Trastuzumab deruxtecan versus trastuzumab emtansine in HER2-positive metastatic breast cancer patients with brain metastases from the randomized DESTINY-Breast03 trial.

BACKGROUND: DESTINY-Breast03 is a randomized, multicenter, open-label, phase III study of trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) previously treated with trastuzumab and a taxane. A statistically significant improvement in progression-free survival (PFS) versus T-DM1 was reported in the primary analysis. Here, we report exploratory efficacy data in patients with and without brain metastases (BMs) at baseline. PATIENTS AND METHODS: Patients were randomly assigned 1 : 1 to receive T-DXd 5.4 mg/kg or T-DM1 3.6 mg/kg. Patients with clinically inactive/asymptomatic BMs were eligible. Lesions were measured as per modified RECIST, version 1.1. Outcomes included PFS by blinded independent central review (BICR), objective response rate (ORR), and intracranial ORR as per BICR. RESULTS: As of 21 May 2021, 43/261 patients randomized to T-DXd and 39/263 patients randomized to T-DM1 had BMs at baseline, as per investigator assessment. Among patients with baseline BMs, 20/43 in the T-DXd arm and 19/39 in the T-DM1 arm had not received prior local BM treatment. For patients with BMs, median PFS was 15.0 months [95% confidence interval (CI) 12.5-22.2 months] for T-DXd versus 3.0 months (95% CI 2.8-5.8 months) for T-DM1; hazard ratio (HR) 0.25 (95% CI 0.13-0.45). For patients without BMs, median PFS was not reached (95% CI 22.4 months-not estimable) for T-DXd versus 7.1 months (95% CI 5.6-9.7 months) for T-DM1; HR 0.30 (95% CI 0.22-0.40). Confirmed systemic ORR was 67.4% for T-DXd versus 20.5% for T-DM1 and 82.1% for T-DXd versus 36.6% for T-DM1 for patients with and without BMs, respectively. Intracranial ORR was 65.7% with T-DXd versus 34.3% with T-DM1. CONCLUSIONS: Patients with HER2-positive mBC whose disease progressed after trastuzumab and a taxane achieved a substantial benefit from treatment with T-DXd compared with T-DM1, including those with baseline BMs.

Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047).

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.

Treatment outcome, recurrence and safety of multidrug-resistant TB treated with low-dose linezolid.

BACKGROUND: Linezolid (LZD) is a key treatment option for patients with multidrug-resistant/rifampicin-resistant TB (MDR/RR-TB). We investigated the long-term treatment outcomes and safety of MDR/RR-TB treatment using low-dose LZD.METHODS: Medical records of patients with MDR/RR-TB treated with LZD ≥4 weeks between 2004 and 2018 at the Asan Medical Center, Seoul, Republic of Korea, were reviewed. Standard-dose and low-dose LZD groups were defined as patients initially administered LZD ≥600 mg/day or 300 mg/day, respectively.RESULTS: Among 94 patients, 65 were included in the low-dose LZD group; mean age was 43.1 ± 15.6 years, 53 (56.4%) were men and 77 (83.7%) were resistant to fluoroquinolone. The low-dose LZD group showed features of less severe disease, such as limited MDR-TB history and less severe radiological findings. There was no difference in treatment outcomes, relapse and safety between groups. In the low-dose LZD group, 54 (83.1%) succeeded treatment, of whom 48 (88.9%) were followed-up for a median of 38 months; there was no recurrence. Adverse drug reactions were reported in 41 (63.1%); peripheral neuropathy was most frequently reported (n = 31, 47.7%), while myelosuppression was reported in 12 (18.5%).CONCLUSION: Low-dose LZD in selected patients with less severe disease is both effective in the long-term and safe for the treatment of MDR/RR-TB.

Damage control surgery: old concepts and new indications.

PURPOSE OF REVIEW: While the principles of damage control surgery - rapid hemorrhage and contamination control with correction of physiologic derangements followed by delayed definitive reconstruction - have remained consistent, forms of damage control intervention have evolved and proliferated dramatically. This review aims to provide a historic perspective of the early trends of damage control surgery as well as an updated understanding of its current state and future trends. RECENT FINDINGS: Physiologically depleted patients in shock due to both traumatic and nontraumatic causes are often treated with damage control laparotomy and surgical principles. Damage control surgery has also been shown to be safe and effective in thoracic and orthopedic injuries. Damage control resuscitation is used in conjunction with surgical source control to restore patient physiology and prevent further collapse. The overuse of damage control laparotomy, however, is associated with increased morbidity and complications. With advancing technology, catheter- and stent-based endovascular modalities are playing a larger role in the resuscitation and definitive care of patients. SUMMARY: Optimal outcome in the care of the most severely injured patients requires judicious use of damage control surgery supplemented by advancements in resuscitation and surgical adjuncts.

