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Objective This study seeks to clarify whether allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is necessary for adult patients with Philadelphia chromosome‐positive acute lymphoblastic leukemia (Ph+ ALL) in post‐remission based on a comparison with tyrosine kinase inhibitor (TKI) combined with chemotherapy. Methods We searched the Pubmed, Embase, and Web of Science databases and limited the date range for the studies from January 2010 to August 2020. A hazard ratio (HR) with a 95% confidence interval (CI) was employed to assess overall survival (OS) and relapse‐free survival (RFS), and an odds ratio (OR) with a 95% CI was used to evaluate the ratio of non‐relapsed mortality (NRM) and non‐relapsed survival (NRS). All analyses were conducted with Stata software 16.0 and Revman 5.3. Results Fifteen studies, totaling 959 patients, were included in our analysis. Among those patients, 473 underwent allo‐HSCT, and 486 received TKI plus chemotherapy. The pooled results showed no difference in OS between outcomes for patients receiving TKI plus chemotherapy and those treated with allo‐HSCT (HR = 0.76, 95% CI [0.51–1.12], p = 0.16). Patients undergoing allo‐HSCT did better than those receiving TKI plus chemotherapy regarding RFS (HR = 0.48, 95% CI [0.37–0.63], p = 0.00), and NRS (OR = 2.64, 95% CI [1.25–5.57], p = 0.00). The NRM rate of the TKI plus chemotherapy group was significantly lower than the allo‐HSCT group (OR = 2.33, 95% CI [1.51–3.59], p = 0.00). Conclusion TKI combined with chemotherapy can be considered a post‐remission treatment option for adult Ph+ ALL patients who are ineligible for allo‐HSCT. However, more prospective studies with large sample sizes should be carried out in the future., NRM occurred more frequently in the allo‐HSCT patients than in those undergoing TKI plus chemotherapy. TKI combined with chemotherapy can be considered a post‐remission treatment option for adult Ph+ ALL patients who are ineligible for allo‐HSCT.

BACKGROUND Both zoledronic acid, a potent bisphosphonate, and the antiangiogenic drug sunitinib are included in anticancer protocols and have also been associated with jaw osteonecrosis. Our aim was to compare the effect of these drugs on tissue repair at tooth extraction sites. METHODS Wistar rats were allocated into four groups: (1) sunitinib; (2) sunitinib/zoledronic acid; (3) zoledronic acid; (4) control group. The animals underwent tooth extractions and maxillae were macro- and microscopically analyzed. RESULTS On macroscopic evaluation, the zoledronic acid group showed a significantly higher frequency of oral mucosal lesion; lesions in the sunitinib/zoledronic acid group were larger, albeit not significantly so. The sunitinib/zoledronic acid group had significantly less epithelium than the zoledronic acid and control group, but showed no significant difference compared to the sunitinib group. The sunitinib/zoledronic acid and zoledronic acid groups did not differ from each other, but had significantly less connective tissue and more non-vital bone and microbial colonies than sunitinib and control groups, whereas these latter two groups did not significantly differ from each other. Vital bone and inflammatory infiltrate did not significantly differ between groups. CONCLUSION Sunitinib alone is not associated with non-vital bone, whereas the sunitinib/zoledronic acid combination and zoledronic acid alone are.

The mutation status of tumor tissue DNA (n = 389) of resected stage II‐III non‐squamous non–small‐cell lung cancer (Ns‐NSCLC) was analyzed using targeted deep sequencing as an exploratory biomarker study (JIPANG‐TR) for the JIPANG study, a randomized phase III study of pemetrexed/cisplatin (Pem/Cis) vs vinorelbine/cisplatin (Vnr/Cis). The TP53 mutation, common EGFR mutations (exon 19 deletion and L858R), and KRAS mutations were frequently detected. The frequency of the EGFR mutation was significant among female patients. Patients with an EGFR mutation‐positive status had a significantly shorter recurrence‐free survival (RFS) time (24 mo vs not reached) (HR, 1.64; 95% CI, 1.22‐2.21; P = .0011 for EGFR mutation status). Multivariable analysis identified both the pathological stage and EGFR mutation status as independent prognostic factors for RFS (HR, 1.78; 95% CI, 1.30‐2.44; P = .0003 for disease stage; and HR, 1.57; 95% CI, 1.15‐2.16; P = .0050 for EGFR mutation status). This study demonstrated that the EGFR mutation has either a poor prognostic or predictive impact on a poor response to postoperative chemotherapy with platinum doublet chemotherapy for stage II‐III Ns‐NSCLC patients. This result supports a role for mandatory molecular diagnosis of early‐stage Ns‐NSCLC for precision oncology and signifies the importance of adjuvant for the 3rd generation tyrosine kinase inhibitor rather than platinum‐based chemotherapy. This study is registered with the UMIN Clinical Trial Registry (UMIN 000012237)., Mutation status of stage II‐III Ns‐NSCLC (n = 389) was analyzed using targeted deep sequencing. Patients with an EGFR mutation‐positive status had a significantly shorter recurrence‐free survival (RFS). Both the pathological stage and EGFR mutation status were independent prognostic factors for RFS.

While next-generation sequencing technologies provide excellent strategies to screen for newly defined genetic abnormalities of prognostic or therapeutic significance in patients with B-other-acute lymphoblastic leukaemia (ALL), they are not widely available. We used a dual screening approach, incorporating fluorescence in situ hybridisation (FISH) and Multiplex Ligation-dependent Probe Amplification (MLPA), to establish the frequency and long-term outcome of a representative cohort of specific subgroups of B-other-ALL recruited to the childhood ALL trial, UKALL2003. We focussed on abnormalities of known prognostic significance, including ABL-class fusions and ERG deletions, as a surrogate marker for DUX4-rearranged ALL. ABL-class fusions accounted for ~4% of B-other-ALL and were associated with high levels of minimal residual disease (MRD; 14/23 with MRD >5%) and a high relapse rate (55·7%) following treatment without tyrosine kinase inhibitor (TKI), confirming the importance of prospective screening with a view to incorporating TKI into therapy. Patients with deletions of ERG (~10% of B-other-ALL) had a 10-year event-free-survival of 97·2%, validating previous reports of their excellent outcome. Rearrangements of ZNF384, MEF2D and NUTM1 were observed at low frequencies. Here, we estimate that approximately one third of B-other-ALL patients can be reliably classified into one of the known genetic subgroups using our dual screening method. This approach is rapid, accurate and readily incorporated into routine testing.

Background For lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) sensitive mutation and synchronous brain metastasis (syn-BM), when and how to apply radiotherapy (RT) during first-line tyrosine kinase inhibitor (TKI) treatment remains debatable. Methods From a real-world multicenter database, EGFR-mutant patients with syn-BM diagnosed between 2010-2020 and treated with first-line TKIs were enrolled and divided into upfront TKI + RT and upfront TKI groups. Median intracranial progression-free survival (mIC-PFS), median overall survival (mOS), and their risk factors were estimated. Results There were 60 and 186 patients in the upfront TKI + RT group and upfront TKI group, respectively. Their mIC-PFS were 28.9 months (m) and 17.5 m (p = 0.023), and mOS were 42.7 m and 40.1 m (p = 0.51). Upfront brain RT improved mIC-PFS in patients ≤60-year-old (p = 0.035), with symptomatic BM (p = 0.002), and treated with first-generation TKIs (p = 0.012). There was no significant difference in mOS in any subgroup. Upfront brain stereotactic radiosurgery (SRS) showed a trend of better mIC-PFS and mOS. mIC-PFS was independently correlated with symptomatic BM (HR = 1.54, p = 0.030), EGFR L858R mutation (HR = 1.57, p = 0.019), and upfront brain RT (HR = 0.47, p = 0.001). mOS was independently correlated with being female (HR = 0.54, p = 0.007), ECOG 3-4 (HR = 10.47, p 3 (HR = 2.19, p = 0.002), and third-generation TKI (HR = 0.54, p = 0.044) or antiangiogenic drugs (HR = 0.11, p = 0.005) as first/second-line therapy. Conclusions Upfront brain RT based on first-line EGFR-TKI might improve IC-PFS but not OS in EGFR-mutant lung adenocarcinoma patients, indicating potential survival benefit from brain SRS and early application of drugs with higher intracranial activity.

