Arabidopsis MCTP family member QUIRKY regulates the formation of the STRUBBELIG receptor kinase complex.

Intercellular communication plays a central role in organogenesis. Tissue morphogenesis in Arabidopsis (Arabidopsis thaliana) requires signaling mediated by a cell surface complex containing the atypical receptor kinase STRUBBELIG (SUB) and the multiple C2 domains and transmembrane region protein QUIRKY (QKY). QKY is required to stabilize SUB at the plasma membrane. However, it is unclear what the in vivo architecture of the QKY/SUB signaling complex is, how it is controlled, and how it relates to the maintenance of SUB at the cell surface. We addressed these questions using a combination of genetics, yeast 2-hybrid assays, and Förster resonance energy transfer (FRET)/fluorescence lifetime imaging microscopy (FLIM) in epidermal cells of seedling roots. We found that QKY promotes the formation of SUB homooligomers in vivo. Homooligomerization of SUB appeared to involve its extracellular domain. We also showed that QKY and SUB physically interact and form a complex at the cell surface in vivo. In addition, the data showed that the N-terminal C2A-B region of QKY interacts with the intracellular domain of SUB. They further revealed that this interaction is essential to maintain SUB levels at the cell surface. Finally, we provided evidence that QKY forms homomultimers in vivo in a SUB-independent manner. We suggest a model in which the physical interaction of QKY with SUB mediates the oligomerization of SUB and attenuates its internalization, thereby maintaining sufficiently high levels of SUB at the cell surface required for the control of tissue morphogenesis.

Concordance of breast cancer biomarker testing in core needle biopsy and surgical specimens: A single institution experience.

BACKGROUND: Accurate diagnostic biomarker testing is crucial to treatment decisions in breast cancer. Biomarker testing is performed on core needle biopsies (CNB) and is often repeated in the surgical specimen (SS) after resection. As differences between CNB and SS testing may alter treatment decisions, we evaluated concordance between CNB and SS as well as associated changes in treatment and clinical outcomes. METHODS: We performed a retrospective analysis of breast cancer patients at our institution between January 2010 and May 2020. Concordance between CNB and SS was assessed for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Survival in patients, including recurrence, metastatic recurrence, and death, were assessed using chi-squared likelihood ratio. RESULTS: In total, 961 patients met eligibility criteria. Concordance, minor discordance, total concordance (concordance plus minor discordance), and major discordance between CNB and SS were reported for ER (87.7%, 9.2%, 90.8%, and 2.9%), PR (58.1%, 29.1%, 87.2%, and 12.8%), and HER2 IHC (52.5%, 20.9%, 73.4%, 26.6%), respectively. HER2 FISH concordance and major discordance were 58.5% and 1.2%, respectively. Of major discordance, ER (48.2%, p < 0.001) and HER2 FISH (50.0%) led to more management changes than HER2 IHC (2.4%, p = 0.04) and PR (1.6%, p = 0.10). Patients with ER major discordance had increased risk of death (6.7% concordance vs. 22.2% major discordance, p = 0.004). CONCLUSION: Overall, retesting ER and HER2 was more clinically beneficial than retesting PR. To aid decision-making and minimize healthcare costs, we propose patient-centered guidelines on retesting biomarker profiles.

Transfusion Independence Achieved with Combination Fedratinib and Luspatercept in an Elderly Man with Heavily Pretreated Intermediate-2 Risk Primary Myelofibrosis.

Myelofibrosis (MF)-associated anemia and transfusion dependency are associated with inferior quality of life and poor prognosis. JAK2 inhibitors and TGF-ß superfamily ligand traps are being explored as treatment options for MF-associated anemia. Here, we present the case of a 66-year-old man with heavily pretreated intermediate-2 (INT-2) risk primary MF who had an exceptional response to combination fedratinib and luspatercept therapy. He achieved transfusion independence and experienced a reduction in spleen size from 20 cm to 12 cm, with remarkable improvement in performance status. Compared with other JAK inhibitors, the mechanism of action of fedratinib may explain its milder effect on anemia. It is possible that the addition of luspatercept may result in an additive or synergistic effect of one or both medications. Although the exact biological pathways have not yet been elucidated, combination fedratinib and luspatercept nevertheless is a promising therapy for anemia in patients with transfusion-dependent INT-2 risk MF.

Pembrolizumab-induced autoimmune haemolytic anemia in a patient with chronic lymphocytic leukaemia successfully treated with ibrutinib.

We present a unique case of a patient with a long-standing history of indolent chronic lymphocytic leukaemia (CLL) who suddenly developed autoimmune haemolytic anaemia after starting immune checkpoint inhibitor therapy for bladder cancer. He had no clear indication to start CLL-directed treatment based on current clinical practice guidelines; however, targeted treatment of CLL with ibrutinib proved to be effective in treating the haemolytic anaemia.

Histologic Discordance Between Primary Tumor and Nodal Metastasis in Breast Cancer: Solving a Clinical Conundrum in the Era of Genomics.

