Cardiac radiation dose is associated with inferior survival but not cardiac events in patients with locally advanced non-small cell lung cancer in the era of immune checkpoint inhibitor consolidation.

PURPOSE: We assessed the association of cardiac radiation dose with cardiac events and survival post-chemoradiation therapy (CRT) in patients with locally advanced non-small cell lung cancer (LA-NSCLC) after adoption of modern radiation therapy (RT) techniques, stricter cardiac dose constraints, and immune checkpoint inhibitor (ICI) consolidation. METHODS AND MATERIALS: This single-institution, multi-site retrospective study included 335 patients with LA-NSCLC treated with definitive, concurrent CRT between October 2017 and December 2021. All patients were evaluated for ICI consolidation. Planning dose constraints included heart mean dose < 20 Gy (<10 Gy if feasible) and heart volume receiving ≥ 50 Gy (V50Gy) < 25 %. Twenty-one dosimetric parameters for three different cardiac structures (heart, left anterior descending coronary artery [LAD], and left ventricle) were extracted. Primary endpoint was any major adverse cardiac event (MACE) post-CRT, defined as acute coronary syndrome, heart failure, coronary revascularization, or cardiac-related death. Secondary endpoints were: grade ≥ 3 cardiac events (per CTCAE v5.0), overall survival (OS), lung cancer-specific mortality (LCSM), and other-cause mortality (OCM). RESULTS: Median age was 68 years, 139 (41 %) had baseline coronary heart disease, and 225 (67 %) received ICI consolidation. Proton therapy was used in 117 (35 %) and intensity-modulated RT in 199 (59 %). Median LAD V15Gy was 1.4 % (IQR 0-22) and median heart mean dose was 8.7 Gy (IQR 4.6-14.4). Median follow-up was 3.3 years. Two-year cumulative incidence of MACE was 9.5 % for all patients and 14.3 % for those with baseline coronary heart disease. Two-year cumulative incidence of grade ≥ 3 cardiac events was 20.4 %. No cardiac dosimetric parameter was associated with an increased risk of MACE or grade ≥ 3 cardiac events. On multivariable analysis, cardiac dose (LAD V15Gy and heart mean dose) was associated with worse OS, driven by an association with LCSM but not OCM. CONCLUSIONS: With modern RT techniques, stricter cardiac dose constraints, and ICI consolidation, cardiac dose was associated with LCSM but not OCM or cardiac events in patients with LA-NSCLC.

Proteomics analysis of an individual formalin-fixed paraffin-embedded tissue section using isobaric-tag amplification.

RATIONALE: The comprehensive analysis of formalin-fixed paraffin-embedded (FFPE) tissues is essential for retrospective clinical studies. However, detecting low-abundance proteins and obtaining proteome-scale data from FFPE samples pose analytical challenges in mass spectrometry-based proteomics. To overcome this challenge, our study focuses on implementing an isobaric labeling approach to improve the detection of low-abundance target proteins in FFPE tissues, thereby enhancing the qualitative and quantitative analysis. METHODS: We employed an isobaric labeling approach utilizing synthetic peptides or proteins to enable the qualitative and quantitative measurement of target proteins in FFPE tissue samples. To achieve this, we incorporated tandem mass tag (TMT)-labeled recombinant proteins or synthetic peptides into TMT-labeled metastatic breast cancer FFPE tissues. Through this strategy, we successfully detect coexisting CD276 (B7-H3) and CD147 proteins while identifying over 6000 proteins using targeted analysis of individual FFPE tissue sections. RESULTS: Our findings provide compelling evidence that the incorporation of isobaric labeling, along with the inclusion of TMT-labeled peptides or proteins, greatly enhances the detection of target proteins in FFPE tissue samples. By employing this approach, we were able to obtain robust qualitative measurements of CD276 and CD147 proteins, showcasing its effectiveness in identifying more than 6000 proteins in FFPE samples. CONCLUSIONS: The integration of an isobaric labeling approach, in conjunction with synthetic peptides or proteins, presents a valuable strategy for enhancing the detection and validation of target proteins in FFPE tissue analysis. This technique holds immense potential in retrospective clinical studies, as it enables comprehensive analysis of low-abundance proteins and facilitating proteome-scale investigations in FFPE samples. By leveraging this methodology, researchers can unlock new insights into disease mechanisms and advance our understanding of complex biological processes.