Rule of four: an anatomic and value-based approach to stent-graft inventory for blunt thoracic aortic injury.

PURPOSE: As blunt thoracic aortic injury (BTAI) treatment has shifted from open to thoracic endovascular aortic repair (TEVAR), logistical challenges exist in creating and maintaining inventories of appropriately sized stent-grafts, including storage demands, shelf-life management and cost. We hypothesized that most injured aortas can be successfully repaired with a narrow range of stent-graft sizes and present a value-based anatomic approach to optimizing inventory. METHODS: CT-scans of all patients with BTAI admitted to our Level I trauma center from Apr 2010-Dec 2018 were reviewed. Patients with anatomy incompatible with TEVAR were excluded. For each patient, after aortic sizing a set of two stent-grafts most likely to be utilized was selected from a list of twenty commercially available GORE conformable TAG endografts based on manufacturer instructions. Stent-graft sizes were then ranked based on the number of cases they would be suitable for. MATLAB was utilized to determine the combinations of stent-grafts which would cover the most patients. RESULTS: Twenty-eight patients with BTAI were identified and three were excluded based on iliac diameter. Most patients were male (68%), mean age 42.3 ± 20.2 years, mean ISS 37.0 ± 9.8. Overall mortality was 25%. Of the 20 available stent-graft options, a combination of four stent-grafts would successfully treat 100% of the patients in this series. CONCLUSIONS: Based on actual CT-scan aortic measurements, we demonstrated that an inventory of four sent-graft sizes was sufficient to treat 100% of patients with BTAI. These data can be utilized as a value-based anatomic approach to aortic stent-graft institutional inventory creation and maintenance.

Concordance of diagnostic modalities in atypical skin and soft tissue infections in hospitalized patients.

Skin and soft tissue infections (SSTIs) have high rates of morbidity and mortality worldwide but lack reliable standards for diagnostic workup. As a result, atypical infections, more prevalent among immunocompromised patients, can be missed due to deviance from classic features only to be revealed later through inconsistently performed ancillary studies. Our objectives included to evaluate the sensitivities of clinical impression, histopathology, tissue culture, and molecular and non-molecular ancillary tests in diagnosing inpatient SSTIs, as well as to qualitatively discuss the unusual features making a subset of infections "atypical." To do so, we retrospectively reviewed the histopathologic reports and charts of inpatient dermatologic consults at a single tertiary care institution over a 3-year period. We identified a total of 111 cases of SSTIs evaluated by the inpatient dermatology consultation service with concurrent skin or soft tissue biopsy, with 32.4% representing atypical infections. Among these, clinical impression suggested infection in 9(25.0%), routine histopathology in 21(58.3%), specialized stains for microorganisms in 22(68.8%), and tissue culture in 15(68.2%). Due to incomplete picture that each modality by itself creates, we conclude that clinicians and pathologists should carry a low threshold for including SSTIs in their differential diagnoses and should evaluate with skin biopsy, special stains for microorganisms, and ancillary studies, particularly in critically ill individuals who necessitate timely diagnoses.

The promising role of risk scoring system for Cushing syndrome: Time to reconsider current screening recommendations.

Despite the current screening approach for Cushing syndrome (CS), delayed diagnosis is common due to broad spectrum of presentation, poor discriminant symptoms featured in diabetes and obesity, and low clinical index of suspicion. Even if initial tests are recommended to screen CS, divergent results are not infrequent. As global prevalence of type 2 diabetes and obesity increases, CS may not be frequent enough to back routine screening to avoid false-positive results. This represents a greater challenge in countries with limited health resources. The development of indexes incorporates clinical features and biochemical data that are largely used to provide a tool to predict the presence of disease. In clinical endocrinology, indexes have been used in Graves' ophthalmology, hirsutism, and hypothyroidism. The use of clinical risk scoring system may assist clinicians in discriminating CS in the context of at-risk populations and, thus, may provide a potential intervention to decrease time to diagnosis. Development and validation of clinical model to estimate pre-test probability of CS in different geographic source population may help to establish regional prediction model for CS. Here, we review on the latest progress in clinical risk scoring system for CS and attempt to raise awareness for the use, validation, and/or development of clinical risk scores in CS.

A retrospective cohort study of infection risk in hospitalized patients evaluated for Sweet syndrome.

