TP53 gain-of-function mutations promote osimertinib resistance via TNF-α-NF-κB signaling in EGFR-mutated lung cancer.

EGFR tyrosine kinase inhibitors (TKIs) are effective against EGFR-mutated lung cancer, but tumors eventually develop resistance to these drugs. Although TP53 gain-of-function (GOF) mutations promote carcinogenesis, their effect on EGFR-TKI efficacy has remained unclear. We here established EGFR-mutated lung cancer cell lines that express wild-type (WT) or various mutant p53 proteins with CRISPR-Cas9 technology and found that TP53-GOF mutations promote early development of resistance to the EGFR-TKI osimertinib associated with sustained activation of ERK and expression of c-Myc. Gene expression analysis revealed that osimertinib activates TNF-α-NF-κB signaling specifically in TP53-GOF mutant cells. In such cells, osimertinib promoted interaction of p53 with the NF-κB subunit p65, translocation of the resulting complex to the nucleus and its binding to the TNF promoter, and TNF-α production. Concurrent treatment of TP53-GOF mutant cells with the TNF-α inhibitor infliximab suppressed acquisition of osimertinib resistance as well as restored osimertinib sensitivity in resistant cells in association with attenuation of ERK activation and c-Myc expression. Our findings indicate that induction of TNF-α expression by osimertinib in TP53-GOF mutant cells contributes to the early development of osimertinib resistance, and that TNF-α inhibition may therefore be an effective strategy to overcome such resistance in EGFR-mutant lung cancer with TP53-GOF mutations.

Evaluation of appropriate conditions for Oncomine DxTT testing of FFPE specimens for driver gene alterations in non-small cell lung cancer.

BACKGROUND: The Oncomine Dx Target Test Multi-CDx System (ODxTT) is a next-generation sequencing panel approved as a companion diagnostic for drugs targeted to corresponding gene alterations in non-small cell lung cancer. However, appropriate slide conditions for ODxTT have remained unclear. METHODS: We focused on the production of the number of tumor cells on a formalin-fixed paraffin-embedded (FFPE) section and the number of prepared slides, designated the TS value, and determined a TS value of ≥4000 as a target slide condition for ODxTT. We evaluated the impact of this condition on ODxTT testing with tumor specimens found to have a TS of <4000 (n = 23) or a TS of ≥4000 (n = 142). RESULTS: A positive correlation was apparent between the TS value and the concentrations of both DNA and RNA. Among the 142 samples with a TS of ≥4000, a sufficient concentration of DNA or RNA for ODxTT analysis was achieved in 100% and 98% samples, respectively. Among samples explored for driver gene alterations after determination of the target slide condition (TS ≥4000), most (84.9%) had a TS of ≥4000 and were submitted for ODxTT analysis. CONCLUSION: Our findings indicate that a TS of ≥4000 is a feasible and relevant criterion for ODxTT testing, and its adoption should help to improve the success rate of such testing in clinical practice.

Mutant forms of EGFR promote HER2 trafficking through efficient formation of HER2-EGFR heterodimers.

INTRODUCTION: Human epidermal growth factor receptor 2 (HER2) forms homodimers and is retained at the surface of cancer cells positive for HER2 amplification. The dimerization, internalization, and intracellular trafficking of HER2 in cancer cells without HER2 amplification have remained uncharacterized, however. MATERIALS AND METHODS: HER2 homodimers and heterodimers were detected in various cell lines with the use of an in situ proximity ligation assay. The effects of wild-type or mutant forms of epidermal growth factor receptor (EGFR) on intracellular trafficking of HER2 were examined by live-cell imaging. The sensitivity of cell lines without HER2 amplification to ado-trastuzumab emtansine (T-DM1), an anti-HER2 (trastuzumab)-cytotoxic drug conjugate (ADC) was also investigated. RESULTS: HER2 preferentially formed heterodimers with EGFR rather than homodimers and was rapidly internalized together with EGFR in cells without HER2 amplification. HER2-EGFR heterodimers were more abundant and HER2 was more efficiently transferred to lysosomes in such cells with than in those without EGFR activating mutations. T-DM1 showed a high cytotoxic efficacy in the cells with EGFR mutations, suggesting that mutant forms of EGFR promote the transfer of HER2-bound T-DM1 to lysosomes through efficient formation of HER2-EGFR heterodimers. CONCLUSION: Our findings reveal that HER2 trafficking is affected by EGFR, especially by mutant forms of the receptor, and they provide a rationale for the use of HER2-targeting ADCs in the treatment of EGFR-mutated lung cancer.

Association of thyroid transcription factor-1 (TTF-1) expression with efficacy of PD-1/PD-L1 inhibitors plus pemetrexed and platinum chemotherapy in advanced non-squamous non-small cell lung cancer.