The cell walls of different Chara species are characterized by branched galactans rich in 3-O-methylgalactose and absence of AGPs.

Streptophyte algae are the closest relatives to land plants; their latest common ancestor performed the most drastic adaptation in plant evolution around 500 million years ago: the conquest of land. Besides other adaptations, this step required changes in cell wall composition. Current knowledge on the cell walls of streptophyte algae and especially on the presence of arabinogalactan-proteins (AGPs), important signalling molecules in all land plants, is limited. To get deeper insights into the cell walls of streptophyte algae, especially in Charophyceae, we performed sequential cell wall extractions of four Chara species. The three species Chara globularis, Chara subspinosa and Chara tomentosa revealed comparable cell wall compositions, with pectins, xylans and xyloglucans, whereas Chara aspera stood out with higher amounts of uronic acids in the pectic fractions and lack of reactivity with antibodies binding to xylan- and xyloglucan epitopes. Search for AGPs in the four Chara species and in Nitellopsis obtusa revealed the presence of galactans with pyranosidic galactose in 1,3-, 1,6- and 1,3,6-linkage, which are typical galactan motifs in land plant AGPs. A unique feature of these branched galactans was high portions of 3-O-methylgalactose. Only Nitellopsis contained substantial amounts of arabinose A bioinformatic search for prolyl-4-hydroxylases, involved in the biosynthesis of AGPs, revealed one possible functional sequence in the genome of Chara braunii, but no hydroxyproline could be detected in the four Chara species or in Nitellopsis obtusa. We conclude that AGPs that is typical for land plants are absent, at least in these members of the Charophyceae.

Lateral interactions between CD276 and CD147 are essential for stemness in breast cancer: a novel insight from proximal proteome analysis.

Oncogenic cell-surface membrane proteins contribute to the phenotypic and functional characteristics of cancer stem cells (CSCs). We employed a proximity-labeling proteomic approach to quantitatively analyze the cell-surface membrane proteins in close proximity to CD147 in CSCs. Furthermore, we compared CSCs to non-CSCs to identify CSC-specific cell-surface membrane proteins that are closely interact with CD147 and revealed that lateral interaction between CD147 and CD276 concealed within the lipid raft microdomain in CSCs, confers resistance to docetaxel, a commonly used chemotherapy agent for various cancer types, including metastatic breast cancer. Moreover, we investigated the clinical relevance of CD147 and CD276 co-expression in HER2+ breast cancer (BC) and triple-negative breast cancer patients who underwent chemotherapy. We observed poor disease-free survival and Overall survival rates in patients of CD147 and CD276 (p = 0.04 and 0.08, respectively). Subsequent immunohistochemical analysis in independent cohorts of HER2+ BC support for the association between co-expression of CD147 and CD276 and a poor response to chemotherapy. Collectively, our study suggests that the lateral interaction between CD147 and its proximal partners, such as CD276, may serve as a poor prognostic factor in BC and a predictive marker for the critical phenotypic determinant of BC stemness.

Utilization and Factors Precluding Receipt of Checkpoint Inhibitor Consolidation for Stage III NSCLC in a Large US Academic Health System.

