoxifene may be a promising targeted treatment for patients with ESR1-mutated mBC and warrants further investigation.

Bioenergy crop production and carbon sequestration potential under changing climate and land use: A case study in the upper River Taw catchment in southwest England.

Reductions in CO2 emissions are essential to support the UK in achieving its net zero policy objective by around mid-century. Both changing climate and land use change (LUC) offer an opportunity to deploy suitable bioenergy crops strategically to enhance energy production and C sequestration to help deliver net zero through capturing atmospheric CO2. Against this background, we applied process-based models to evaluate the extent of net primary productivity (NPP) losses/gains associated with perennial bioenergy crops and to assess their C sequestration potential under changing climate in the upper River Taw observatory catchment in southwest England. In so doing, we also determined whether LUC from permanent grassland to perennial bioenergy crops, considered in this study, can increase the production and C sequestration potential in the study area. The results show that a warming climate positively impacts the production of all crops considered (permanent grassland, Miscanthus and two cultivars of short rotation coppice (SRC) willow). Overall, Miscanthus provides higher aboveground biomass for energy compared to willow and grassland whereas the broadleaf willow cultivar 'Endurance' is best suited, among all crops considered, for C sequestration in this environment, and more so in the changing climate. In warmer lowlands, LUC from permanent grassland to Miscanthus and in cooler uplands from permanent grassland to 'Endurance', enhances NPP. Colder areas are predicted to benefit more from changing climate in terms of above and belowground biomass for both Miscanthus and willow. The study shows that the above LUC can help augment non-fossil energy production and increase C sequestration potential if C losses from land conversion do not exceed the benefits from LUC. In the wake of a changing climate, aboveground biomass for bioenergy and belowground biomass to enhance carbon sequestration can be managed by the careful selection of bioenergy crops and targeted deployment within certain climatic zones.

Impact of encorafenib on survival of patients with BRAFV600E-mutant metastatic colorectal cancer in a real-world setting.

PURPOSE: Patients with BRAFV600E-mutant metastatic colorectal cancer (mCRC) have a dismal prognosis. The best strategies in these patients remain elusive. Against this background, we report the clinical course of patients with BRAFV600E-mutant mCRC to retrieve the best treatment strategy. PATIENTS AND METHODS: Clinico-pathological data were extracted from the electronic health records. Kaplan-Meier method was used to estimate overall (OS) and progression-free survival (PFS). Objective response rate (ORR) was assessed according to RECIST 1.1. RESULTS: In total, 51 patients were enrolled. FOLFOXIRI was administered to 12 patients; 29 patients received FOLFOX or FOLFIRI as first-line treatment. Median OS was 17.6 months. Median PFS with FOLFOXIRI (13.0 months) was significantly prolonged (HR 0.325) as compared to FOLFOX/FOLFIRI (4.3 months). However, this failed to translate into an OS benefit (p = 0.433). Interestingly, addition of a monoclonal antibody to chemotherapy associated with superior OS (HR 0.523). A total of 64.7% patients received further-line therapy, which included a BRAF inhibitor in 17 patients. Targeted therapy associated with very favourable OS (25.1 months). CONCLUSION: Patients with BRAFV600E-mutated mCRC benefit from the addition of an antibody to first-line chemotherapy. Further-line treatment including a BRAF inhibitor has a dramatic impact on survival.

Translating and applying a simulation model to enhance understanding of grassland management.

Each new generation of grassland managers could benefit from an improved understanding of how modification of nitrogen application and harvest dates in response to different weather and soil conditions will affect grass yields and quality. The purpose of this study was to develop a freely available grass yield simulation model, validated for England and Wales, and to examine its strengths and weaknesses as a teaching tool for improving grass management. The model, called LINGRA-N-Plus, was implemented in a Microsoft Excel spreadsheet and iteratively evaluated by students and practitioners (farmers, consultants, and researchers) in a series of workshops across the UK over 2 years. The iterative feedback led to the addition of new algorithms, an improved user interface, and the development of a teaching guide. The students and practitioners identified the ease of use and the capacity to understand, visualize and evaluate how decisions, such as variation of cutting intervals, affect grass yields as strengths of the model. We propose that an effective teaching tool must achieve an appropriate balance between being sufficiently detailed to demonstrate the major relationships (e.g., the effect of nitrogen on grass yields) whilst not becoming so complex that the relationships become incomprehensible. We observed that improving the user-interface allowed us to extend the scope of the model without reducing the level of comprehension. The students appeared to be interested in the explanatory nature of the model whilst the practitioners were more interested in the application of a validated model to enhance their decision making.

