trastuzumab (BP 02 / BP02)

Brain-shuttle biologics chart new paths across the blood-brain barrier.

Dolgin Elie E

A 24-Year-Old Man with Disseminated Tuberculosis and A Corticosteroid-Refractory Paradoxical Reaction to Anti-Tuberculous Treatment.

Charalampidis Charalampos C, Karantana Valentina V, Kavatha Dimitra D, Tsiodras Sotirios S et al.

Paradoxical reactions during anti-tuberculosis treatment are immune-mediated reactions that complicate treatment even in immunocompetent patients. We present the case of a previously healthy 24-year-old man with disseminated tuberculosis, who experienced persistent fever, weight loss, and radiological deterioration despite appropriate treatment. These findings were consistent with a paradoxical reaction to treatment, after extensive work-up excluded treatment failure, co-infections, and systemic inflammatory conditions. However, high-dose corticosteroids failed to achieve improvement. Ultimately, an interleukin-1 receptor antagonist (anakinra) was initiated as a salvage therapy for this corticosteroid-refractory paradoxical reaction, resulting in rapid defervescence, normalization of inflammatory markers, and radiological improvement. This case underscores the diagnostic and therapeutic challenges when managing severe reactions in tuberculosis patients, while highlighting the importance of biologics like anakinra in corticosteroid-refractory paradoxical reactions. Paradoxical reactions to anti-tuberculosis treatment remain an overlooked cause of non-resolving fever in immunocompetent and immunocompromised patients with tuberculosis and should be considered after ruling out treatment-refractory or complicated infection in persistently febrile patients.Prompt treatment of severe reactions prevents major complications and improves clinical outcomes.Corticosteroid-refractory paradoxical reactions illustrate the potential role of biologics, such as tumour necrosis factor inhibitors and, in our case, interleukin-1 receptor antagonists, in controlling excessive inflammation in tuberculosis.

Targetable S100-RAGE signaling mediates intrinsic trastuzumab deruxtecan resistance in metastatic breast cancer.

Dong Wenjuan W, Wang Shiruo S, Chan Bill B, Vasquez Matthew M et al.

Trastuzumab deruxtecan (T-DXd) has improved outcomes in metastatic breast cancer; however, a substantial subset of patients experience early lack of clinical benefit that is not reliably predicted by routine clinicopathologic variables. In an institutional cohort of 109 T-DXd-treated metastatic lesions, HER2 expression level, ER/PR status, Ki-67 index, and metastatic site were not significantly associated with response, highlighting the need to define mechanistic determinants of intrinsic resistance. We performed spatial transcriptomic and proteomic profiling using NanoString GeoMx Digital Spatial Profiling on pretreatment bone, brain, and soft-tissue metastases from patients with clinical benefit (response) versus early progression (resistance) on T-DXd. Tumor (PanCK⁺) and immune (CD45⁺) compartments were analyzed to link tumor architecture and region-resolved signaling states with therapeutic response. Candidate resistance pathways were functionally evaluated in HER2-positive breast cancer cell lines and in vivo metastasis models treated with T-DXd alone or combined with the RAGE inhibitor TTP488. Spatial proteogenomics revealed recurrent upregulation of S100 family alarmins in resistant tumor regions, associated with activation of a RAGE-centered pro-survival signaling program characterized by ERK, AKT, and STAT3 phosphorylation. Pharmacologic RAGE inhibition enhanced T-DXd-induced apoptosis, restored drug sensitivity in vitro, and significantly reduced metastatic burden in lung and brain metastasis models. Spatial proteogenomics identifies a conserved S100-RAGE-driven survival state coupled to immune-excluded tumor architecture as a mechanism of intrinsic T-DXd resistance across metastatic niches. Targeting this pathway with an orally available RAGE antagonist restores T-DXd responsiveness and offers an immediately translatable strategy to overcome resistance in metastatic breast cancer.

Defining minimal clinical disease activity and remission in severe asthma: a modified Delphi consensus.

Couillard S S, Bourdin A A, Brusselle G G, Dorscheid D D et al.

The introduction of biologics in the treatment of severe asthma, has led to improved patient outcomes and increased discussions around remission. Due to varying descriptions of remission, there is a clear need for a standardised definition of remission as a target for patients. Remission has stringent criteria to achieve the best possible outcomes for patients; however not all patients achieve remission dependent on their disease severity and duration. Therefore, less stringent criteria should also be considered such as a patient state of minimal clinical disease activity (MCDA). To explore these definitions, a Steering Committee of respiratory healthcare professionals (HCPs) employed a systematic literature review (SLR) and modified Delphi consensus. Outputs of the SLR were used to draft consensus statements that underwent two rounds of review with the Steering Committee and one round of review with a wider group of HCPs. Initial definitions of MCDA and remission were drafted based on the consensus statements and finalised in a Steering Committee meeting. The definitions include criteria for asthma exacerbations, steroid use, lung function, and quality of life. These definitions serve as a starting point for improving disease management in patients with severe asthma and should be validated in real-world settings.