OBJECTIVES: We sought to determine the proportion of patients with stage III non-small cell lung cancer (NSCLC) who initiate consolidation durvalumab or other immune checkpoint inhibitors (ICIs) after concurrent chemoradiotherapy (cCRT), as well as reasons for nonreceipt and prognostic implications. MATERIALS AND METHODS: We retrospectively identified consecutive patients with unresectable stage III NSCLC treated with definitive cCRT between October 2017 and December 2021 within a large US academic health system. Patients either received consolidation ICIs (ICI group) or did not (no-ICI group). Baseline characteristics and overall survival (OS) of the groups were assessed. Factors predictive of ICI nonreceipt were evaluated using logistic regression. RESULTS: Of 333 patients who completed cCRT, 229 (69%) initiated consolidation ICIs; 104 (31%) did not. Reasons for ICI nonreceipt included progressive disease post-cCRT (N = 31, 9%), comorbidity or intercurrent illness (N = 25, 8%), cCRT toxicity (N = 23, 7%; 19/23 pneumonitis), and EGFR/ALK alteration (N = 14, 4%). The no-ICI group had worse performance status and a higher rate of baseline pulmonary comorbidity. Larger planning target volume was associated with post-cCRT progressive disease, and higher lung radiation dose with cCRT toxicity. Median OS was 16 months in the no-ICI group and 34.4 months in the ICI group. In the no-ICI group, OS was superior among those with EGFR/ALK alterations (median 44.5 months) and worst among those with progressive disease (median 5.9 months, P < 0.001). CONCLUSION: 31% of patients who completed cCRT for stage III NSCLC did not receive consolidation ICIs. Survival amongst these patients is poor, especially for those with progressive disease post-cCRT.

Fern cell walls and the evolution of arabinogalactan proteins in streptophytes.

Significant changes have occurred in plant cell wall composition during evolution and diversification of tracheophytes. As the sister lineage to seed plants, knowledge on the cell wall of ferns is key to track evolutionary changes across tracheophytes and to understand seed plant-specific evolutionary innovations. Fern cell wall composition is not fully understood, including limited knowledge of glycoproteins such as the fern arabinogalactan proteins (AGPs). Here, we characterize the AGPs from the leptosporangiate fern genera Azolla, Salvinia, and Ceratopteris. The carbohydrate moiety of seed plant AGPs consists of a galactan backbone including mainly 1,3- and 1,3,6-linked pyranosidic galactose, which is conserved across the investigated fern AGPs. Yet, unlike AGPs of angiosperms, those of ferns contained the unusual sugar 3-O-methylrhamnose. Besides terminal furanosidic arabinose, Ara (Araf), the main linkage type of Araf in the ferns was 1,2-linked Araf, whereas in seed plants 1,5-linked Araf is often dominating. Antibodies directed against carbohydrate epitopes of AGPs supported the structural differences between AGPs of ferns and seed plants. Comparison of AGP linkage types across the streptophyte lineage showed that angiosperms have rather conserved monosaccharide linkage types; by contrast bryophytes, ferns, and gymnosperms showed more variability. Phylogenetic analyses of glycosyltransferases involved in AGP biosynthesis and bioinformatic search for AGP protein backbones revealed a versatile genetic toolkit for AGP complexity in ferns. Our data reveal important differences across AGP diversity of which the functional significance is unknown. This diversity sheds light on the evolution of the hallmark feature of tracheophytes: their elaborate cell walls.

Toxicities and Deaths From Intercurrent Disease Following Contemporary Postoperative Radiotherapy in Resected Non-Small-Cell Lung Cancer.

INTRODUCTION: The role of postoperative radiotherapy (PORT) in patients with resected locally advanced non-small-cell lung cancer (NSCLC) remains controversial due to the radiation techniques used in randomized trials. We conducted a retrospective cohort study evaluating contemporary PORT techniques to evaluate the safety of PORT and risk of death from intercurrent disease . MATERIALS AND METHODS: We analyzed consecutive patients with NSCLC treated in a single center that underwent PORT for pN2 disease and/or positive margin, with 3-dimensional conformal radiotherapy (3DRT), intensity modulated radiotherapy , or proton RT (PRT), between 2008 and 2019. Clinical details were collected including intercurrent deaths, defined as death without cancer recurrence. Kaplan-Meier and Cox-Proportional Hazards Models were used. RESULTS: Of 119 patients, 21 (17.6%) received 3DRT, 47 (39.5%) intensity modulated radiotherapy, and 51 (42.9%) PRT. Median follow-up was 40 months (range 8-136) and median RT dose was 5040cGy. Most patients (65.5%) received sequential adjuvant chemoRT; 18.5% received concurrent chemoRT. The rate of grade 3 toxicities was 9.2%. There were 13 (10.9%) deaths from intercurrent diseases, including 6 from second primary cancers and 2 from cardiopulmonary diseases. There were 2 additional deaths from cardiopulmonary disease in patients with cancer progression at time of death. Mean, V5Gy, V30Gy heart doses and mean lung doses were significantly lower with PRT. Three-year OS and disease-free-survival were 70.1% and 49.9%. CONCLUSION: PORT using contemporary techniques was well tolerated with acceptable toxicity and low rates of intercurrent deaths. Proton therapy significantly reduced heart and lung doses, but radiotherapy modality was not associated with differences in intercurrent disease.