Genotypic and phenotypic spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency.

OBJECTIVES: Pathogenic biallelic variants in PCK1 coding for the cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) cause PEPCK-C deficiency, a rare disorder of gluconeogenesis presenting with hypoglycemia, lactic acidosis, and hepatopathy. To date, there has been no systematic analysis of its phenotypic, biochemical, and genetic spectrum. METHODS: All currently published individuals and a novel patient with genetically confirmed PEPCK-C deficiency were included. Clinical, biochemical, and genetic findings were analyzed. Protein and in-silico prediction score modeling was applied to analyze potential variant effects. RESULTS: Thirty-two individuals from 25 families were found, including one previously unreported patient. The typical biochemical pattern was hypoglycemia triggered by catabolic situations, elevated urinary concentrations of tricarboxylic acid cycle metabolites, mildly elevated alanine and aspartate aminotransferase and elevated lactate concentrations in serum. Plasma glutamine concentrations were elevated in some patients and may be a suitable marker for newborn screening. With adequate treatment, biochemical abnormalities usually normalized following a hypoglycemic episode. Symptom onset usually occurred in infancy with a broad range from neonatal age to adulthood. Regardless of the genotype, different phenotypes with a broad clinical spectrum were found. To date, eight genotypes with nine different PCK1 variants were identified, of which alleles with the recurrent variant c.925G > A; p.(Gly309Arg) are predominant and appear to be endemic in the Finnish population. Protein modeling suggests altered manganese- and substrate-binding as superordinate pathomechanisms. CONCLUSIONS: Environmental factors appear to be the main determinant for the phenotype in patients with biallelic variants in PCK1. Based on the biochemical pattern, PEPCK-C deficiency is a recognizable cause of childhood hypoglycemia. It is a treatable disease and early diagnosis is important to prevent metabolic derailment and morbidity. Newborn screening can identify at least a sub-cohort of affected individuals through elevated glutamine concentrations in dry blood.

Exploring the effects of land management change on productivity, carbon and nutrient balance: Application of an Ensemble Modelling Approach to the upper River Taw observatory, UK.

Agriculture is challenged to produce healthy food and to contribute to cleaner energy whilst mitigating climate change and protecting ecosystems. To achieve this, policy-driven scenarios need to be evaluated with available data and models to explore trade-offs with robust accounting for the uncertainty in predictions. We developed a novel model ensemble using four complementary state-of-the-art agroecosystems models to explore the impacts of land management change. The ensemble was used to simulate key agricultural and environmental outputs under various scenarios for the upper River Taw observatory, UK. Scenarios assumed (i) reducing livestock production whilst simultaneously increasing the area of arable where it is feasible to cultivate (PG2A), (ii) reducing livestock production whilst simultaneously increasing bioenergy production in areas of the catchment that are amenable to growing bioenergy crops (PG2BE) and (iii) increasing both arable and bioenergy production (PG2A + BE). Our ensemble approach combined model uncertainty using the tower property of expectation and the law of total variance. Results show considerable uncertainty for predicted nutrient losses with different models partitioning the uncertainty into different pathways. Bioenergy crops were predicted to produce greatest yields from Miscanthus in lowland and from SRC-willow (cv. Endurance) in uplands. Each choice of management is associated with trade-offs; e.g. PG2A results in a significant increase of edible calories (6736 Mcal ha-1) but reduced soil C (-4.32 t C ha-1). Model ensembles in the agroecosystem context are difficult to implement due to challenges of model availability and input and output alignment. Despite these challenges, we show that ensemble modelling is a powerful approach for applications such as ours, offering benefits such as capturing structural as well as data uncertainty and allowing greater combinations of variables to be explored. Furthermore, the ensemble provides a robust means for combining uncertainty at different scales and enables us to identify weaknesses in system understanding.

Treatment of Postoperative Lymphatic Leakage Applying Transpedal Lymphangiography - Experience in 355 Consecutive Patients.