A standardised method for cardiovascular risk stratification in chronic myeloid leukaemia patients treated with tyrosine kinase inhibitors is lacking. We report an algorithm for risk stratification applicable to all patients commencing tyrosine kinase inhibitor therapy based on age, prior cardiovascular disease and Framingham Risk Score, incorporating coronary artery calcium scoring in patients at intermediate Framingham Risk Score risk. Of 88 patients retrospectively studied, major adverse cardiovascular event rates in our study-defined low-, intermediate- and high-risk categories were 0%, 10% and 19% respectively. Of nine patients down-classified from intermediate to low risk on the basis of coronary artery calcium scoring, none went on to experience a major adverse cardiovascular event.

Lung cancer is the most malignant tumor in the worldwide. About 3%‐5% non‐small cell lung cancer (NSCLC) patients carry anaplastic lymphoma kinase (ALK) gene fusions and receive great benefits from ALK‐targeted therapy. However, drug resistance inevitably occurs even with the most potent inhibitor drug lorlatinib. About half of the resistance are caused by alteration in ALK proteins for earlier ALK TKI drugs and near one‐third of loratinib resistant cases are caused by compound mutations without current effective treatment strategy in clinic. Novel strategies are in great need to overcome drug resistance. Lately, two novel strategies have been developed and attracted great attentions for their potentials to overcome drug resistance problems: (1) developed small compact macrocyclic ALK kinase inhibitors and (2) developed ALK targeted proteolysis‐targeting chimera (PROTAC) drugs. The macrocyclic molecules are small and compact in size, brain barrier permeable, and highly potent against lorlatinib‐resistant compound mutations. Developed ALK targeted PROTAC molecules could degrade oncogenic ALK driver proteins. Some showed superiority in killing ALK positive cancer cells and inhibiting the growth of cells expressing G1202R resistant ALK proteins comparing to inhibitor drugs. The update on these two treatment strategies was reviewed., Acquired resistance mutations including G1202R and L1196M, alone or in compound form, in ALK proteins lead to drug resistance to ALK‐targeted therapy. Two novel strategies showed great potential in overcoming such resistance: (1) More effective inhibition by small and compact macrocyclic inhibitors; (2) Degradation of oncogenic ALK proteins including those with resistant mutations by ALK targeted proteolysis‐targeting chimeras.

Background For advanced nonsquamous non‐small cell lung cancer (NSCLC), the mechanisms of resistance to first‐line immunotherapy are not clear. Immune checkpoint inhibitors (ICIs) in combination with agents targeting other pathways may serve as second‐line therapy options. Apatinib (a vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor) could increase the efficacy of camrelizumab (an ICI agent). The efficacy and safety of this combination regimen as a second‐line therapy for NSCLC patients after failure on first‐line immunotherapy has not previously been evaluated. Methods In this single‐arm, multicenter, phase II trial, metastatic nonsquamous NSCLC patients previously treated with single‐agent ICI or ICI plus chemotherapy will be enrolled. Participants will receive intravenous camrelizumab 200 mg D1 and oral apatinib 250 mg D1‐21 for a 21‐day cycle. The study treatment will continue until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint is progression‐free survival by investigator. Secondary endpoints are overall survival, objective response rate, disease control rate, duration of response by investigator, quality of life, safety, and toxicity. Conclusions This trial will provide evidence of the benefit of treatment with camrelizumab combined with apatinib in advanced nonsquamous NSCLC patients who were previously treated with first‐line immunotherapy., Treatment for advanced nonsquamous non‐small cell lung cancer patients previously treated with first‐line immunotherapy is limited. Immunotherapy plus antiangiogenetic agents have synergistic effects and may serve as new treatment options. In this phase II trial, the efficacy and safety of camrelizumab (anti‐PD‐1 antibody) + apatinib (VEGFR2 tyrosine kinase inhibitor) will be evaluated. The primary endpoint is progression‐free survival.

Background We investigated the role of epidermal growth factor (EGF) and transforming growth factor α (TGFα) on Asian head and neck cancer patient cell lines; in terms of Epithelial to Mesenchymal Transition (EMT) and cell migration to determine whether these changes could be reversed using tyrosine kinase inhibitors (Gefitinib and Erlotinib). Methods Cell migration, protrusion and EMT were assessed using both Scatter assay and Scratch assay. Protein expression and localisation were evaluated using Immunofluorescence, SDS-PAGE and Western Blotting techniques to identify the involvement of phosphorylated MAPK (Thr202/Tyr204), phosphorylated EGFR (Y1068) and phosphorylated AKT (Ser473) protein expression. Results EGF and TGFα induced an EMT like phenotypical change, cellular protrusion and cell migration while Gefitinib and Erlotinib blocked these morphological changes and cell migration. We also examined the effect of EGF/TGF α ± tyrosine kinase inhibitors on phosphorylation sites Y1068 of Epidermal Growth Factor Receptor (EGFR). Y1068 was phosphorylated in all test condition and all tested concentration of inhibitors did not inhibit Y1068 phosphorylation. EGF and TGFα increased phosphorylation of MAPK (Thr202/Tyr204) residues compared with serum free control while a one-hour pre-treatment with tyrosine kinase inhibitor(s) before addition of growth factors completely blocked this phosphorylation. Phosphorylation of Akt Ser 473 was also induced by EGF and TGFα and a one-hour pre-treatment with the tyrosine kinas inhibitor(s) reduced this phosphorylation. Conclusion These data suggests that Gefitinib and Erlotinib prevent activation of downstream signalling proteins MAPK (Thr202/Tyr204) and Akt (Ser473) thereby blocking phenotypic change and cell migration. This study supports the potential therapeutic value of Gefitinib and Erlotinib in targeting head and neck cancer.

The highly selective, covalent Bruton’s tyrosine kinase inhibitor evobrutinib is under investigation for treatment of patients with multiple sclerosis (MS). Early clinical studies in healthy participants and patients with relapsing MS indicated that evobrutinib is well‐tolerated and effective. We undertook a mass balance study in six men who received a single 75‐mg oral dose of evobrutinib containing ~ 3.6 MBq (100 μCi) 14C‐evobrutinib, to determine the absorption, metabolic pathways, and routes of excretion of evobrutinib. The primary objectives of this phase I study ({"type":"clinical-trial","attrs":{"text":"NCT03725072","term_id":"NCT03725072"}}NCT03725072) were to (1) determine the rates and routes of total radioactivity excretion, including the mass balance of total drug‐related radioactivity in urine and feces, (2) assess the pharmacokinetics (PKs) of total radioactivity in blood and plasma, and (3) characterize the plasma PKs of evobrutinib. Exploratory end points included identifying and quantifying evobrutinib and its metabolites in plasma and excreta (urine and feces) and exploring key biotransformation pathways and clearance mechanisms. Evobrutinib was primarily eliminated in feces (arithmetic mean percentage, SD, 71.0, 2.1) and, to a lesser extent, in urine (20.6, 2.0), with most of the total radioactivity (85.3%) excreted in the first 72 h after administration. No unchanged evobrutinib was detected in excreta. Evobrutinib was rapidly absorbed and substantially metabolized upon absorption. Only one major metabolite M463‐2 (MSC2430422) was identified in plasma above the 10% of total drug exposure threshold, which classifies M463‐2 (MSC2430422) as a major metabolite according to the US Food and Drug Administration (FDA; metabolites in safety testing [MIST]) and the European Medicines Agency (EMA; International Conference on Harmonization [ICH] M3). These results support further development of evobrutinib and may help inform subsequent investigations.