Death without progression as an endpoint to describe cardiac radiation effects in locally advanced non-small cell lung cancer.

Background and purpose: Prior studies have examined associations of cardiovascular substructure dose with overall survival (OS) or cardiac events after chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC). Herein, we investigate an alternative endpoint, death without cancer progression (DWP), which is potentially more specific than OS and more sensitive than cardiac events for understanding CRT toxicity. Materials and methods: We retrospectively reviewed records of 187 patients with locally advanced or oligometastatic NSCLC treated with definitive CRT from 2008 to 2016 at a single institution. Dosimetric parameters to the heart, lung, and ten cardiovascular substructures were extracted. Charlson Comorbidity Index (CCI), excluding NSCLC diagnosis, was used to stratify patients into CCI low (0-2; n = 66), CCI intermediate (3-4; n = 78), and CCI high (≥5; n = 43) groups. Primary endpoint was DWP, modeled with competing risk regression. Secondary endpoints included OS. An external cohort consisted of 140 patients from another institution. Results: Median follow-up was 7.3 years for survivors. Death occurred in 143 patients (76.5 %), including death after progression in 118 (63.1 %) and DWP in 25 (13.4 %). On multivariable analysis, increasing CCI stratum and mean heart dose were associated with DWP. For mean heart dose ≥ 10 Gy vs < 10 Gy, DWP was higher (5-year rate, 16.9 % vs 6.7 %, p = 0.04) and OS worse (median, 22.9 vs 34.1 months, p < 0.001). Ventricle (left, right, and bilateral) and pericardial but not atrial substructure dose were associated with DWP, whereas all three were inversely associated with OS. Cutpoint analysis identified right ventricle mean dose ≥ 5.5 Gy as a predictor of DWP. In the external cohort, we confirmed an association of ventricle, but not atrial, dose with DWP. Conclusion: Cardiovascular substructure dose showed distinct associations with DWP. Future cardiotoxicity studies in NSCLC could consider DWP as an endpoint.

Life-threatening altered mental status secondary to memantine in an adolescent undergoing cranial radiotherapy for medulloblastoma.

INTRODUCTION: Memantine is used for neurocognitive protection in patients undergoing cranial radiotherapy for central nervous system tumors and is reported to be well-tolerated. CASE REPORT: Presented is a case of memantine-induced altered mental status requiring an intensive care unit admission. An 18-year-old male with relapsed, progressive medulloblastoma presented with severe altered mental status shortly after the first fraction of palliative whole brain radiotherapy. At the time, the patient was on day five of memantine therapy, which had been prescribed to reduce neurocognitive toxicity risk. MANAGEMENT & OUTCOME: Memantine was withheld while dexamethasone, valproate, and morphine were continued for headache. Approximately 50 h after admission, the patient's confusion significantly improved. Evaluation of acute altered mental status was unrevealing, including but not limited to negative urinary toxicology screen and lack of disease progression on imaging. Whole brain radiotherapy was resumed after a two-day cessation and he was discharged home after four days with complete resolution of symptoms. DISCUSSION: Clinicians should be aware of and consider the risk of altered mental status with memantine, given the increased utilization and upcoming clinical trials in pediatric patients.