Sweet syndrome (SS) is divided into malignancy-associated, classical, and drug-induced subtypes. Features associated with SS, such as fevers, neutropenia, and cancer, are also high risk for serious infection. We aimed to describe hospitalized patients with a documented concern for SS on initial dermatologic evaluation, their risk of infection, and the impact of SS subtype on treatment and outcomes. We descriptively analyzed hospitalizations at The Ohio State University evaluated for SS by dermatology and performed a retrospective cohort analysis of malignancy-associated and non-malignancy-associated SS patients. Eighty-seven patient hospitalizations were evaluated for SS from 2012 to 2019. Thirty-one hospitalizations were complicated by neutropenia. Lesions in 12.9% (n = 4/31) of neutropenic hospitalizations were infected with Fusarium species (n = 2) or methicillin-resistant staphylococcus aureus (n = 2). One patient with fungal disease died within 30 days of hospitalization. Thirty-three patients were confirmed to have a final diagnosis of SS. In the confirmed SS cohort, malignancy was associated with greater overall dapsone use (p = .021), less initial (p = .046) and overall (p = .013) corticosteroid use, and fewer SS-related readmissions within one year (p = .020) and overall (p = .004). Corticosteroid treatment delay should be considered for a short period in neutropenic patients while excluding infection. Malignancy-associated SS patients were more frequently treated with dapsone and favorable outcomes were seen in cancer patients.

Peri-operative neurological monitoring with electroencephalography and cerebral oximetry: a narrative review.

Surgery and anaesthesia subject the brain to considerable stress in the peri-operative period. This may be caused by potentially neurotoxic anaesthetic drugs, impaired cerebral perfusion and reperfusion injury related to surgery or thromboembolic events. Patient monitoring using electroencephalogram and cerebral oximetry can assist in optimising depth of anaesthesia and assessment of cerebral metabolic activity. However, research findings have been contradictory as to whether these monitors can help ameliorate peri-operative neurocognitive complications. In this narrative review, we will discuss recent evidence in the use of electroencephalography and cerebral oximetry and the underlying scientific principles. It is important to appreciate the raw electroencephalographic changes under anaesthesia and those associated with ageing, in order to interpret depth of anaesthesia indices correctly. Cerebral oximetry is useful not only for the detection of cerebral desaturation but also to identify those patients who are particularly vulnerable to injury, for better risk stratification. An algorithm-based approach may be most effective in managing the episodes of cerebral desaturation.

Erratum: Properties of a New Group of Cosmic Nuclei: Results from the Alpha Magnetic Spectrometer on Sodium, Aluminum, and Nitrogen [Phys. Rev. Lett. 127, 021101 (2021)].

This corrects the article DOI: 10.1103/PhysRevLett.127.021101.

Properties of a New Group of Cosmic Nuclei: Results from the Alpha Magnetic Spectrometer on Sodium, Aluminum, and Nitrogen.

We report the properties of sodium (Na) and aluminum (Al) cosmic rays in the rigidity range 2.15 GV to 3.0 TV based on 0.46 million sodium and 0.51 million aluminum nuclei collected by the Alpha Magnetic Spectrometer experiment on the International Space Station. We found that Na and Al, together with nitrogen (N), belong to a distinct cosmic ray group. In this group, we observe that, similar to the N flux, both the Na flux and Al flux are well described by the sums of a primary cosmic ray component (proportional to the silicon flux) and a secondary cosmic ray component (proportional to the fluorine flux). The fraction of the primary component increases with rigidity for the N, Na, and Al fluxes and becomes dominant at the highest rigidities. The Na/Si and Al/Si abundance ratios at the source, 0.036±0.003 for Na/Si and 0.103±0.004 for Al/Si, are determined independent of cosmic ray propagation.

Discovery of macrocyclic HDACs 1, 2, and 3 selective inhibitors for HIV latency reactivation.

A series of unique macrocyclic HDACs 1, 2, and 3 selective inhibitors were identified with good enzymatic activity and high selectivity over HDACs 6 and 8. These macrocyclic HDAC inhibitors used an ethyl ketone as the zinc-binding group. Compounds 25 and 26 stood out as leads due to their low double-digit nM EC50s in the 2C4 cell-based HIV latency reactivation assay. The PK profiles of these macrocyclic HDAC inhibitors still needed improvement.

Properties of Iron Primary Cosmic Rays: Results from the Alpha Magnetic Spectrometer.

We report the observation of new properties of primary iron (Fe) cosmic rays in the rigidity range 2.65 GV to 3.0 TV with 0.62×10^{6} iron nuclei collected by the Alpha Magnetic Spectrometer experiment on the International Space Station. Above 80.5 GV the rigidity dependence of the cosmic ray Fe flux is identical to the rigidity dependence of the primary cosmic ray He, C, and O fluxes, with the Fe/O flux ratio being constant at 0.155±0.006. This shows that unexpectedly Fe and He, C, and O belong to the same class of primary cosmic rays which is different from the primary cosmic rays Ne, Mg, and Si class.

Genome-wide surveillance of transcription errors in response to genotoxic stress.

