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Context.--Recently, a new type of antibody-drug conjugate, trastuzumab-deruxtecan (T-DXd), has been approved for the treatment of metastatic breast cancer with low level of human epidermal growth factor receptor 2 (HER2) gene expression. Thereby, eligibility relies on an accurate diagnosis of HER2-low status defined by immunohistochemistry IHC 1+/2+ with no gene amplification. Objective.--To assess pathologists' accuracy and training efficacy in the diagnosis of HER2-low. Design.--Agreement rates of HER2-low scoring in breast cancer tissue were assessed between expert consensus and real-world pathologists (n = 77 from 14 countries) before and after a specific 4-hour training for HER2-low detection. Two assays were evaluated, the Ventana Pathway 4B5 CDx and the Dako HercepTest (polyclonal). Concordance of the pathologists with consensus score and efficacy of training were measured by Cohen k, overall rater agreement, and receiver operating characteristic (ROC) curve statistics. Results.--In the Ventana 4B5 HER2-low category, baseline agreement rates were >80% but Conclusions.--The ability of pathologists to achieve acceptable diagnostic accuracy in identifying patients with HER2-low breast cancer could be enhanced by short-term training. Potential routes to improve the quality of HER2-low scoring in clinical practice have been identified. doi: 10.5858/arpa.2024-0052OA, During the past 20 years, diagnosis of human epidermal growth factor receptor 2 (HER2) status has been essential in determining eligibility of breast cancer patients for HER2-targeted therapies. (1,2) Although [...]

Simple Summary: Personalised cancer treatment improves outcome for patients but requires that each individual tumour is classified using molecular tools. Extensive genomic studies for each individual patients are out of reach for the majority of the population, therefore, pathologists need to apply readily available tests to achieve molecular classification for all cancer patients. This paper describes how gastric cancer can be classified using on slide tests already used by histopathologists. Using this classification, oncologists can select more effective treatment for each patient. Background and Objectives: Gastric cancer (GC) is one of the most commonly diagnosed cancers and the fourth cause of cancer death worldwide. Personalised treatment improves GC outcomes. A molecular classification is needed to choose the appropriate therapy. A classification that uses on-slide biomarkers and formalin-fixed and paraffin-embedded (FFPE) tissue is preferable to comprehensive genomic analysis. In 2016, Setia and colleagues proposed an on-slide classification; however, this is not in widespread use. We propose a modification of this classification that has six subgroups: GC associated with Epstein–Barr virus (GC EBV+), GC with mismatch-repair deficiency (GC dMMR), GC with epithelial–mesenchymal transformation (GC EMT), GC with chromosomal instability (GC CIN), CG that is genomically stable (GC GS) and GC not otherwise specified (GC NOS). This classification also has a provision for biomarkers for current or emerging targeted therapies (Her2, PD-L1 and Claudin18.2). Here, we assess the implementation and feasibility of this inclusive working classification. Materials and Methods: We constructed a tissue microarray library from a cohort of 79 resection cases from FFPE tissue archives. We used a restricted panel of on-slide markers (EBER, MMR, E-cadherin, beta-catenin and p53), defined their interpretation algorithms and assigned each case to a specific molecular subtype. Results: GC EBV(+) cases were 6%, GC dMMR cases were 20%, GC EMT cases were 14%, GC CIN cases were 23%, GC GS cases were 29%, and GC NOS cases were 8%. Conclusions: This working classification uses markers that are widely available in histopathology and are easy to interpret. A diagnostic subgroup is obtained for 92% of the cases. The proportion of cases in each subgroup is in keeping with other published series. Widescale implementation appears feasible. A study using endoscopic biopsies is warranted. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) accounts for approximately 12% to 17% of all breast cancers and has an aggressive clinical behavior. Increased tumor-infiltrating lymphocyte counts are prognostic for survival in TNBC, making this disease a potential target for cancer immunotherapy. Research on immunophenotyping of tumor-infiltrating lymphocytes is revealing molecular and structural organization in the tumor microenvironment that may predict patient prognosis. The anti-programmed death-ligand 1 (PD-L1) antibody atezolizumab plus nab-paclitaxel was the first cancer immunotherapy combination to demonstrate progression-free survival benefit and clinically meaningful overall survival benefit in the first-line treatment of metastatic TNBC (mTNBC) in patients with PD-L1-expressing tumor-infiltrating immune cells in 1% or more of the tumor area. This led to its United States and European Union approval for mTNBC and US approval of the VENTANA PD-L1 (SP142) assay as a companion diagnostic immunohistochemistry assay. Subsequently, the anti-programmed death-1 (PD-1 ) antibody pembrolizumab plus chemotherapy was approved by the US Food and Drug Administration for mTNBC based on progression-free survival benefit in patients with a combined positive score of at least 10 by its concurrently approved 22C3 companion diagnostic assay. Treatment guidelines now recommend PD-L1 testing for patients with mTNBC, and the testing landscape will likely become increasingly complex as new anti-PD-L1 and anti-PD-1 agents and diagnostics are approved for TNBC. Integrating PD-L1 testing into current diagnostic workflows for mTNBC may provide more treatment options for these patients. Therefore, it is critical for medical oncologists and pathologists to understand the available assays and their relevance to therapeutic options to develop an appropriate workflow for immunohistochemistry testing. [ABSTRACT FROM AUTHOR]