Acute skin radiation toxicity seen with concurrent T-DM1: A single institutional report of 35 patients.

Trastuzumab emtansine (T-DM1) is a novel therapeutic for HER2+ breast cancer patients with residual disease after neoadjuvant chemotherapy. Concurrent radiotherapy (RT) is offered to a subset of patients based on results from the KATHERINE trial which showed a favorable safety profile. With emerging therapies that necessitate concurrent RT, we must closely follow rates of skin toxicity. Our first 35 patients who underwent concurrent T-DM1 treatment with breast/chest wall (CW) ± nodal irradiation are reported. Most patients (22/35) had grade 2+ toxicity and 3 patients had grade 3 toxicities. We add our experience with radiation dermatitis and concurrent T-DM1 to contribute to existing reports.

Use of Glucocorticoids in Patients With Cancer: Potential Benefits, Harms, and Practical Considerations for Clinical Practice.

PURPOSE: Glucocorticoids are commonly used in patients with cancer for symptom relief or as part of their anticancer treatment. Despite their frequent use, indications and dosing regimens are not exclusively evidence-based and can come with a multitude of adverse effects, some of which can be life-threatening. The objective of this review is to update our current state of knowledge on the use of glucocorticoids in adult patients with cancer. METHODS AND MATERIALS: A comprehensive literature review (1949-2022) was conducted using search terms "glucocorticoids," "corticosteroids," and "cancer." Information was organized by main concepts including indications, potential benefits, and prevention and management of common side effects of glucocorticoid therapy, in addition to appropriate dosing and taper regimens. RESULTS: Glucocorticoids can be highly effective in improving outcomes and quality of life in patients with cancer. Their uses include management of disease manifestations, symptoms, and complications of cancer treatment. The lowest effective dose should be used and treatment duration should be minimized as clinically feasible. Side effects can be minimized by careful monitoring, continued assessment of benefits versus harms, and preventative measures for expected side effects. CONCLUSIONS: This review provides general principles and practical recommendations on the use of glucocorticoids in patients with cancer. Further prospective studies on the outcomes of patients on glucocorticoids may help guide practice.

Severe acute radiation dermatitis after palbociclib therapy in the setting of palliative radiotherapy.

INTRODUCTION: Cyclin-dependent-kinase 4/6(CDK4/6) inhibitors are widely used as a first-line systemic treatment for patients with hormone receptor-positive, human epidermal growth factor receptor-2 negative metastatic breast cancer. Although many patients with metastatic breast cancer require palliative radiotherapy (RT), there are limited data on the safety of combining a CDK4/6 inhibitor with palliative RT. CASE REPORT: Presented is a case of acute high-grade radiation dermatitis with low-dose palliative RT following administration of palbociclib. A 49-year-old woman with newly diagnosed hormone receptor-positive invasive ductal carcinoma of the left breast presented with lytic bone lesions in the left femur and lumbar spine. The patient initiated treatment with goserelin, tamoxifen, and palbociclib. She underwent prophylactic surgical fixation of the left femur and received post-operative RT encompassing the entire surgical nail (30 Gy/10 fractions) and palliative RT to the lumbar spine for pain relief (20 Gy/5 fractions). During cycle 4, palbociclib was stopped 3 days prior to the start of RT to reduce the risk of toxicity risk. However, 16 days after starting RT, she developed painful erythematous papules and bullae with moist desquamation on the left groin and lumbar spine. MANAGEMENT & OUTCOME: Her symptoms were managed with topical Aquaphor-lidocaine, silver sulfadiazine, and aluminum acetate soaks. Dermatitis subsided to dry desquamation within 2 weeks. The patient denied late toxicity at 11 months follow-up. DISCUSSION: Larger retrospective or prospective studies are needed to further elucidate the safety of combined CDK4/6 inhibitors and RT. In the meantime, special precautions are warranted in patients receiving combined therapy.

Acute toxicity in patients treated with concurrent chemoradiotherapy with proton versus intensity-modulated radiation therapy for nonmetastatic head and neck cancers.