Background Despite atezolizumab and bevacizumab (A + B) is currently the first‐line treatment for hepatocellular carcinoma (HCC) patients, some patients will not be adequate for this combination. In the setting of sorafenib some adverse events have been proposed as prognostic factors. Objective To characterize the early diarrhoea development as prognostic factor in 344 HCC patients. Methods The development of early diarrhoea in sorafenib treatment defined as patients who developed diarrhoea and needed dose modification within the first 60 days of treatment (e‐diarrhoea) and 3‐grouping variables were analysed: Patients with e‐diarrhoea, patients who developed diarrhoea after the first 60 days of treatment (L‐diarrhoea) and patients that never developed diarrhoea (never diarrhoea). Results The median overall survival in sorafenib treated patients was significantly different across groups (6.8 months for e‐diarrhoea, 26.7 months for L‐diarrhoea and 13.3 months for never‐diarrhoea). The emergence of e‐diarrhoea was associated with poor outcomes (hazard ratio [HR] 1.84 [95%CI 1.15–2.95]), while there was no increased/decreased risk of dismal evolution in patients with L‐diarrhoea (HR 0.66 [95%CI 0.42–1.03]). Conclusion The emergence of e‐diarrhoea in HCC patients treated with sorafenib is an early predictor of dismal evolution under this therapy. Thus, prompt identification of these non‐responders may be useful for an early switch to second‐line therapies., Key Summary Established knowledge on this subject Diarrhoea is a frequent adverse event of sorafenib and its emergence has been associated to better outcomes. What are the significant and/or new findings of this study? Early diarrhoea (e‐diarrhoea) in hepatocellular carcinoma patients treated with sorafenib is an early predictor of dismal evolution.Diarrhoea under sorafenib should not be taken as a predictive parameter of lack of benefit.E‐diarrhoea could be used as clinical biomarker for switching to second‐line therapies.

Introduction Delayed onset of immune-related adverse events following immune-checkpoint inhibitor discontinuation is underrecognized because of little available evidence. Case presentation A 50-year-old man with metastatic renal cell carcinoma (Case 1) and 58-year-old woman with renal cell carcinoma and retroperitoneal lymph node metastasis (Case 2) underwent nivolumab therapy. Case 1: Progressive disease forced nivolumab discontinuance after 18 months, and he underwent two courses of tyrosine kinase inhibitor therapy. immune-related adverse events of pneumonitis, hepatitis, and renal dysfunction were diagnosed 142 days after nivolumab discontinuation, and he recovered with immunosuppressive treatment. Case 2: The immune-related adverse event of pneumonitis forced nivolumab discontinuance after 14 months, and two courses of tyrosine kinase inhibitor therapy were administered. The immune-related adverse event of hepatitis was diagnosed 436 days after nivolumab discontinuation, and she recovered with immunosuppressive treatment. Conclusion Two patients with delayed onset of immune-related adverse events after nivolumab discontinuation were recovered with immunosuppressive treatment.

Mobocertinib (TAK‐788) is an investigational oral tyrosine kinase inhibitor targeting epidermal growth factor receptor and human epidermal growth factor 2. A phase 1 open‐label, 2‐period, fixed‐sequence, 2‐part study ({"type":"clinical-trial","attrs":{"text":"NCT03928327","term_id":"NCT03928327"}}NCT03928327) characterized effects of a strong CYP3A4 inhibitor (itraconazole) and inducer (rifampin) on the pharmacokinetics (PK) of mobocertinib and its active metabolites, AP32960 and AP32914. Healthy volunteers (n = 12 per part) received a single dose of mobocertinib alone (20 mg, part 1; 160 mg, part 2) and with multiple doses of itraconazole 200 mg once daily (part 1) or rifampin 600 mg once daily (part 2). Coadministration of itraconazole with mobocertinib increased the combined molar area under the plasma concentration‐time curve from time 0 to infinity (AUC0‐∞) of mobocertinib, AP32960, and AP32914 by 527% (geometric least‐squares mean [LSM] ratio, 6.27; 90% confidence interval [CI], 5.20‐7.56). Coadministration of rifampin with mobocertinib decreased the combined molar AUC0‐∞ of mobocertinib, AP32960, and AP32914 by 95% (geometric LSM ratio, 0.05; 90%CI, 0.04‐0.07). Based on these results, the strong CYP3A inhibitor itraconazole and inducer rifampin significantly influenced the PK of mobocertinib and its active metabolites. Coadministration of mobocertinib with moderate and strong CYP3A inhibitors or inducers is not recommended in ongoing clinical trials.

Dasatinib, a tyrosine kinase inhibitor, has a protective effect on experimental acute respiratory distress syndrome (ARDS). This study investigated the effect and mechanism of dasatinib in ARDS. C57BL/6 mice were administered with dasatinib (1 and 10 mg/kg) after lipopolysaccharide (LPS) treatment to evaluate the effect of dasatinib on white blood cells (WBC), neutrophils, lymphocytes and macrophages in bronchoalveolar lavage fluid (BALF). The levels and mRNA expressions of inflammation-related cytokines in lung tissues and RAW 264.7 cells were detected by enzyme-linked immunosorbent assay and quantitative real-time PCR, respectively. The protein expressions of nuclear factor E2-related factor 2 (Nrf2) and heme oxygenase 1 (HO1) were determined by Western blot. MTT assay was performed to detect the viability of RAW 264.7 cell. Rescue experiments were used to assess the effect of Nrf2 silencing on the LPS- and dasatinib-treated mice. Under LPS treatment, levels of the WBC, neutrophils, lymphocytes and macrophages in BALF and mRNA expressions of IL-6, TNF-α and IL-10 as well as expression of iNOS were increased, but the expression of arginase-1 was inhibited, while no obvious changes of the protein expressions of Nrf2 and HO1 were observed. Dasatinib partially reversed the effects of LPS above, and further promoted the mRNA expression of IL-10 and the protein expressions of Nrf2 and HO1, while Nrf2 silencing counteracted the effect of dasatinib. Dasatinib induced the polarization of M2 subtype of macrophages and alleviated LPS-induced ARDS through activating Nrf2 signaling pathway, which may provide a new strategy for the treatment of ARDS.