Mutagenic compounds are a potent source of human disease. By inducing genetic instability, they can accelerate the evolution of human cancers or lead to the development of genetically inherited diseases. Here, we show that in addition to genetic mutations, mutagens are also a powerful source of transcription errors. These errors arise in dividing and nondividing cells alike, affect every class of transcripts inside cells, and, in certain cases, greatly exceed the number of mutations that arise in the genome. In addition, we reveal the kinetics of transcription errors in response to mutagen exposure and find that DNA repair is required to mitigate transcriptional mutagenesis after exposure. Together, these observations have far-reaching consequences for our understanding of mutagenesis in human aging and disease, and suggest that the impact of DNA damage on human physiology has been greatly underestimated.

Influence of propofol-based total intravenous anaesthesia on peri-operative outcome measures: a narrative review.

Propofol-based total intravenous anaesthesia is well known for its smooth, clear-headed recovery and anti-emetic properties, but there are also many lesser known beneficial properties that can potentially influence surgical outcome. We will discuss the anti-oxidant, anti-inflammatory and immunomodulatory effects of propofol and their roles in pain, organ protection and immunity. We will also discuss the use of propofol in cancer surgery, neurosurgery and older patients.

Systematic Dual Targeting of Dendritic Cell C-Type Lectin Receptor DC-SIGN and TLR7 Using a Trifunctional Mannosylated Antigen.

Dendritic cells (DCs) are important initiators of adaptive immunity, and they possess a multitude of Pattern Recognition Receptors (PRR) to generate an adequate T cell mediated immunity against invading pathogens. PRR ligands are frequently conjugated to tumor-associated antigens in a vaccination strategy to enhance the immune response toward such antigens. One of these PPRs, DC-SIGN, a member of the C-type lectin receptor (CLR) family, has been extensively targeted with Lewis structures and mannose glycans, often presented in multivalent fashion. We synthesized a library of well-defined mannosides (mono-, di-, and tri-mannosides), based on known "high mannose" structures, that we presented in a systematically increasing number of copies (n = 1, 2, 3, or 6), allowing us to simultaneously study the effect of mannoside configuration and multivalency on DC-SIGN binding via Surface Plasmon Resonance (SPR) and flow cytometry. Hexavalent presentation of the clusters showed the highest binding affinity, with the hexa-α1,2-di-mannoside being the most potent ligand. The four highest binding hexavalent mannoside structures were conjugated to a model melanoma gp100-peptide antigen and further equipped with a Toll-like receptor 7 (TLR7)-agonist as adjuvant for DC maturation, creating a trifunctional vaccine conjugate. Interestingly, DC-SIGN affinity of the mannoside clusters did not directly correlate with antigen presentation enhancing properties and the α1,2-di-mannoside cluster with the highest binding affinity in our library even hampered T cell activation. Overall, this systematic study has demonstrated that multivalent glycan presentation can improve DC-SIGN binding but enhanced binding cannot be directly translated into enhanced antigen presentation and the sole assessment of binding affinity is thus insufficient to determine further functional biological activity. Furthermore, we show that well-defined antigen conjugates combining two different PRR ligands can be generated in a modular fashion to increase the effectiveness of vaccine constructs.

Personalizing post-treatment cancer care: a cross-sectional survey of the needs and preferences of well survivors of breast cancer.

Background: Improved treatments resulting in a rising number of survivors of breast cancer (bca) calls for optimization of current specialist-based follow-up care. In the present study, we evaluated well survivors of bca with respect to their supportive care needs and attitudes toward follow-up with various care providers, in varying settings, or mediated by technology (for example, videoconference or e-mail). Methods: A cross-sectional paper survey of well survivors of early-stage pT1-2N0 bca undergoing posttreatment follow-up was completed. Descriptive and univariable logistic regression analyses were performed to examine associations between survivor characteristics, supportive care needs, and perceived satisfaction with follow-up options. Qualitative responses were analyzed using conventional content analysis. Results: The 190 well survivors of bca who participated (79% response rate) had an average age of 63 ± 10 years. Median time since first follow-up was 21 months. Most had high perceived satisfaction with in-person specialist care (96%, 177 of 185). The second most accepted model was shared care involving specialist and primary care provider follow-up (54%, 102 of 190). Other models received less than 50% perceived satisfaction. Factors associated with higher perceived satisfaction with non-specialist care or virtual follow-up by a specialist included less formal education (p < 0.01) and more met supportive care needs (p < 0.05). Concerns with virtual follow-up included the perceived impersonal nature of virtual care, potential for inadequate care, and confidentiality. Conclusions: Well survivors of bca want specialists involved in their follow-up care. Compared with virtual follow-up, in-person follow-up is perceived as more reassuring. Certain survivor characteristics (for example, met supportive care needs) might signal survivor readiness for virtual or non-specialist follow-up. Future work should examine multi-stakeholder perspectives about barriers to and facilitators of shared multimodal follow-up care.