BACKGROUND: We evaluated if proton therapy is associated with decreased acute toxicities compared to intensity-modulated radiation therapy (IMRT) in patients receiving concurrent chemoradiotherapy for head and neck cancers. METHODS: We analyzed 580 patients with nonmetastatic head and neck cancers. Primary endpoint was any 90-day grade ≥3 toxicity, prospectively collected and graded per CTCAEv4. Modified Poisson regression models were used. RESULTS: Ninety-five patients received proton and 485 IMRT. The proton group had more HPV-positive tumors (65.6 vs. 58.0%, p = 0.049), postoperative treatment (76.8 vs. 62.1%, p = 0.008), unilateral neck treatment (18.9 vs. 6.6%, p < 0.001) and significantly lower doses to organs-at-risk compared to IMRT group. Adjusted for patient and treatment characteristics, the proton group had decreased grade 2 dysgeusia (RR0.67, 95%CI 0.53-0.84, p = 0.004) and a trend toward lower grade ≥3 toxicities (RR0.60, 95%CI 0.41-0.88, p = 0.06). CONCLUSIONS: Proton therapy was associated with significantly reduced grade 2 dysgeusia and nonstatistically significant decrease in acute grade ≥3 toxicities compared to IMRT.

The cell wall of hornworts and liverworts: innovations in early land plant evolution?

An important step for plant diversification was the transition from freshwater to terrestrial habitats. The bryophytes and all vascular plants share a common ancestor that was probably the first to adapt to life on land. A polysaccharide-rich cell wall was necessary to cope with newly faced environmental conditions. Therefore, some pre-requisites for terrestrial life have to be shared in the lineages of modern bryophytes and vascular plants. This review focuses on hornwort and liverwort cell walls and aims to provide an overview on shared and divergent polysaccharide features between these two groups of bryophytes and vascular plants. Analytical, immunocytochemical, and bioinformatic data were analysed. The major classes of polysaccharides-cellulose, hemicelluloses, and pectins-seem to be present but have diversified structurally during evolution. Some polysaccharide groups show structural characteristics which separate hornworts from the other bryophytes or are too poorly studied in detail to be able to draw absolute conclusions. Hydroxyproline-rich glycoprotein backbones are found in hornworts and liverworts, and show differences in, for example, the occurrence of glycosylphosphatidylinositol (GPI)-anchored arabinogalactan-proteins, while glycosylation is practically unstudied. Overall, the data are an appeal to researchers in the field to gain more knowledge on cell wall structures in order to understand the changes with regard to bryophyte evolution.

Activity Monitoring for Toxicity Detection and Management in Patients Undergoing Chemoradiation for Gastrointestinal Malignancies.

PURPOSE: Physical activity is associated with decreased hospitalization during cancer treatment. We hypothesize that activity data can help identify and triage high-risk patients with GI cancer undergoing concurrent chemoradiation. MATERIALS AND METHODS: This prospective study randomly assigned patients to activity monitoring versus observation. In the intervention arm, a 20% decrease in daily steps or 20% increase in heart rate triggered triage visits to provide supportive care, medication changes, and escalation of care. In the observation group, activity data were recorded but not monitored. The primary objective was to show a 20% increase in triage visits in the intervention group. Secondary objectives were estimating the rates of emergency department (ED) visits and hospitalizations. Crude and adjusted odds ratios were computed using logistic regression modeling. RESULTS: There were 22 patients in the intervention and 18 in the observation group. Baseline patient and treatment characteristics were similar. The primary objective was met, with 3.4 more triage visits in the intervention group than in the observation group (95% CI, 2.10 to 5.50; P < .0001). Twenty-six (65.0%) patients required at least one triage visit, with a higher rate in the intervention arm compared with that in the observation arm (86.4% v 38.9%; odds ratio, 9.95; 95% CI, 2.13 to 46.56; P = .004). There was no statistically significant difference in ED visit (9.1% v 22.2%; P = .38) or hospitalization (4.5% v 16.7%; P = .31). CONCLUSION: It is feasible to use activity data to trigger triage visits for symptom management. Further studies are investigating whether automated activity monitoring can assist with early outpatient management to decrease ED visits and hospitalizations.