Programmed death-ligand-1 (PD-L1) is a ligand for programmed death receptor (PD-1) that plays a major role in cell-mediated immune response; it regulates T-cell activation and regulates survival and functions of activated T cells. Expression of PD-L1 can induce chronic inflammation and activate mechanisms of immune evasion. PD-L1 is expressed in most of human carcinomas. Porphyromonas gingivalis (P. gingivalis) is a major keystone pathogen in periodontitis that invade host cells and disposes a variety of virulence factors. The aim of the present study was to clarify the signaling pathway of P. gingivalis molecules that induce PD-L1 up-regulation in colon carcinoma cells. Additionally, it was investigated which components of P. gingivalis are responsible for PD-L1 induction. Colon cancer cells (CL-11) were stimulated with total membrane (TM) fractions, peptidoglycans (PDGs) and viable P. gingivalis bacteria. Seven signaling molecule inhibitors were used: receptor-interacting serine/threonine-protein kinase 2 (RIP2) tyrosine kinase inhibitor, nucleotide-binding oligomerization domain (NOD)-like receptor 1&2 inhibitor, NOD-like receptor, nuclear factor kappa B inhibitor, c-Jun N-terminal kinases inhibitor, mitogen-activated protein/extracellular signal-regulated kinase inhibitor, mitogen activated kinase (MAPK) inhibitor. PD-L1 protein expression was examined by western blot analysis and quantitative real time PCR. It was demonstrated that the TM fraction and PDG induced up-regulation of PD-L1 expression in colon cancer cells. In conclusion, the results of this study suggest that PDG of P. gingivalis plays a major role in PD-L1 up-regulation in colon cancer cells. In addition, the mechanism of PD-L1 up-regulation depends on NOD 1 and NOD 2 and involves activation of RIP2 and MAPK signaling pathways.

Although total duration of tyrosine kinase inhibitor (TKI) therapy and of molecular response at 4 log reduction or deeper (MR4) correlates with treatment-free remission (TFR) success after TKI discontinuation, the optimal cut-off values of the duration remain unresolved. Thus, 131 patients were enrolled into the Canadian TKI discontinuation study. The molecular relapse-free survival (mRFS) was defined from imatinib discontinuation till molecular recurrence, that is, major molecular response (MMR) loss and/or MR4 loss. We evaluated mRFS at 12 months after imatinib discontinuation, analyzed it according to the imatinib treatment duration and MR4 duration, and calculated P value, positive (PPV) and negative predictive value (NPV) in the yearly cut-off period of time. The shortest cut-off was sought that met the joint criteria of a P value ≤ 0·05, PPV ≥ 60% and NPV ≥ 60%. We propose six years as the shortest imatinib duration cut-off with a P value 0·01, PPV 68% and NPV 62%: The patients treated with imatinib duration ≥ 6 years showed a superior mRFS rate (61·8%) compared to those with less treatment (36·0%). Also, 4·5 years MR4 duration as the shortest cut-off with a P value 0·003, PPV 63% and NPV 61%: those with MR4 duration ≥ 4·5 years showed a higher mRFS rate (64·2%) than those with a shorter MR4 duration (41·9%).

Lorlatinib treatment should be positively considered even for patients with ALK‐positive NSCLC with severe neurocognitive disturbance and poor performance status due to CNS metastases, including leptomeningeal carcinomatosis.

Interleukin (IL)-10 has anti-inflammatory and CD8+ T-cell-stimulating properties. Pegilodecakin (pegylated recombinant human IL-10) induces intratumoral antigen-specific CD8 + T-cells and upregulates IFNγ and major histocompatibility complexes (MHC) I and II. Pegilodecakin has single-agent activity with manageable toxicity in advanced renal cell carcinama (aRCC) (data cutoff 24 March 2016). Pegilodecakin with pembrolizumab or nivolumab revealed clinical activity in aRCC (data cutoff 1 July 2018). Here, we report for the first time the results of pegilodecakin+ pazopanib, and final results for monotherapy and long-term follow-up with pegilodecakin + anti-programmed cell death 1 (anti-PD-1) inhibitors (data cutoff 19 February 2019). Phase 1/1b multi-cohort dose escalation IVY study enrolled 353 patients. Sixty-six patients with aRCC were treated with pegilodecakin alone or with pazopanib or anti-PD-1 inhibitor in cohorts A, G, H and I (data cutoff 19 February 2019). Primary endpoints included safety and tolerability. Secondary endpoint was tumor response by immune-related response criteria (irRC). Pegilodecakin plus nivolumab or pembrolizumab yielded median progression-free survival (mPFS) of 13.9 months and 6-month PFS probability of 60%, 76% 1-year overall survival (OS) probability and 61% 2-year OS probability. Pegilodecakin monotherapy produced mPFS of 1.8 months, 6-month PFS probability 25%, 1-year OS 50%, and 2-year OS 17%. Median OS was not reached in both combinations. Objective response rates (ORRs) were 33% with pazopanib and 43% with anti-PD-1. Most common Grade 3/4 treatment-related adverse events included anemia, thrombocytopenia and hypertriglyceridemia. In these heavily pretreated renal cell carcinama cohorts of IVY, pegilodecakin+anti-PD-1 inhibitor showed promising clinical activity. Safety profile of pegilodecakin alone and with anti-PD-1 inhibitors was consistent as previously reported.

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in adults in the UK. Ibrutinib, an oral Bruton tyrosine kinase inhibitor (BTKi) for CLL approved by the UK's National Institute for Health and Care Excellence in January 2017, represented a major shift in CLL management. Real-world data on ibrutinib use in routine clinical practice will inform patients' and physicians' decision-making. We conducted a retrospective medical chart review of UK patients with CLL who initiated ibrutinib between January 2017 and July 2018. Data for 259 patients were contributed by 34 haematology-oncology specialists, with a median follow-up duration of 16.7 months. Median age at ibrutinib initiation was 71 years. Ibrutinib first-line monotherapy was prescribed in 20.1% of patients. Ibrutinib was permanently discontinued in 15.4% of patients, mostly owing to progressive disease. Adverse events (AEs) were reported in 151 patients (58.3%). The most common were bruising (19.3% of patients), cytopenias (17.0%) and diarrhoea (11.6%). Ibrutinib dose reduction was observed in 14.3% of patients and was temporarily discontinued in 10.4% of patients, with the main reason for both being toxicity. These results expand the real-world evidence on ibrutinib therapy and demonstrate a high burden of AEs, highlighting the need for more tolerable BTKis.

Additional data on blast phase (BP) chronic myeloid leukaemia (CML) in children and adolescents is essential for improving diagnostic and therapeutic approaches of this rare but serious condition. Here, we describe distinct clinical and genetic characteristics of 18 paediatric patients with de novo (n = 10) and secondary (n = 8) BP CML enrolled in the CML-PAED-II trial and registry. Our findings suggest that paediatric patients exhibit a diverse cytogenetic profile compared to adults with BP CML. In addition, patients with de novo BP CML in this cohort presented at a younger age, whereas patients with secondary BP CML more often harboured complex karyotypes.

Background As a highly heterogeneous disease, lung cancer has a multitude of cellular components and patterns of gene expression which are not dependent on a single mutation or signaling pathway. Thus, using combined drugs to treat lung cancer may be a practical strategy. Methods The combined antitumor effects of HS-10296, a third-generation EGFR inhibitor targeting EGFR T790M mutation, with the multitargeted tyrosine kinase inhibitor (TKI) famitinib in non-small cell lung cancer (NSCLC) were evaluated by in vitro methods such as cell proliferation, apoptosis, angiogenesis assays, and in vivo animal efficacy studies. Results Famitinib strengthened the effects of HS-10296 on inhibiting proliferation and inducing apoptosis of NSCLC cells, possibly by synergistic inhibition of AKT and ERK phosphorylation. Meanwhile, HS-10296 significantly potentiated the effects of famitinib on inhibiting the proliferation and migration of HUVEC, which may be through synergistic inhibition of ERK phosphorylation in HUVEC, suggesting that HS-10296 may improve the inhibition of angiogenesis by famitinib. Moreover, combination of HS-10296 and famitinib exerted synergistic antitumor activity in NCI-H1975 and PC-9 xenograft models, and this effect may be accomplished by synergistic inhibition of phosphorylation of AKT and ERK and tumor angiogenesis in tumor tissues. Conclusions Collectively, our results indicate that HS-10296 and famitinib exhibit significant synergistic antitumor activity, suggesting that the third-generation EGFR inhibitor combined with VEGFR inhibitor provides a promising strategy in the treatment of EGFR-mutant NSCLC.