PURPOSE: Report of experience from a single institution in treating postoperative lymphatic leakage (PLL) applying conventional transpedal lymphangiography (TL). MATERIALS AND METHODS: 453 patients with the initial diagnosis of PLL receiving TL between 03/1993 and 09/2018 were identified in the database. Only patients with confirmed PLL were included in the study. The technical success, safety, and treatment success of TL were evaluated. Independent predictors of TL treatment failure were examined using univariate and multivariate logistic regression analysis. RESULTS: 355 consecutive patients (218 men, 137 women; median age of 62 years) who underwent TL for PLL (e. g., chylothorax) after ineffective conservative treatment were included. The median time between causal surgery and TL was 27 days. The median technical success rate of TL was 88.5 %, with a median volume of Lipiodol of 10.0 ml. No complication of TL was recorded. Three groups were defined according to the different clinical courses: group A (41/355, 11.5 %) - TL with technical failure; group B (258/355, 72.7 %) - "therapeutic" TL alone with technical success; and group C (56/355, 15.8 %) - "diagnostic" TL with simultaneously invasive treatment (incl. surgical revision and percutaneous sclerotherapy). Treatment success rate and median time to treatment success were higher in group C than in group B, but without significant differences (64.3 % vs. 61.6 %, p = 0.710; six vs. five days, p = 0.065). Univariate and multivariate logistic regression analyses for group B confirmed drainage volume (> 500 ml/d) and Lipiodol extravasation as independent predictors of TL clinical failure (odds ratios [ORs] of 2.128 and 2.372 [p = 0.005 and p = 0.003, respectively]). CONCLUSION: TL is technically reliable, safe, and effective in treating PLL. When conservative treatment fails, TL can be regarded as the next treatment option. KEY POINTS: · TL is technically reliable, safe, and effective for treating PLL.. · When conservative treatment fails, TL can be regarded as the next treatment option.. · Drainage volume > 500 ml/day is an independent predictor of clinical failure after TL.. · Lipiodol extravasation is an independent predictor of clinical failure after TL.. CITATION FORMAT: · Pan F, Richter GM, Do TD et al. Treatment of Postoperative Lymphatic Leakage Applying Transpedal Lymphangiography - Experience in 355 Consecutive Patients. Fortschr Röntgenstr 2022; 194: 634 - 643.

Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study.

BACKGROUND: Adjuvant abemaciclib combined with endocrine therapy (ET) previously demonstrated clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer at the second interim analysis, however follow-up was limited. Here, we present results of the prespecified primary outcome analysis and an additional follow-up analysis. PATIENTS AND METHODS: This global, phase III, open-label trial randomized (1 : 1) 5637 patients to adjuvant ET for ≥5 years ± abemaciclib for 2 years. Cohort 1 enrolled patients with ≥4 positive axillary lymph nodes (ALNs), or 1-3 positive ALNs and either grade 3 disease or tumor ≥5 cm. Cohort 2 enrolled patients with 1-3 positive ALNs and centrally determined high Ki-67 index (≥20%). The primary endpoint was IDFS in the intent-to-treat population (cohorts 1 and 2). Secondary endpoints were IDFS in patients with high Ki-67, DRFS, overall survival, and safety. RESULTS: At the primary outcome analysis, with 19 months median follow-up time, abemaciclib + ET resulted in a 29% reduction in the risk of developing an IDFS event [hazard ratio (HR) = 0.71, 95% confidence interval (CI) 0.58-0.87; nominal P = 0.0009]. At the additional follow-up analysis, with 27 months median follow-up and 90% of patients off treatment, IDFS (HR = 0.70, 95% CI 0.59-0.82; nominal P < 0.0001) and DRFS (HR = 0.69, 95% CI 0.57-0.83; nominal P < 0.0001) benefit was maintained. The absolute improvements in 3-year IDFS and DRFS rates were 5.4% and 4.2%, respectively. Whereas Ki-67 index was prognostic, abemaciclib benefit was consistent regardless of Ki-67 index. Safety data were consistent with the known abemaciclib risk profile. CONCLUSION: Abemaciclib + ET significantly improved IDFS in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer, with an acceptable safety profile. Ki-67 index was prognostic, but abemaciclib benefit was observed regardless of Ki-67 index. Overall, the robust treatment benefit of abemaciclib extended beyond the 2-year treatment period.

DLL3 (delta-like protein 3) expression correlates with stromal desmoplasia and lymph node metastases in medullary thyroid carcinomas.