Safety of cyclin-dependent kinase4/6 inhibitor combined with palliative radiotherapy in patients with metastatic breast cancer.

INTRODUCTION: Cyclin-dependent kinase (CDK)4/6 inhibitor is a first-line therapy for metastatic ER+/HER2-breast cancer. However, there are limited data on safety of combined radiotherapy (RT) and CDK4/6 inhibition. METHODS: We conducted a retrospective study of women with metastatic breast cancer who received palliative RT within 14 days of CDK4/6 inhibitor use. The primary endpoint was toxicity per Common Terminology Criteria for Adverse Events v5. Secondary endpoints were pain response and local control based on clinical assessment and imaging. RESULTS: Thirty patients underwent 36 RT courses with palbociclib (n = 34 courses, 94.4%) or abemaciclib (n = 2, 5.6%). RT was delivered before, concurrently or after CDK4/6 inhibitors in 7 (19.4%), 8 (22.2%), and 21 (58.3%) of cases with median 3.5 days from RT to closest CDK4/6 inhibitor administration. Median RT dose was 30Gy (range 8-40.05Gy). Treated sites included brain (n = 5, 11.6%), spine (n = 19, 44.2%), pelvis (n = 9, 20.9%), other bony sites (n = 6, 14.0%) and others (n = 4, 9.3%). No acute grade ≥3 non-hematologic toxicity occurred. No increased hematologic toxicity was attributable to RT with grade 3 hematologic toxicities rates 16.7%, 0%, and 6.7% before, during, and 2 weeks after RT completion. All but one patient (29/30) achieved symptom relief. Local control rates were 94.4%, 91.7% at 6 and 12 months. CONCLUSIONS: The use of RT within 2 weeks of CDK4/6 inhibitors had low acceptable toxicity and high efficacy, suggesting that it is safe for palliation of metastatic breast cancer.

Neisseria gonorrhoeae Multivalent Maxibody with a Broad Spectrum of Strain Specificity and Sensitivity for Gonorrhea Diagnosis.

Gonorrhea is one of the most common, but still hidden and insidious, sexually transmitted diseases caused by Neisseria gonorrhoeae (gonococci). However, the diagnosis and treatment of gonorrhea are hampered by antigenic variability among gonococci, the lack of acquired immunity, and antimicrobial resistance. Further, strains resistant to cephalosporins, including ceftriaxone, the last line of defense, represent a growing threat, which prompted us to develop gonococci-specific diagnostic antibodies with broad-spectrum binding to gonococci strains to generate gonorrhea-detecting reagents. This study reports the identification of gonococci antibodies via bio-panning on gonococci cells using scFv-phage libraries. Reformatting the lead scFv-phage Clones 1 and 4 to a multivalent scFv1-Fc-scFv4 maxibody increased the sensitivity by up to 20-fold compared to the single scFv-Fc (maxibody) alone. Moreover, the multivalent maxibody showed broader cross-reactivity with clinical isolates and the ceftriaxone antibiotic-resistant World Health Organization (WHO) reference strain L. In contrast, the selected antibodies in the scFv-phage, maxibody, and multivalent maxibody did not bind to N. sicca, N. meningitides, and N. lactamica, suggesting the clinical and pharmaceutical diagnostic value of these selected antibodies for gonorrheal infections. The present study illustrates the advantages and potential application of multivalent maxibodies to develop rapid and sensitive diagnostic reagents for infectious diseases and cancer.

Clinical development of valbenazine for tics associated with Tourette syndrome.