Sunitinib (Sun), a tyrosine kinase inhibitor of vascular endothelial growth factor receptor, is the standard first‐line treatment against advanced clear cell renal cell carcinoma (RCC), but resistance to therapy is inevitable. Reactive oxygen species production is associated with sensitivity to chemotherapy, but the underlying mechanisms are not completely understood. Here, we investigated the mechanisms contributing to Sun resistance using the RCC cell lines ACHN and 786‐O. We report that Sun‐resistant cells exhibited reduced apoptosis, increased cell viability, increased reactive oxygen species production and disrupted mitochondrial function. Furthermore, chronic Sun treatment resulted in an up‐regulation of Sirt5/isocitrate dehydrogenase 2 (IDH2) expression levels. Knockdown of Sirt5/IDH2 impaired mitochondrial function and partially attenuated Sun resistance. Finally, up‐regulation of Sirt5 enhanced the expression of IDH2 via modulation of succinylation at K413 and promoted protein stability. In conclusion, dysregulation of Sirt5/IDH2 partially contributes to Sun resistance in RCC cells by affecting antioxidant capacity., Sunitinib‐resistant cells exhibited up‐regulation of Sirt5/isocitrate dehydrogenase 2 (IDH2) expression levels, which confer drug resistance. Up‐regulation of Sirt5 enhanced the expression of IDH2 via modulation of succinylation at K413 and promotion of protein stability. Dysregulation of Sirt5/IDH2 partially contributes to Sun resistance by disturbing mitochondrial functions and affecting antioxidant capacity of renal cell carcinoma cells.

Background T790M mutation causes resistance to tyrosine kinase inhibitors (TKIs) in approximately 49% of patients with epidermal growth receptor-mutant non-small cell lung cancer (NSCLC). The cause of resistance in the remaining half of the cases is a minor mutation or unknown. Here, we conducted a retrospective study of epidermal growth receptor-mutant NSCLC patients with T790M-negative or an unidentified mutation to appraise the therapeutic response to first- or second-generation tyrosine kinase inhibitors as a second-line treatment. Methods The study included 39 patients treated in our institution from April 2012 through March 2020 with second-line tyrosine kinase inhibitors or chemotherapy after completing a first-line therapy with tyrosine kinase inhibitors. Results The patients were allocated to two groups: chemotherapy (n = 28) and a tyrosine kinase inhibitor (n = 11) groups. The median progression-free survival (PFS) was 5.4 months in the chemotherapy group and 3.4 months in the tyrosine kinase inhibitor group (p-value = 0.36), while the median overall survival (OS) was 16.1 months in the chemotherapy group and 12.8 months in the tyrosine kinase inhibitor group (p- value = 0.20). This study showed no significant difference in PFS and OS between the chemotherapy and tyrosine kinase inhibitor groups. Conclusions These observations suggest that first- and second-generation tyrosine kinase inhibitors are not recommended for second-line treatment in epidermal growth factor receptor-mutated NSCLC patients with T790M-negative mutation who have received tyrosine kinase inhibitors as first-line treatment.

Chronic myeloid leukaemia (CML) is a malignancy of the haematopoietic stem cells. The first line of treatment for CML, especially in developing countries, remains the first-generation tyrosine kinase inhibitor, Imatinib. Patients with CML are frequently diagnosed with platelet abnormalities. However, the specific mechanism of platelet abnormalities in CML remains unclear and poorly understood. The aim of this study was therefore to determine the apoptotic profiles of CML patients ex vivo on platelets before and after treatment with Imatinib. Blood samples of healthy volunteers and CML patients at diagnosis and after 6 months treatment with Imatinib were collected. Platelet counts, viability and activation were determined. Results showed that CML patients' platelet counts were elevated upon diagnosis and these levels statistically significantly decreased after 6 months of treatment. Platelet activation was significantly increased after 6 months of treatment compared to levels at diagnosis (P-value < .05). Similarly, platelet apoptosis was also increased after 6 months of treatment. Abnormalities in platelet functioning found in this study may partly be due to clonal proliferation of haematopoietic cells in CML patients, specifically of megakaryocyte precursors as well as the inhibition of platelet tyrosine kinase's and the inhibition of platelet-derived growth factor.

Zanubrutinib is a potent, second‐generation Bruton’s tyrosine kinase inhibitor that is currently being investigated in patients with B‐cell malignancies and recently received accelerated approval in the United States for treatment of relapsed/refractory mantle cell lymphoma. The objective of this analysis was to develop a population pharmacokinetic (PK) model to characterize the PKs of zanubrutinib and identify the potential impact of intrinsic and extrinsic covariates on zanubrutinib PK. Data across nine clinical studies of patients with B‐cell malignancies and data of healthy volunteers (HVs) were included in this analysis, at total daily doses ranging from 20 to 320 mg. In total, 4,925 zanubrutinib plasma samples from 632 subjects were analyzed using nonlinear mixed‐effects modeling. Zanubrutinib PKs were adequately described by a two‐compartment model with sequential zero‐order then first‐order absorption, and first‐order elimination. A time‐dependent residual error model was implemented in order to better capture the observed maximum concentration variability in subjects. Baseline alanine aminotransferase and health status (HVs or patients with B‐cell malignancies) were identified as statistically significant covariates on the PKs of zanubrutinib. These factors are unlikely to be clinically meaningful based on a sensitivity analysis. No statistically significant differences in the PKs of zanubrutinib were observed based on age, sex, race (Asian, white, and other), body weight, mild or moderate renal impairment (creatinine clearance ≥ 30 mL/minute as estimated by Cockcroft‐Gault), baseline aspartate aminotransferase, bilirubin, tumor type, or use of acid‐reducing agents (including proton pump inhibitors). These results support that no dose adjustment is considered necessary based on the aforementioned factors.

Tyrosine kinase inhibitors (TKIs) are effective for treating Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). However, the use of TKIs may decrease the number of collected oocytes during fertility preservation procedures. We report the case of a 19-year-old patient with Ph+ALL for whom 21 oocytes were frozen after controlled ovarian stimulation was initiated 2 days after the completion of 28 days of remission induction therapy with dasatinib. After collecting the oocytes, consolidation therapy was initiated immediately, and a hematopoietic stem cell transplant from her younger brother was scheduled. It is believed that a 2-day withdrawal period is sufficient for fertility preservation or that the effect of dasatinib on the number of oocytes obtained is minimal.

