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Background: Although activation of human epidermal growth factor receptor 3 (HER3) is linked to resistance to targeted therapies in several cancer types, the HER3 expression profile during pancreatic cancer treatment remains unknown. Aims: We evaluated the HER3 expression status after chemotherapy for pancreatic cancer and its association with clinicopathological features and clinical outcomes. Materials & Methods: We included patients with pancreatic cancer who underwent chemotherapy and whose post‐treatment archival tissue specimens were collected. HER3 expression was retrospectively assessed by immunohistochemistry scoring (0, 1+, 2+, and 3+) of the membranous staining intensity. Results: HER3 expression after chemotherapy was evaluated in 41 patients, with matched‐pair analysis in five patients before and after chemotherapy. HER3 expression was observed in most of the patients after chemotherapy, demonstrating IHC scores of ≥ 1+ and ≥ 2+ in 40 (98%) and 26 (63%) of 41 patients, respectively. Of the 38 patients with adenocarcinoma, the median overall survival in the HER3 (2+/3+) and HER3 (0/1+) groups was 21.0 and 17.1 months, respectively. The comparison of HER3 expression before and after chemotherapy performed in five cases revealed that scores changed from 2+/3+ to 0/1+ in one case, 0/1+ to 2+/3+ in another case, and remained at 2+/3+ in three cases. Cancer genome profiling tests in eight cases found no HER3 amplification or mutation, and seven of these cases had adenocarcinomas with KRAS and TP53 mutations. Conclusion: A high prevalence of HER3 expression was observed in pancreatic cancer patients after chemotherapy. Our findings indicate that HER3 is a potential therapeutic target for pancreatic cancer, deserving further clinical investigation. [ABSTRACT FROM AUTHOR]

Background and Purpose: Intratumour heterogeneity frequently leads to drug resistance, which is a major issue in drug discovery. Drug distribution is one of the key factors for elucidating the resistance mechanism; however, quantitative and regional drug measurement is challenging. Here, we developed a novel ultra‐sensitive analytical method and applied it to HER3‐targeting antibody–drug conjugate patritumab deruxtecan (HER3‐DXd), aiming to explore its payload (DXd) distribution within heterogeneous tissues. Experimental Approach: The developed analytical method is named LDMS‐CE‐MS, a capillary electrophoresis‐mass spectrometry (CE‐MS) coupled with a novel sample preconcentration/separation method called "large‐volume dual‐sample stacking by micelle collapse and sweeping (LDMS)". First, the analytical performance of LDMS‐CE‐MS for DXd detection was evaluated. Subsequently, we evaluated the bystander effect of HER3‐DXd, where tumour tissues were excised from xenograft models and clinical specimens after administration of HER3‐DXd. HER3‐high expression, adjacent, and HER3‐low expression regions were then sampled by laser microdissection to quantify the released DXd. Key Results: LDMS concentrated DXd by 1000‐fold and separated it from the hydrophilic bio‐matrix through continuous capture and release by the charged micelles, allowing quantification at sub‐attomole‐level. DXd concentrations decreased in the order of antigen‐high expression > adjacent > antigen‐low expression regions in the tumour xenograft model, whereas in clinical specimens, adjacent and antigen‐high expression regions had approximately the same concentration. These distributions represent a bystander effect. Conclusions and Implications: Our LDMS‐CE‐MS successfully visualized the attomole‐level drug distributions in heterogeneous clinical specimens. This new platform opens a new era of quantitative pharmacokinetic analysis, facilitating drug discovery and development. [ABSTRACT FROM AUTHOR]

Shwachman syndrome is an autosomal-recessive disorder characterized by exocrine pancreatic insufficiency, bone-marrow dysfunction, and metaphyseal chondrodysplasia. A de novo balanced translocation was recently documented in a patient with this disease. Toward isolating the gene(s) responsible for Shwachman syndrome, we cloned and sequenced the translocation breakpoints in the DNA of this patient. The nucleotide sequences around the breakpoints contained neither repetitive elements nor motifs reported to be implicated in recombination events, although we did detect gains or losses of oligonucleotides at the translocation junctions. By large-scale genomic sequencing and in silico gene trapping, we identified two novel transcripts in the vicinity of the breakpoints that might represent candidate genes for Shwachman syndrome, one on chromosome 6 and the other on chromosome 12. The gene on chromosome 12 was actually disrupted by the translocation. [ABSTRACT FROM AUTHOR]