Introduction: Significant need exists for effective, well-tolerated pharmacologic treatments for Tourette syndrome (TS). Medications that inhibit vesicular monoamine transporters (i.e. VMAT2 inhibitors) downregulate presynaptic packaging and release of dopamine into the neuronal synapse and are effective in treating hyperkinetic movement disorders such as Huntington's chorea and tardive dyskinesia (TD); thus, they may be useful in treating TS.Areas covered: This review describes the clinical program evaluating the safety and efficacy of valbenazine in the treatment of involuntary tics associated with TS in adult and pediatric subjects. While there was a trend in the 6 completed trials toward greater improvement in valbenazine-treated versus placebo subjects on the primary efficacy endpoint (Yale Global Tic Severity Scale Total Tic Score), this difference did not reach statistical significance. Valbenazine was generally well-tolerated in the studies, and treatment-emergent adverse events were consistent with valbenazine studies in TD.Expert opinion: Due to the failure to meet the primary endpoint in these trials, further investigation of valbenazine for TS is unlikely. Given the need for safe and effective TS therapies and the key role of VMAT2 in modulating dopaminergic activity, it is reasonable for future studies to investigate other VMAT2 inhibitors as potential treatments for TS.

Rapid Evaluation of Antibody Fragment Endocytosis for Antibody Fragment-Drug Conjugates.

Antibody-drug conjugates (ADCs) have emerged as the most promising strategy in targeted cancer treatment. Recent strategies for the optimization ADCs include the development of antibody fragment-drug conjugates (FDCs). The critical factor in the successful development of ADCs and FDCs is the identification of tumor antigen-specific and internalizing antibodies (Abs). However, systematic comparison or correlation studies of internalization rates with different antibody formats have not been reported previously. In this study, we generated a panel of scFv-phage Abs using phage display technology and their corresponding scFv and scFv-Fc fragments and evaluated their relative internalization kinetics in relation to their antibody forms. We found that the relative rates and levels of internalization of scFv-phage antibodies positively correlate with their scFv and scFv-Fc forms. Our systematic study demonstrates that endocytosis of scFv-phage can serve as a predictive indicator for the assessment of Ab fragment internalization. Additionally, the present study demonstrates that endocytic antibodies can be rapidly screened and selected from phage antibody libraries prior to the conversion of phage antibodies for the generation of the conventional antibody format. Our strategic approach for the identification and evaluation of endocytic antibodies would expedite the selection for optimal antibodies and antibody fragments and be broadly applicable to ADC and FDC development.

Hypofractionated radiotherapy and surgery compared to standard radiotherapy in early glottic cancer.

PURPOSE: Early-stage glottic laryngeal cancer is treated with surgery or radiotherapy (RT), but limited randomized data exists to support one modality over the other. This study evaluates survival differences in early glottic cancer patients treated with either surgery or RT. MATERIALS AND METHODS: 14,498 patients with early glottic cancer diagnosed from 2004 to 2015 and treated with surgery or RT were identified in the National Cancer Database. Kaplan-Meier method was used to analyze differences in overall survival (OS) by treatment (surgery vs. RT) and radiation dose fractionation. Cox regression modeling and propensity score-matched (PSM) analysis were performed. Adjusted hazard ratios (aHR) with 95% confidence intervals (95% CI) were computed. RESULTS: Median follow-up and median OS for all patients were 49.5 and 118 months, respectively. The estimated 5-year OS for surgery and RT was 77.5% and 72.6%, respectively (P < 0.0001). On multivariate analysis, aHR (95% CI) for surgery compared to RT was 0.87 (0.81-0.94, P = 0.0004). Compared to RT regimen 63-67.5 Gray (Gy) in 28-30 fractions, worse survival was noted for RT regimen 66-70 Gy in 33-35 fractions (aHR 1.15, 95% CI 1.07-1.23, P = 0.0003). When compared with hypofractionated RT (63-67.5 Gy in 28-30 fractions), patients undergoing surgery no longer showed improved OS (aHR 0.94, 95% CI 0.86-1.02, P = 0.154). The finding was confirmed on PSM analysis (surgery aHR 0.95, 95% CI 0.87-1.05, P = 0.322). CONCLUSION: In early glottic tumors, patients treated with surgery demonstrated improved survival compared to RT, but when hypofractionation was considered, there were no significant differences in OS between patients undergoing surgery or RT.