Tyrosine kinase inhibitor (TKI) can help to increase the survival time in chronic myeloid leukemia (CML) patients; however, the risk of secondary malignancies due to TKIs is a growing concern. Only few reports showed clinical course of patients who developed lymphoma during TKI therapies. Herein, we report a case of high‐grade B‐cell lymphoma diagnosed in the course of CML treatment with bosutinib. The 75‐year‐old male patient had been diagnosed with CML 25 years ago. After receiving TKIs (imatinib, nilotinib, and bosutinib), he achieved a major molecular response. Over 3 years after starting bosutinib, he was diagnosed with a high‐grade B‐cell lymphoma. A total of six courses of DA‐EPOCH‐R therapy brought complete remission of the lymphoma. Moreover, BCR‐ABL1 transcript copies remained undetectable by RT‐PCR, 8 months after stopping bosutinib. The risk of secondary malignancy due to TKI has been controversial. It is reported that TKI induces irreversible chromosomal abnormalities or chromosome aberrations and inhibits the proliferation or function of T cells, B cells, and NK cells. These mechanisms of TKI may contribute to the development of secondary malignancy. There remains no consensus on the management of secondary lymphoma during TKI therapies. At present, the only alternative is to observe patients receiving TKI treatment cautiously and to treat secondary lymphoma in the same manner as de novo lymphoma., There remains no consensus on the management of secondary lymphoma during TKI therapies. The only alternative is to observe patients receiving TKI treatment cautiously and to treat secondary lymphoma in the same manner as de novo lymphoma.

Clonal eosinophilia is a hematologic disorder caused by translocation in growth factor receptor (GFR) genes. Despite the identified molecular mechanisms underlying clonal hypereosinophilia, the distinction between clonal and reactive eosinophilia has remained challenging due to the diversity of partner genes for translocated GFRs. This study aimed to examine the feasibility of phosphoflow cytometry in the diagnosis of clonal hypereosinophilia through evaluating the level of platelet-derived growth factor receptor alpha (PDGFRA) phosphorylation and its correlation with PDGFRA genetic aberration. Blood samples were collected from 45 hypereosinophilia patients and 10 healthy controls. Using phosphoflow cytometry method, the phosphorylation state of PDGFRA was assessed. The specificity of phosflow results was confirmed by western blotting and eventually compared with qRT-PCR expression analysis of 3'-region of PDGFRA. To detect the genetic aberration of PDGFRA, 5'-rapid amplification of cDNA ends (5'-RACE) was performed. Phosflow analysis illustrated that 9 of 45 hypereosinophilic patients had higher level of PDGFRA phosphorylation while sequence analysis of 5'-RACE-PCR fragments confirmed that in seven cases of them, there was a PDGFRA-FIP1L1 fusion. We also verified that two of nine patients with hyperposphorylated PDGFRA hold ETV6-PDGFRA and STRN-PDGFRA rearrangements. Importantly, nine cases also had significantly higher levels of PDGFRA mRNA expression when compared with healthy controls, and cases with no PDGFRA rearrangement. These findings highlight a robust correlation between hyperphosphorylation state of PDGFRA and aberrant PDGFRA gene fusions. This implicates phosflow as an efficient and reliable technique raising an intriguing possibility that it could replace other genomic and cDNA-amplification-based diagnostic approaches with limited effectiveness.

Objectives To compare overall survival between patients with metastatic renal cell carcinoma treated by cytoreductive nephrectomy and those not treated by cytoreductive nephrectomy. Methods We retrospectively evaluated 278 patients with metastatic renal cell carcinoma treated with first-line tyrosine kinase inhibitors between January 2008 and November 2019. Patients were divided into two groups: a cytoreductive nephrectomy group (immediate or deferred cytoreductive nephrectomy) and a group who received systemic tyrosine kinase inhibitor therapies alone without cytoreductive nephrectomy (control group). Overall survival comparisons were made in all patients in the control versus the cytoreductive nephrectomy group, the control versus the immediate cytoreductive nephrectomy group, the control versus the deferred cytoreductive nephrectomy group, and the deferred cytoreductive nephrectomy versus the immediate cytoreductive nephrectomy group. Analyses were weighted using the propensity score-based inverse probability of treatment weighting method to adjust for group imbalances. Results The median (range) age of the patients was 65 (59-73) years. Of the 278 patients, 132 and 146 were in the control group and the cytoreductive nephrectomy (immediate, n = 107 and deferred, n = 39) group, respectively. A significant difference was noted between the control and cytoreductive nephrectomy groups in age, clinical stage, International Metastatic Renal Cell Carcinoma Database Consortium risk factors, and the number of metastatic sites. Inverse probability of treatment weighting-adjusted Cox regression analysis showed a significant difference in overall survival between the control and the cytoreductive nephrectomy groups and between the control and the immediate or deferred cytoreductive nephrectomy groups. However, there was no significant difference in overall survival between the immediate and the deferred cytoreductive nephrectomy groups. Conclusions Our findings suggest that metastatic renal cell carcinoma patients undergoing cytoreductive nephrectomy are more likely to have longer overall survival than those who receive tyrosine kinase inhibitor therapy only.

In this issue of Arthritis & Rheumatology, the paper by Isenberg et al, entitled Efficacy, Safety, and Pharmacodynamic Effects of the Bruton's Tyrosine Kinase Inhibitor, Fenebrutinib (GDC-0853), in Systemic Lupus Erythematosus reports results of a Phase 2 trial of fenebrutinib, an inhibitor of Bruton's tyrosine kinase (BTK). This treatment met expected pharmacodynamic targets, decreasing phosphorylated BTK, dampening plasmablast signals, and lowering anti-dsDNA and IgG. No concerning safety signal was observed.

The European Treatment and Outcome Study (EUTOS) long‐term survival (ELTS) score predicts disease‐specific death in patients with chronic myeloid leukemia (CML) being treated with imatinib during the chronic phase (CP) of the disease. However, it is unclear whether the ELTS score predicts CML‐related events or treatment responses. This study evaluated the predictive value of the ELTS score regarding prognosis and treatment response in patients with CML‐CP. Clinical data were retrospectively obtained from patients enrolled in the CML Cooperative Study Group (CML‐CSG), which included patients diagnosed with CML‐CP from April 2001 to January 2016, and treated with any tyrosine kinase inhibitor (TKI) as first‐line therapy. Among 342 eligible patients, the ELTS scores indicated low‐, intermediate‐, and high‐risk in 74%, 21%, and 5% of patients, respectively. Patients with high ELTS scores had significantly higher disease‐specific mortality and worse event‐free survival, progression‐free survival, and overall survival. Among four risk scores, including the Sokal, Hasford, EUTOS, and ELTS scores, risk stratification by the ELTS score had the highest predictive value in assessing patient prognosis, and also in treatment responses. In fact, the EUTOS and ELTS scores were able to predict the major molecular response within 12 months. Most importantly, the ELTS score was the only scoring system that predicted deep molecular response at any time, regardless of risk level (65.0%, 43.7%, and 23.5% in low‐, intermediate‐, and high‐risk groups, respectively). Compared to other risk scores, the ELTS score was the most sensitive risk classification tool for the four endpoints of interest in this study, as well as molecular responses in patients with CML‐CP., In this real‐world TKIs treated CML‐CP patients cohort, the EUTOS long‐term survival (ELTS) score was the most sensitive risk classification tool to predict CML‐specific deaths, EFS, PFS, and OS compared to the Sokal, Hasford, and EUTOS scoring systems. Notably, the ELTS score was the only scoring system that predicted cumulative incidence of deep molecular response.