Medullary thyroid carcinomas (MTC) are rare and aggressive neuroendocrine tumors of the thyroid. About 70% of MTC are sporadic; approximately 50% of those harbor somatic RET mutation. DLL3 is widely expressed in many neuroendocrine tumors and has been evaluated as a potential therapeutic target. Since stromal desmoplasia in sporadic MTC has been identified as a reliable predictor of aggressive behavior and development of lymph node metastases, a possible correlation of DLL3 expression with the presence of stromal desmoplasia was of particular interest. 59 paraffin-embedded samples of sporadic MTC with (44 cases) and without (15 cases) stromal desmoplasia and known lymph node status were included. DLL3 expression was determined by immunohistochemistry; no expression (0%), low expression (1-49%) and high expression (≥50%) were correlated with clinicopathological data. The proportion of DLL3 positivity was significantly correlated with both stromal desmoplasia (P < 0.0001) and lymph node metastases (P < 0.0001). MTC without stromal desmoplasia consistently lack DLL3 expression. This is the first study to focus on MTC regarding DLL3 expression and the relationship to various factors. Our results demonstrate that expression of DLL3 in MTC represents a reliable surrogate marker for stromal desmoplasia and lymph node metastases and might be an indicator for aggressive clinical behavior. DLL3 expression in ≥50% of tumor cells virtually excludes MTC without stromal desmoplasia. DLL3 was discussed as a potential therapeutic target in malignant tumors of other locations with positive immunohistochemical reaction and might therefore be a new therapeutic option in MTC, as well.

Modelling spatio-temporal patterns of soil carbon and greenhouse gas emissions in grazing lands: Current status and prospects.

The sustainability of grazing lands lies in the nexus of human consumption behavior, livestock productivity, and environmental footprint. Due to fast growing global food demands, many grazing lands have suffered from overgrazing, leading to soil degradation, air and water pollution, and biodiversity losses. Multidisciplinary efforts are required to understand how these lands can be better assessed and managed to attain predictable outcomes of optimal benefit to society. This paper synthesizes our understanding based on previous work done on modelling the influences of grazing of soil carbon (SC) and greenhouse gas emissions to identify current knowledge gaps and research priorities. We revisit three widely-used process-based models: DeNitrification DeComposition (DNDC), DayCent, and the Pasture Simulation model (PaSim) and two watershed models: The Soil & Water Assessment Tool (SWAT) and Variable Infiltration Capacity Model (VIC), which are widely used to simulate C, nutrient and water cycles. We review their structures and ability as process-based models in representing key feedbacks among grazing management, SOM decomposition and hydrological processes in grazing lands. Then we review some significant advances in the use of models combining biogeochemical and hydrological processes. Finally, we examine challenges of incorporating spatial heterogeneity and temporal variability into modelling C and nutrient cycling in grazing lands and discuss their weakness and strengths. We also highlight key research direction for improving the knowledge base and code structure in modelling C and nutrient cycling in grazing lands, which are essential to conserve grazing lands and maintain their ecosystem goods and services.

Conventional Lymphangiography (CL) in the Management of Postoperative Lymphatic Leakage (PLL): A Systematic Review.

BACKGROUND: Postoperative lymphatic leakage (PLL) is usually managed by conservative and/or surgical treatments but these procedures can be challenging to perform and potentially clinically ineffective. Therefore, conventional lymphangiography (CL) has emerged as an important alternative. The aim of this review is to present the available outcome data on CL in the management of PLL. METHOD: A systematic literature search (PubMed) using the MeSH term "lymphangiography" was performed and the search was restricted to literature published between January 2007 and August 2019. Identification, screening, and assessment for eligibility and inclusion were conducted in accordance with PRISMA. RESULTS: From the initially obtained 1006 articles (identification), 28 articles with a total of 201 patients were finally included (inclusion). The methodological quality of all included articles corresponds to level 4 (Oxford Centre for Evidence-based Medicine - Levels of Evidence, March 2009). PLL occurs after oncological and non-oncological surgery in the form of chylothorax, chylous ascites, and cervical, thoracic, abdominal and peripheral lymph fistula and/or lymphocele. The technical success rate of CL is 75-100 %. Access for CL is transpedal (176 patients) or intranodal (25 patients). Lipiodol is used as the contrast material in all articles, with a maximum amount of 20 ml for transpedal CL and 30 ml for intranodal CL. The X-ray imaging modalities used for CL are fluoroscopy, radiography and/or CT. Two articles report CL-associated major complications and CL-associated morbidity and mortality. The PLL cure rate is 51-70 % for transpedal CL (time to PLL cure: 2-29 days) and 33-100 % for intranodal CL (time to PLL cure: 2-< 30 days). Bailout procedures in the case of clinically ineffective CL include a range of treatments. CONCLUSION: CL is feasible, safe, and effective in the management of PLL. Lipiodol as the contrast material is essential in CL because the highly viscous iodinated poppy-seed oil has not only diagnostic but therapeutic effects. Guidelines and randomized controlled trials are further steps towards defining the ultimate value of CL. KEY POINTS: · PLL is a difficult-to-treat and potentially life-threatening surgical complication.. · CL has emerged as an alternative to conservative/surgical treatment of PLL.. · CL is feasible, safe, and effective in the management of PLL. · Lipiodol-based CL can be regarded as a therapeutic procedure.. · Guidelines and randomized controlled trials are further important steps.. CITATION FORMAT: · Sommer CM, Pieper CC, Itkin M et al. Conventional Lymphangiography (CL) in the Management of Postoperative Lymphatic Leakage (PLL): A Systematic Review. Fortschr Röntgenstr 2020; 192: 1025 - 1035.