Next-generation sequencing (NGS) technologies have become increasingly used for managing breast cancer. In addition to the conventional use of NGS for predicting recurrence risk and identifying potential actionable mutations, NGS can also serve as a powerful tool to understand clonal origin and evolution of tumor pairs and play a unique role in clarifying complex clinical presentations. We report an unusual case of early-stage breast cancer in which the primary tumor and draining axillary node were histologically discordant. The primary tumor was invasive lobular carcinoma, whereas the nodal metastasis was invasive ductal carcinoma. This discordance led us to question whether the tumors had the same origin. NGS performed on both specimens identified no overlapping variants, leading us to conclude that the patient had two separate primary breast cancers, with the nodal tumor representing metastasis from an occult breast cancer. DNA sequencing of the primary tumor and the nodal metastasis allowed us to predict the patient's recurrence risk, and we initiated adjuvant chemotherapy and hormonal therapy based on these results. This case illustrates the utility of NGS for successfully managing a rare and challenging case. KEY POINTS: A degree of molecular concordance is expected for tumors originating from a common stem or progenitor cell. Histological discordance and absence of any genomic overlap should raise suspicion for two separate primary tumors. Paired DNA sequencing of the primary tumor and nodal metastasis can inform clinical decisions when primary breast tumor and axillary metastasis are histologically discordant. Molecular/Precision Oncology Tumor Board is the best setting to facilitate such decisions in these challenging cases. Paired DNA sequencing under these rare circumstances may suggest an occult breast tumor.

Neutrophil-to-Lymphocyte Ratio Is a Predictive Biomarker in Patients with Epidermal Growth Factor Receptor (EGFR) Mutated Advanced Non-Small Cell Lung Cancer (NSCLC) Treated with Tyrosine Kinase Inhibitor (TKI) Therapy.

BACKGROUND: First-line treatment for patients with non-small cell lung cancer (NSCLC) with a sensitizing epidermal growth factor receptor (EGFR) mutation is a tyrosine kinase inhibitor (TKI). Despite higher response rates and prolonged progression free survival (PFS) compared with platinum doublet chemotherapy, a subset of these patients do not receive prolonged benefit from these agents. We investigate if the neutrophil-to-lymphocyte ratio (NLR) and other markers of cachexia and chronic inflammation correlate with worse outcomes in these patients. METHODS: This study is a retrospective review of 137 patients with advanced EGFR-mutated NSCLC treated with TKIs at Rush University Medical Center and University of Chicago Medicine from August 2011 to July 2019, with outcomes followed through July 2020. The predictive value of NLR and body mass index (BMI) was assessed at the start of therapy, and after 6 and 12 weeks of treatment by univariable and multivariable analyses. RESULTS: On univariable analysis, NLR ≥ 5 or higher NLR on a continuous scale were both associated with significantly worse PFS and overall survival (OS) at treatment initiation, and after 6 or 12 weeks of treatment. On multivariable analysis, NLR ≥ 5 was associated with increased risk of death at 12 weeks of therapy (HR 3.002, 95% CI 1.282-7.029, p = 0.011), as was higher NLR on a continuous scale (HR 1.231, 95% CI 1.063-1.425, p = 0.0054). There was no difference in PFS and OS and amongst BMI categories though number of disease sites and Eastern Cooperative Oncology Group (ECOG) performance status was associated with worse PFS and OS. CONCLUSIONS: Patients with NLR ≥ 5 have a worse median PFS and median OS than patients with NLR < 5. NLR may have value as a predictive biomarker and may be useful for selecting patients for therapy intensification in the front-line setting either at diagnosis or after 12 weeks on therapy. NLR needs to be validated prospectively.

Utility of Chest Radiographs in Children Presenting to a Pediatric Emergency Department With Acute Asthma Exacerbation and Chest Pain.

OBJECTIVES: Previous studies have not evaluated the utility of obtaining chest radiographs (CXR) in patients with acute asthma exacerbation reporting chest pain. The aims of this study were to evaluate the symptom of chest pain as a predictor for clinicians obtaining a CXR in these patients and to evaluate chest pain as a predictor of a positive CXR finding. METHODS: This was a retrospective chart review of patients, ages 2 to 18 years, presenting for acute asthma exacerbation to the emergency department from August 1, 2014, to March 31, 2016. Data collected included demographics, clinical data, provider type, and CXR results. Chest radiographs were classified as positive if they showed evidence of pneumonia, pneumothorax, or pneumomediastinum. Multivariate logistic regression models were developed with dependent variables of "obtaining a CXR" and "a positive CXR finding." RESULTS: Seven hundred ninety-three subjects were included in the study. Two hundred thirty-one (29.1%) reported chest pain. Chest radiographs were obtained in 184 patients (23.2%). Of those, 74 patients (40.2%) had chest pain and 21 (11.4%) had a positive CXR. Providers were more likely to obtain CXRs in patients who reported chest pain (odds ratio = 2.2 [95% confidence interval = 1.5-3.2]). Patients reporting chest pain were more likely to have a positive CXR although this difference was not statistically significant (odds ratio = 2.0 [95% confidence interval = 0.7-5.6]). CONCLUSIONS: Providers are more likely to obtain CXRs in asthmatic patients complaining of chest pain; however, these CXRs infrequently yield positive findings. This further supports limiting the use of chest radiography in patients with acute asthma exacerbation.

Orbital Mucosa-Associated Lymphoid Tissue Lymphoma and Primary Cutaneous Classical Hodgkin Lymphoma: A Rare Case Report and Review of the Literature.

A 60-year-old woman was diagnosed with isolated mucosa-associated lymphoid tissue (MALT) lymphoma of the ocular adnexa and treated with two years of weekly rituximab for eight doses followed by rituximab maintenance. After nearly two years of maintenance therapy, she developed a tender, indurated mass on the left neck. Biopsy results were consistent with primary cutaneous classical Hodgkin lymphoma (PCCHL).