Thymic carcinoma is a rare and highly aggressive mediastinal tumor. Most patients are diagnosed at surgically unresectable stages. Current prospective and retrospective studies have indicated that platinum and anthracycline‐based chemotherapy are the first choice drugs of first‐line therapy for advanced thymic carcinoma. However, there is no optimal treatment after progression for patients who have undergone first‐line and subsequent chemotherapy. Anlotinib, a novel small molecule tyrosine kinase multitarget inhibitor, was approved by the China Food and Drug Administration as a third‐line treatment for advanced non‐small cell lung cancer (NSCLC) in May 2018. Herein we report a case of an advanced thymic squamous cell carcinoma patient harboring EGFR exon 20 insertion who had previously received multiline therapy, including chemotherapy, radiotherapy as well as antiangiogenic therapy. Also as an angiogenesis inhibitor, anotinib had controlled his mediastinal mass after failure of the apatinib treatment. To date, over 23 months of progression‐free survival (PFS) and six years of overall survival (OS) have been achieved. Compared with apatinib, the adverse reactions have been mild and tolerable and the patient's quality of life has improved. To our knowledge, this is the first report where anlotinib has been effective in controlling the progression of thymic carcinoma. In the multiline treatment of advanced thymic carcinoma, anlotinib appears to show great potential when utilized as a salvage treatment., We present the case of a patient with an advanced TC harboring EGFR exon 20 insertion who successively benefited from two antiangiogenic agents after multiline therapy. After the failure of one tyrosine kinase inhibitor, the other was still active and effectively controlled the growth of the lesion.

Tucatinib is a potent tyrosine kinase inhibitor selective for human epidermal growth factor receptor 2 (HER2) approved by the US Food and Drug Administration for the treatment of HER2‐positive metastatic breast cancer and in development for other HER2‐positive solid tumors. Modest, reversible serum creatinine (SCr) elevations have been observed in tucatinib clinical trials. SCr is conveyed by the renal drug transporters organic cation transporter 2 (OCT2) and multidrug and toxin extrusion protein 1 (MATE1) and 2‐K (MATE2‐K) and can increase in the presence of inhibitors of these transporters. In vitro, tucatinib inhibited OCT2‐, MATE1‐, and MATE2‐K‐mediated transport of metformin, with IC50 values of 14.7, 0.340, and 0.135 µM, respectively. Tucatinib also inhibited OCT2‐ and MATE1‐mediated transport of creatinine, with IC50 values of 0.107 and 0.0855 µM, respectively. A phase 1 study with metformin administered orally in the absence and presence of tucatinib was conducted in 18 healthy subjects. Renal function was assessed by measuring glomerular filtration rate (GFR; based on iohexol plasma clearance) and endogenous markers (SCr, cystatin C‐based estimated glomerular filtration rate [eGFR]) with and without tucatinib. Metformin exposure increased (1.4‐fold) and renal clearance decreased (29.99‐17.64 L/h) with tucatinib, with no effect on metformin maximum concentration. Creatinine clearance transiently decreased 23% with tucatinib. GFR and eGFR, which are unaffected by OCT2 and/or MATE1/2‐K transport, were unchanged with tucatinib. These data demonstrate that tucatinib inhibits OCT2‐ and MATE1/2‐K‐mediated tubular secretion of creatinine, which may manifest as mild SCr elevations that are not indicative of renal impairment.

Aim Dasatinib is a small molecule tyrosine kinase inhibitor with multiple targets including kit, PDGFR, and SRC. This prospective study evaluated the efficacy and safety of dasatinib as third‐line treatment for gastrointestinal stromal tumors (GIST). Methods The study enrolled adult patients (≥18 years of age) with histologically confirmed unresectable and/or metastatic GIST whose disease progressed despite imatinib and sunitinib therapy. Dasatinib (50 mg twice daily) was given orally for 1 week and escalated to 70 mg twice daily orally. The primary endpoint was to the 3‐month progression‐free survival (PFS) rate. Blood samples were acquired before dasatinib therapy for examination of gene mutations by next‐generation sequencing (NGS). Results From May 2016 to June 2018, 58 patients from 9 Chinese medical centers were enrolled in this study. The 3‐month PFS rate was 53.4% and the median overall survival (OS) was 14.0 months. Neither primary nor secondary gene mutations predicted the efficacy of dasatinib. Wild‐type GIST patients had longer PFS (5.5 months). The most common adverse events were anemia, proteinuria, fatigue, neutropenia, and diarrhea. The concordance of KIT/PDGFRA mutation was 61.9% between tissue and peripheral blood samples and additional KIT mutations were detected in the peripheral blood samples in 28.6% of the patients. Some SNV and CNV such as ATRX, TP53, TEKT4, STK11, SDHC, and CDKN2C related to tumor signaling pathways were detected. Patients with TP53 mutations and SDHC and TMEM127 gene copy number loss had longer OS. Conclusion Dasatinib has modest antitumor activity with tolerable toxicities in patients with metastatic GISTs who have failed imatinib and sunitinib therapy., This is the first prospective trial to evaluate the efficacy of dasatinib in third line treatment of GIST and reached the expected primary endpoint. The results of NGS ananlysis and liquid biopsy are also very important to clinical practice.

Background Chromosomal rearrangements are common in clear cell renal cell carcinoma (ccRCC) and their roles in mediating sensitivity to tyrosine kinase inhibitors (TKIs) and mTOR inhibitors (mTORi) remain elusive. Methods We developed an in silico strategy by screening copy number variance (CNV) that was potentially related to TKI or mTORi sensitivity in ccRCC by reproducing the TCGA and GDSC datasets. Candidate genes should be both significantly prognostic and related to drug sensitivity or resistance, and were then validated in vitro. Results ADCYAP1 loss and GNAS gain were associated with sensitivity and resistance and to Cabozantinib, respectively. ACRBP gain and CTBP1 loss were associated with sensitivity and resistance and to Pazopanib, respectively. CDKN2A loss and SULT1A3 gain were associated with sensitivity and resistance and to Temsirolimus, respectively. CCNE1 gain was associated with resistance to Axitinib and LRP10 loss was associated with resistance to Sunitinib. Mutivariate analysis showed ADCYAP1, GNAS, and CCNE1 remained independently prognostic when adjusted for the rest. Conclusion Here we show CNVs of several genes that are associated with sensitivity and resistance to commonly used TKIs and mTORi in ccRCC. Further validation and functional analyses are therefore needed., Sensitivity and resistance to cabozantinib.

The development of systemic therapies, including vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKI) and mammalian target of rapamycin (mTOR) inhibitors, represents a major breakthrough in the treatment of patients with renal cell carcinoma (RCC). However, inherent resistance is observed in some patients and acquired resistance commonly develops in many patients within several months of the initiation of systemic therapies. Since these treatments rarely cure patients, their aim is to suppress tumor progression and prolong survival. Therefore, the establishment of dependable criteria that predict responses and resistance to systemic therapies is clinically important, and the underlying molecular mechanisms also need to be elucidated for the future development of more effective therapies. We herein review recent advances in research on the molecular mechanisms underlying resistance, with a focus on morphological characteristics, tumor angiogenesis, and the tumor immune microenvironment in RCC and their relationships with VEGF-TKI treatments. Recent therapies using immune checkpoint inhibitors (ICI) and newly developed VEGF-TKI also appear to be effective for advanced RCC, with stable and durable responses to ICI being observed in some RCC patients. These new drugs and their outcomes have been briefly described.

ERBB2 mutations are found in about 2% of patients with non‐small cell lung cancer (NSCLC). A recent study reported that pyrotinib (an irreversible pan ErbB inhibitor) had superior antitumor effect compared to other tyrosine kinase inhibitor therapies in patients with ERBB2 mutations. Bone marrow metastasis is rare in lung adenocarcinoma, and has been reported to be associated with poor prognosis. Here, we report the case of a 62‐year‐old female diagnosed with lung adenocarcinoma and bone marrow metastasis. ERBB2 exon 20 insertion mutation was confirmed by next‐generation sequencing (NGS) of lung tissue as well as bone marrow. The patient achieved stable disease and recovery of pancytopenia after two months of pyrotinib therapy. This is the first report of homogenous mutations of ERBB2 detected in bone marrow, as well as a good response of bone marrow to pyrotinib therapy. Key points This is the first report of a homogenous mutation of ERBB2 detected in the bone marrow of an NSCLC patient with bone marrow metastasis. Our patient with NSCLC ERBB2 mutation and bone marrow metastasis responded well to pyrotinib therapy.