Gamma Knife radiosurgery (GKRS) is the standard of single fraction high-dose irradiation of relatively small brain lesion. Despite the steep radiation dose gradient inherent to the GKRS treatment, eloquent structures that lie within 2 mm of the traditional single-session highdose radiation target are at risk. This may represent a problem for the treatment of large benign tumor close to the optic pathways. Hypofractionation has the advantage of achieving a desired therapeutic effect with a tolerable dose of radiation to the optic apparatus, but it’s not very comfortable for the patient to perform a multisession treatment with the stereotaxic frame. Leksell Gamma Knife Icon makes it possible to overcome the problem of holding the frame, without however the accuracy of the latter. In order to evaluating the efficacy and safety of treatment by repositioning with Gamma Knife Icon, we reviewed our case series, analyzing the clinical and radiological outcome of all patients treated in a frameless modality from September 2017 to December 2020. Patients with benign perioptic lesion, including skull base meningiomas, pituitary adenomas and craniopharingioma treated with Gamma Knife Icon were included. For each patient we collected demographic and clinical data, as well as radiological imaging. Pretreatment volumes have been calculated using the Leksell Gamma Plan Treatment Planning System, as well as the treatment plan. For clinical follow up we evaluated the onset of visual disturbances (both of the visual and of the visual field); moreover we evaluate radiological follow up We collected a total of 78 patients (59 female and 19 male) with a mean age of 60,8 years (from 38 yrs to 85 yrs). The most frequent lesion are meningiomas (64 patients), followed by 11 patients with pituitary adenomas, 2 patients with craniopharingiomas and 1 patient with solitary fibrous tumor. The average tumor volume was 5,136 cm3. 27 patients (34,6 %) presesented neurological symptoms at the time of treatment and pre-existing disorders mainly included diplopia and visual disturbance. Of these 27 patients, only 3 had a worsening of previous symptoms, in particular in one case there was a worsening of diplopia and in two patients a slight worsening of campimetric deficit. None of the asymptomatic patients developed post GKRS neurological disorders. At a mean follow-up of two years, all patients presented radiological stability of the treated lesions. In this preliminary report, hypofractionation with Gamma Knife Icon represents a good option for tumors close to the optic pathway. [ABSTRACT FROM AUTHOR]

This study reports the experience of a single institute concerning the treatment of brain metastases in fractional mode (frame modality and frameless) with a review of the literature. We preferred fractionation for metastases close to critical structures or with a large volume. We used two modalities of fractionation: hypofractionated stereotactic radiosurgery (HSRS), which consists of three or five consecutive days of treatment and staged stereotactic radiosurgery (SSRS), which consists of two fractions delivered with an interval of about four / five weeks. All procedures were performed with Gamma Knife Icon. Seven patients were treated with HSRS and five patients with SSRS. In the HSRS group two patients have metastases close to critical organs; median volume was 6,441 cm3(range 0,815 – 17,357 cm3) and median total marginal dose was 25 Gy at 50% (range 21 – 32,5 Gy) in three or five days. For the SSRS group median volume at the first treatment was 11,214 cm3 (range 8,1 – 26,777 cm3) and 7,627 cm3 (range 3,757 – 18,46 cm3) at the second treatment; the median total marginal dose was 12 Gy for both first and second fraction. Follow up (FU): At 12 months 7 patients were alive and 4 deceased (extracranial disease progression), one patient was lost to FU. At 18 months 3 patients were alive and 7 deceased (in one case for cerebral progression, the other cases extracranial disease progression) while 2 patients were lost to FU. Complications: we observed one case of radionecrosis in a patient previously radiotherapy and one case of seizure. From the literature review it emerged that positive predictive factors are: controlled extracranial tumor, prolonged fractionation days in HSRS and decrease of the tumor volume between fractions in SSRS. Our experience partly reflects these results: the patients undergoing surgery post Gamma Knife surgery had not experienced a reduction in volume between the first and second fractions, while the patients with less favorable clinical course up to death presented extracranial metastates and poor control of the disease. We didn’t observe significant difference in survival in patients undergoing treatments lasting 3 days compared to 5 days. Fractionated radiosurgery with Gamma Knife offers a slightly or non-invasive therapeutic alternative for treating more fragile patients and without longterm healing chances with large brain metastases or metastases closed to critical organs. [ABSTRACT FROM AUTHOR]

Triple-negative breast cancer (TNBC) accounts for approximately 12% to 17% of all breast cancers and has an aggressive clinical behavior. Increased tumor-infiltrating lymphocyte counts are prognostic for survival in TNBC, making this disease a potential target for cancer immunotherapy. Research on immunophenotyping of tumor-infiltrating lymphocytes is revealing molecular and structural organization in the tumor microenvironment that may predict patient prognosis. The anti-programmed death-ligand 1 (PD-L1) antibody atezolizumab plus nab-paclitaxel was the first cancer immunotherapy combination to demonstrate progression-free survival benefit and clinically meaningful overall survival benefit in the first-line treatment of metastatic TNBC (mTNBC) in patients with PD-L1-expressing tumor-infiltrating immune cells in 1% or more of the tumor area. This led to its United States and European Union approval for mTNBC and US approval of the VENTANA PD-L1 (SP142) assay as a companion diagnostic immunohistochemistry assay. Subsequently, the anti-programmed death-1 (PD-1 ) antibody pembrolizumab plus chemotherapy was approved by the US Food and Drug Administration for mTNBC based on progression-free survival benefit in patients with a combined positive score of at least 10 by its concurrently approved 22C3 companion diagnostic assay. Treatment guidelines now recommend PD-L1 testing for patients with mTNBC, and the testing landscape will likely become increasingly complex as new anti-PD-L1 and anti-PD-1 agents and diagnostics are approved for TNBC. Integrating PD-L1 testing into current diagnostic workflows for mTNBC may provide more treatment options for these patients. Therefore, it is critical for medical oncologists and pathologists to understand the available assays and their relevance to therapeutic options to develop an appropriate workflow for immunohistochemistry testing., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)