Trastuzumab emtansine (T-DM1) is the standard treatment in the current second-line therapy of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. However, a useful therapy after T-DM1 resistance has not been established. In this study, we established two different HER2-positive T-DM1-resistant cancer cells and evaluated the antitumor effect of trastuzumab in combination with pertuzumab (TRAS + PER).
 
  Single-cell-cloned OE19 and BT-474 cells were cultured with increasing concentrations of T-DM1 to generate T-DM1-resistant OE19bTDR and BT-474bTDR cells, respectively. HER2 expression was assessed by immunohistochemistry. Multidrug resistance proteins (MDR1 and MRP1) were evaluated by real-time polymerase chain reaction and western blotting. Intracellular trafficking of T-DM1 was examined by flow cytometry and immunofluorescence staining. Efficacy of TRAS + PER was evaluated by cell proliferation assay, HER3 and AKT phosphorylation, caspase 3/7 activity, and antitumor activity.
 
  HER2 expression of both resistant cells was equivalent to that of the parent cells. Overexpression of MDR1 and MRP1 was observed and affected the T-DM1 sensitivity in the OE19bTDR cells. Abnormal localization of T-DM1 into the lysosomes was observed in the BT-474bTDR cells. In BT-474bTDR cells, TRAS + PER inhibited the phosphorylation of AKT involved in HER2-HER3 signaling, and apoptosis induction and cell proliferation inhibition were significantly higher with TRAS + PER than with the individual drugs. TRAS + PER significantly suppressed tumor growth in the OE19bTDR xenograft model compared with each single agent.
 
  The results suggest that the TRAS + PER combination may be effective in T-DM1-resistant cancer cells where HER2 overexpression is maintained.
 The results suggest that the TRAS + PER combination may be effective in T-DM1-resistant cancer cells where HER2 overexpression is maintained.
  The usefulness of the histopathology of biopsy samples for predicting the efficacy of immunotherapy in non-squamous, non-small cell lung cancer (NSq NSCLC) patients remains unclear.
 
  We retrospectively investigated the associations between the histopathological features in biopsy samples and survival outcomes in advanced NSq NSCLC patients receiving pembrolizumab. NSq NSCLC was classified histopathologically as morphological adenocarcinoma or non-small cell carcinoma (NSCC absence of definitive features of either adenocarcinoma or a squamous morphology). We investigated the association between the tumor morphological features and immune/genetic features by examining the tumor PD-L1 expression and tumor mutation burden (TMB).
 
  Among 33 advanced NSq NSCLC patients with tumor PD-L1 scores ≥ 50% receiving pembrolizumab as first-line therapy, a biopsy diagnosis of NSCC was associated with a significantly longer progression-free survival [median 16.8 vs. 2.3months; hazard ratio (HR) 0.26; 95% CI 0.10-0.62, P = 0.01] and overall survival (median NR vs. 10.1months; HR 0.35; 0.12-0.97, P = 0.04) as compared to that of morphological adenocarcinoma.  https://www.selleckchem.com/products/vvd-214.html  In an analysis of 367 biopsy samples, the NSCC group showed a higher percentage of samples with PD-L1 scores ≥ 50% than the morphological adenocarcinoma group (35% vs. 10%). The NSCC group (n = 8) also showed a significantly higher TMB than the morphological adenocarcinoma group (n = 7) (median 236 vs. 25 mutations/whole exome, P = 0.01).
 
  Absence of definitive morphological features in a biopsy sample could be a useful predictor of the efficacy of pembrolizumab in NSq NSCLC patients with tumor PD-L1 scores ≥ 50%, as these tumors are likely to show high tumor PD-L1 expression and high TMB.
 Absence of definitive morphological features in a biopsy sample could be a useful predictor of the efficacy of pembrolizumab in NSq NSCLC patients with tumor PD-L1 scores ≥ 50%, as these tumors are likely to show high tumor PD-L1 expression and high TMB.As a first of its kind, we developed a highly sensitive colorimetric nanoprobe for phytic acid (PA) and Fe(III) ion detection based on 4-mercaptophenol (4MP) and thioglycolic acid (TGA)-functionalized gold nanoparticles AuNPs@(4MP-TGA). AuNPs were easily derivatized by 4MP and TGA through -SH binding to gold. Fe(III) ions possibly are bound first to the phenolate groups of 4MP-AuNPs, and further coordinated several nanoparticles via the carboxylate groups of TGA-AuNPs to cause aggregation, resulting in a red-to-purple color change and a bathochromic shift in the SPR absorption band of the nanoprobe. With the addition of PA to the AuNPs@(4MP-TGA)-Fe(III) system, the aggregated particles were released due to strong complex formation between Fe(III) and PA, resulting in a restoration of the color (purple-to-red) and of the SPR band to the original 520 nm wavelength maximum. Thus, the 650-nm absorption is attenuated and the 520-nm band is enhanced upon PA-Fe(III) chelation. This means that the absorption ratio A650/A520 is an indication of Fe(III) whereas the reverse ratio A520/A650 of the PA content of complex samples. The limits of detection (LOD) of the AuNPs@(4MP-TGA) were 1.0 μM for Fe(III) ions and 0.15 μM for PA. Phytic acid extracted from bean grains was determined with the proposed probe, yielding good recoveries. In addition, common metal ions, anions, and several biomolecules did not show an adverse effect on the nanoprobe performance for ferric ions and phytate. The developed method was statistically validated against a LC-MS/MS literature method. Graphical abstract Mercaptophenolate (4MP)- and thioglycolic acid (TGA)-functionalized gold nanoparticles were prepared as nanoprobes to detect Fe(III) ions through nanoparticle aggregation accompanied by red-to-purple color shift. The same nanoprobe determined phytic acid in food through disaggregation of Fe(III)-aggregated nanoparticles by strong Fe(III)-phytate chelation and restoration of solution color from purple to red.Cancer patients frequently require central venous catheters for therapy and parenteral nutrition and are at high risk of central venous catheter-related infections (CRIs). Moreover, CRIs prolong hospitalization, cause an excess in resource utilization and treatment cost, often delay anti-cancer treatment, and are associated with a significant increase in mortality in cancer patients. We therefore summoned a panel of experts by the Infectious Diseases Working Party (AGIHO) of the German Society of Hematology and Medical Oncology (DGHO) and updated our previous guideline on CRIs in cancer patients. After conducting systematic literature searches on PubMed, Medline, and Cochrane databases, video- and meeting-based consensus discussions were held. In the presented guideline, we summarize recommendations on definition, diagnosis, management, and prevention of CRIs in cancer patients including the grading of strength of recommendations and the respective levels of evidence. This guideline supports clinicians and researchers alike in the evidence-based decision-making in the management of CRIs in cancer patients.