Background: Thyroid transcription factor-1 (TTF-1) expression in advanced non-squamous non-small cell lung cancer (NSCLC) has been associated with the efficacy of pemetrexed plus platinum chemotherapy. However, the relation between TTF-1 expression and efficacy of the combination of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors plus pemetrexed and platinum chemotherapy, a standard first-line treatment regimen for advanced non-squamous NSCLC, has remained unclear. Methods: We retrospectively evaluated TTF-1 expression in tumor tissue of patients with advanced or recurrent non-squamous NSCLC treated with PD-1/PD-L1 inhibitors plus pemetrexed and platinum chemotherapy in the first-line setting. Clinical characteristics and pathological data for each patient were assessed, and progression-free survival (PFS) was evaluated. Bias due to patient background was minimized by application of inverse probability of treatment weighting (IPTW) analysis. Results: A total of 122 patients, 75 (61.5%) of whom were positive for TTF-1 immunostaining in tumor specimens, was included in this multicenter study. At the time of analysis, 89 (73.0%) patients had experienced progression events and 44 (36.1%) had died [median follow-up 14.6 months (range, 0.53-29.5 months)]. PFS was longer for TTF-1-positive patients than for TTF-1-negative patients [median, 12.2 vs. 6.0 months; hazard ratio (HR) =0.63 (95% CI: 0.37-1.06); log-rank P=0.028]. IPTW-adjusted PFS was significantly longer for TTF-1-positive than for TTF-1-negative patients [HR =0.62 (95% CI: 0.46-0.83); log-rank P=0.024]. Conclusions: TTF-1 expression in advanced non-squamous NSCLC can serve as a basis for prediction of PFS in patients treated with PD-1/PD-L1 inhibitors plus pemetrexed and platinum chemotherapy in the first-line setting.

A Rare Case of Pulmonary Tumor Thrombotic Microangiopathy Associated with Micropapillary Urothelial Carcinoma of the Urinary Bladder: An Autopsy Case.

A 70-year-old woman was hospitalized with dyspnea. A transthoracic echocardiogram indicated an elevated systolic pulmonary artery pressure, and the cytology specimens obtained using a pulmonary artery catheter confirmed adenocarcinoma metastasis. Diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) detected high-signal-intensity lesions in the urinary bladder. The patient died of respiratory failure and a postmortem examination was performed. Tumor cells in the bladder were immunohistochemically positive for GATA3, indicating micropapillary urothelial carcinoma, which is a rare variant of urothelial carcinoma and considered an adenocarcinoma subtype. This case is the first autopsy case of pulmonary tumor thrombotic microangiopathy (PTTM) associated with micropapillary urothelial carcinoma of the urinary bladder.

Tumor Embolism as a Cause of Renal Artery Occlusion and Acute Kidney Injury Diagnosed and Treated with Endovascular Intervention in a Patient with Mediastinal Undifferentiated Sarcoma.

A 72-year-old man presented with back pain due to a mass in the left posterior mediastinum that had surrounded and partly infiltrated the descending aorta. Mediastinal undifferentiated sarcoma was diagnosed. After the diagnosis, sudden anuria was observed. Contrast-enhanced computed tomography revealed an enhancement defect at the origins of the bilateral renal arteries. He received catheter-directed thrombolysis and was weaned off dialysis. The aspirated artery thrombus contained tumor cells, proving our diagnosis of acute kidney injury secondary to bilateral renal artery tumor embolism. In cancer patients, endovascular intervention may be a useful diagnostic and therapeutic option in cases of acute kidney injury secondary caused by peripheral thromboembolic complications.

Splenic volume in pneumococcal pneumonia patients is associated with disease severity and mortality.

Splenectomy is a risk factor for serious pneumococcal disease like overwhelming post-splenectomy infection (OPSI). In healthy individuals with small spleen, fulminant pneumococcal infection similar to OPSI has been reported. Furthermore, it is reported that small spleen was associated with severe pneumococcal infection patients treated in an intensive care unit. However, the association between the small spleen and pneumococcal pneumonia was not investigated enough. We retrospectively analyzed patients with pneumococcal pneumonia who underwent computed tomography examination with measurement of the splenic volume at Harasanshin Hospital between 2004 and 2019. Data on their background characteristics, laboratory findings, and clinical courses were collected. 413 patients were included in the final analysis. The splenic volume was significantly lower in the moderate (P < 0.001), severe (P < 0.00005), and extremely severe (P < 0.001) pneumonia groups compared with the mild pneumonia group. Furthermore, the splenic volume was significantly lower in patients died within 30 days of pneumonia treatment (median of 73.49 versus 110.77 cm3, P < 0.005) or during hospitalization (median of 71.69 versus 111.01 cm3, P < 0.0005). Splenic volume <40 cm3 was significantly associated with mortality within 30 days and total hospital mortality as a risk factor in univariate analysis. Splenic volume <40 cm3 was an independent risk factor for mortality within 30 days (odds ratio: 5.0, 95% confidence interval: 1.2-21.1, P < 0.05) and total hospital mortality (odds ratio: 7.4, 95% confidence interval: 1.8-30.6, P < 0.01) in multivariate logistic regression analysis. These results suggest that small spleen is a risk factor for severity and mortality of pneumococcal pneumonia.