A combinatorial biomarker predicts pathologic complete response to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2+ breast cancer.

BACKGROUND: HER2-positive (+) breast cancers, defined by HER2 overexpression and/or amplification, are often addicted to HER2 to maintain their malignant phenotype. Yet, some HER2+ tumors do not benefit from anti-HER2 therapy. We hypothesize that HER2 amplification levels and PI3K pathway activation are key determinants of response to HER2-targeted treatments without chemotherapy. PATIENTS AND METHODS: Baseline HER2+ tumors from patients treated with neoadjuvant lapatinib plus trastuzumab [with endocrine therapy for estrogen receptor (ER)+ tumors] in TBCRC006 (NCT00548184) were evaluated in a central laboratory for HER2 amplification by fluorescence in situ hybridization (FISH) (n = 56). HER2 copy number (CN) and FISH ratios, and PI3K pathway status, defined by PIK3CA mutations or PTEN levels by immunohistochemistry were available for 41 tumors. Results were correlated with pathologic complete response (pCR; no residual invasive tumor in breast). RESULTS: Thirteen of the 56 patients (23%) achieved pCR. None of the 11 patients with HER2 ratio <4 and/or CN <10 achieved pCR, whereas 13/45 patients (29%) with HER2 ratio ≥4 and/or CN ≥10 attained pCR (P = 0.0513). Of the 18 patients with tumors expressing high PTEN or wild-type (WT) PIK3CA (intact PI3K pathway), 7 (39%) achieved pCR, compared with 1/23 (4%) with PI3K pathway alterations (P = 0.0133). Seven of the 16 patients (44%) with HER2 ratio ≥4 and intact PI3K pathway achieved pCR, whereas only 1/25 (4%) patients not meeting these criteria achieved pCR (P = 0.0031). CONCLUSIONS: Our findings suggest that there is a clinical subtype in breast cancer with high HER2 amplification and intact PI3K pathway that is especially sensitive to HER2-targeted therapies without chemotherapy. A combination of HER2 FISH ratio and PI3K pathway status warrants validation to identify patients who may be treated with HER2-targeted therapy without chemotherapy.

Optimizing the bioenergy water footprint by selecting SRC willow canopy phenotypes: regional scenario simulations.

BACKGROUND AND AIMS: Bioenergy is central for the future energy mix to mitigate climate change impacts; however, its intricate link with the water cycle calls for an evaluation of the carbon-water nexus in biomass production. The great challenge is to optimize trade-offs between carbon harvest and water use by choosing cultivars that combine low water use with high productivity. METHODS: Regional scenarios were simulated over a range of willow genotype × environment interactions for the major UK soil × climate variations with the process-based model LUCASS. Soil available water capacity (SAWC) ranged from 51 to 251 mm and weather represented the north-west (wet, cool), north-east (dry, cool), south-west (wet, warm) and south-east (dry, warm) of the UK. Scenario simulations were evaluated for small/open narrow-leaf (NL) versus large/closed broad-leaf (BL) willow canopy phenotypes using baseline (1965-89) and warmer recent (1990-2014) weather data. KEY RESULTS: The low productivity under baseline climate in the north could be compensated by choosing BL cultivars (e.g. 'Endurance'). Recent warmer climate increased average productivity by 0.5-2.5 t ha-1, especially in the north. The modern NL cultivar 'Resolution' had the smallest and most efficient water use. On marginal soils (SAWC <100 mm), yields remained below an economic threshold of 9 t ha-1 more frequently under baseline than recent climate. In the drought-prone south-east, 'Endurance' yielded less than 'Resolution', which consumed on average 17 mm year-1 less water. Assuming a planting area of 10 000 ha, in droughty years between 1.3 and 4.5 × 106 m3 of water could be saved, with a small yield penalty, for 'Resolution'. CONCLUSIONS: With an increase in air temperature and occasional water scarcities expected with climate change, high-yielding NL cultivars should be the preferred choice for sustainable use of marginal lands and reduced competition with agricultural food crops.