Remarkable response to nivolumab in sarcomatoid malignant pleural mesothelioma with high PD-L1.

We report herein a case of sarcomatoid malignant pleural mesothelioma (MPM) with high PD-L1 expression who was refractory to standard chemotherapy but had a remarkable and sustained response to nivolumab. A 78-year-old man presented with right chest pain. Computed tomography (CT) showed a solid mass extending to the right pleura. Histopathological examination revealed the proliferation of spindle to pleomorphic ovoid shaped tumour cells, which are positive for calretinin and podoplanin. The patient was diagnosed with sarcomatoid MPM. Despite treatment with carboplatin and pemetrexed, the primary lesion rapidly progressed and new multiple pleural metastases were observed. Although his performance status decreased with advancing of symptoms and adverse events, nivolumab was administered. After the nivolumab treatment, CT showed a significant reduction in pleural tumours with a marked improvement in symptoms. In the primary specimens, TPS of PD-L1 was 80%. The patient has continued this treatment with sustained and remarkable effectiveness with good quality of life (QOL).

Retrospective cohort study on the safety and efficacy of docetaxel in Japanese non-small cell lung cancer patients with nondialysis chronic kidney disease stage 3b or higher.

BACKGROUND: It has been reported that 20% of lung cancer patients have renal impairment caused by chronic kidney disease (CKD). Since docetaxel is predominantly excreted by the hepatobiliary system, it is administered to non-small cell lung cancer (NSCLC) patients with renal impairment. However, few clinical data are available on the toxicity and efficacy of docetaxel for patients with nondialysis renal impairment. Furthermore, some cases of tubular nephrotoxicity caused by docetaxel in NSCLC patients have been reported. Therefore, a retrospective cohort study was conducted to assess the influence of nondialysis CKD on the toxicity and efficacy of docetaxel in NSCLC patients. METHODS: NSCLC patients who received docetaxel were assessed for renal function, occurrence of adverse events and treatment efficacy. RESULTS: A total of 34 NSCLC patients who received docetaxel were studied. Eight (23.5%) patients had nondialysis CKD stage 3b or higher, with an estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2 . Although the differences were not statistically significant, the starting dose of docetaxel (mg/m2 ) was lower (60 mg/m2 ; 37.5% vs. 69.2%) in patients with an eGFR <45 than that in patients with an eGFR ≥45. No significant association was observed between pretreatment eGFR and hematological and nonhematological toxicities. No significant difference was observed in the disease control rate (62.5% vs. 65.4%, P = 1.000) or in the median overall survival (10.7 vs. 11.7, P = 0.735) between patients with an eGFR <45 and those with an eGFR ≥45. CONCLUSION: Docetaxel is a reasonable option for NSCLC patients with nondialysis CKD stage 3b or higher. Dose reduction of docetaxel is also a possibility for NSCLC patients with CKD stage 3b or higher.

Comparison of End-Tidal, Arterial, Venous, and Transcutaneous PCO2.

BACKGROUND: We investigated the measurement of end-tidal partial pressure of carbon dioxide (PETCO2 ) with a capnometer in patients with respiratory failure, and we determined whether this technique could provide an alternative to measurement of PaCO2 using arterial blood gas analysis in the clinical setting. METHODS: We measured PETCO2 in subjects with hypoxemic and hypercarbic respiratory failure using a capnometer. We simultaneously measured PaCO2 , venous partial pressure of carbon dioxide (Pv̄CO2 ), and transcutaneously measured partial pressure PCO2 (PtcCO2 ). We analyzed agreements among these parameters with Bland-Altman analysis. We obtained 30 samples from subjects with hypoxemic respiratory failure and 30 samples from subjects with hypercarbic respiratory failure. RESULTS: Thirty subjects with hypoxemic respiratory failure and 18 subjects with hypercarbic respiratory failure participated in this study. Significant relationships were found between PETCO2 and PaCO2 , between PtcCO2 and PaCO2 , and between Pv̄CO2 and PaCO2 . Bland-Altman analysis of PETCO2 and PaCO2 in all subjects revealed a bias of 6.48 mm Hg (95% CI 4.93-8.03, P < .001) with a precision of 6.01 mm Hg. Bland-Altman analysis of PETCO2 and PaCO2 with hypoxemic respiratory failure revealed a bias of 5.14 mm Hg (95% CI 3.35-6.93, P < .001) with a precision of 4.80 mm Hg. Bland-Altman analysis of PETCO2 and PaCO2 in subjects with hypercarbic respiratory failure revealed a bias of 7.83 mm Hg (95% CI 5.27-10.38, P < .001) with a precision of 6.83 mm Hg. CONCLUSIONS: PETCO2 can be measured simply using a capnometer, and PETCO2 measurements can estimate PaCO2 . However, the limits of agreement were wide. Therefore, care providers must pay attention to the characteristics and errors of these devices. These results suggest that measurement of PETCO2 might be useful for screening for hypercarbic respiratory failure in the clinical setting.