Background Given the active research on targeted therapy using tyrosine kinase (TK) inhibitors (TKIs) in the field of oncology, further studies have recently been conducted to evaluate their use in autoimmune disorders. Based on immunological investigations, previous studies have suggested that granulomatous meningoencephalomyelitis (GME) and necrotizing encephalomyelitis (NE) are similar to multiple sclerosis (MS), which is a human autoimmune demyelinating central nervous system disease. Objectives Considering this perspective, we hypothesized that canine GME and NE have significant expression of one or more TKs, which are associated with human MS pathogenesis. Methods To determine the possible use of conventional multi‐targeted TKIs as a treatment for canine GME and NE, we characterized the immunohistochemical expression of platelet‐derived growth factor receptor (PDGFR)‐α, PDGFR‐ß, vascular endothelial growth factor receptor (VEGFR)‐2, c‐Abl and c‐Kit in GME and NE samples. Results Histological samples from four dogs with GME and three with NE were retrieved. All samples stained positive for PDGFR‐ß (7/7 [100%]). PDGFR‐α and c‐Kit were expressed in 3/7 (42.8%) samples each. c‐Abl was identified in 2/7 (28.5%) samples; no sample showed VEGFR‐2 (0%) expression. Co‐expression of TKs was identified in 6/7 (85.7%) dogs. Conclusions All samples were positive for at least one or more of PDGFR‐α, PDGFR‐ß, c‐Kit and c‐Abl, which are known as the target TKs of conventional multi‐targeted TKIs. Their presence does suggest that these TKs may play a role in the pathogenesis of GME and NE. Therefore, multi‐targeted TKIs may provide benefits in the treatment of canine GME and NE by suppressing the activity of these TKs., All GME and NE samples expressed one or more of the known targets of conventional multi‐targeted TKIs, suggesting that these kinases may play a role in the pathogenesis and development of GME and NE. Furthermore, multi‐targeted therapy with TKIs may provide benefits in the treatment of canine GME and NE by suppressing the activity of these TKs.

To elucidate dynamic changes in native BCR‐ABL and alternatively spliced tyrosine kinase inhibitor (TKI)‐resistant but function‐dead BCR‐ABLIns35bp variant, following commencement or discontinuation of TKI therapy, each transcript was serially quantified in patients with chronic myeloid leukemia (CML) by deep sequencing. Because both transcripts were amplified together using conventional PCR system for measuring International Scale (IS), deep sequencing method was used for quantifying such BCR‐ABL variants. At the initial diagnosis, 7 of 9 patients presented a small fraction of cells possessing BCR‐ABLIns35bp, accounting for 0.8% of the total IS BCR‐ABL, corresponding to actual BCR‐ABLIns35bp value of 1.1539% IS. TKI rapidly decreased native BCR‐ABL but not BCR‐ABLIns35bp, leading to the initial increase in the proportion of BCR‐ABLIns35bp. Thereafter, both native BCR‐ABL and BCR‐ABLIns35bp gradually decreased in the course of TKI treatment, whereas small populations positive for TKI‐resistant BCR‐ABLIns35bp continued fluctuating at low levels, possibly underestimating the molecular response (MR). Following TKI discontinuation, sequencing analysis of 54 patients revealed a rapid relapse, apparently derived from native BCR‐ABL + clones. However, IS fluctuating at low levels around MR4.0 marked a predominant persistence of cells expressing function‐dead BCR‐ABLIns35bp, suggesting that TKI resumption was unnecessary. We clarified the possible mechanism underlying mis‐splicing BCR‐ABLIns35bp, occurring at the particular pseudo‐splice site within intron8, which can be augmented by TKI treatment through inhibition of RNA polymerase II phosphorylation. No mutations were found in spliceosomal genes. Therefore, monitoring IS functional BCR‐ABL extracting BCR‐ABLIns35bp would lead us to a correct evaluation of MR status, thus determining the adequate therapeutic intervention., Dynamic changes were observed in BCR‐ABL and BCR‐ABLIns35bp after TKI discontinuation. BCR‐ABL+ cells responsible for early relapse after cessation of TKI treatment might derive from the residual native BCR‐ABL addicted clones. In contrast, some patients whose MRD mainly consisted of BCR‐ABLIns35bp transiently lost DMR during a relatively late phase after TKI discontinuation and thereafter regained DMR spontaneously without TKI resumption.

Background Overexpression of ATP‐binding cassette (ABC) transporter is a major contributor to multidrug resistance (MDR), in which cancer cells acquire resistance to a wide spectrum of chemotherapeutic drugs. In this work, we evaluated the sensitizing effect of sitravatinib, a broad‐spectrum tyrosine kinase inhibitor (TKI), on ATP‐binding cassette subfamily B member 1 (ABCB1)‐ and ATP‐binding cassette subfamily C member 10 (ABCC10)‐mediated MDR. Methods MTT assay was conducted to examine cytotoxicity and evaluate the sensitizing effect of sitravatinib at non‐toxic concentrations. Tritium‐labeled paclitaxel transportation, Western blotting, immunofluorescence analysis, and ATPase assay were carried out to elucidate the mechanism of sitravatinib‐induced chemosensitization. The in vitro findings were translated into preclinical evaluation with the establishment of xenograft models. Results Sitravatinib considerably reversed MDR mediated by ABCB1 and partially antagonized ABCC10‐mediated MDR. Our in silico docking simulation analysis indicated that sitravatinib strongly and stably bound to the transmembrane domain of ABCB1 human‐mouse chimeric model. Furthermore, sitravatinib inhibited hydrolysis of ATP and synchronously decreased the efflux function of ABCB1. Thus, sitravatinib could considerably enhance the intracellular concentration of anticancer drugs. Interestingly, no significant alterations of both expression level and localization of ABCB1 were observed. More importantly, sitravatinib could remarkably restore the antitumor activity of vincristine in ABCB1‐mediated xenograft model without observable toxic effect. Conclusions The findings in this study suggest that the combination of sitrvatinib and substrate antineoplastic drugs of ABCB1 could attenuate the MDR mediated by the overexpression of ABCB1.

Background Long-term treatment-free remission (TFR) represents a new goal for chronic myeloid leukemia (CML). In clinical practice, tyrosine kinase inhibitor (TKI) dose reductions can be considered a means of preventing adverse effects and improving quality of life. We hypothesized that administration of low-dose TKIs before treatment discontinuation does not impair TFR in patients with CML who have a deep molecular response (DMR, ≥MR4 ). Methods We conducted a retrospective analysis of 77 patients with CML who discontinued treatment with TKIs. Twenty-six patients had been managed with low-dose TKIs before stopping treatment. Patients were to be exposed to TKIs for ≥5 years and to low-dose TKIs for ≥1 year and in DMR for ≥2 years. The loss of major molecular response (MMR) was considered a trigger for restarting therapy. Results In the low-dose group, 61.5% of patients received second-generation TKIs, and dose reduction was ≥50% for 65.4% of patients. With a median follow-up of 61.5 months, TFR at 12 months was 56.8% in the full-dose TKI group and 80.8% in the low-dose group, and TFR at 60 months was 47.5% and 58.8%, respectively. The median time to molecular recurrence (≥MMR) from TKI discontinuation in the entire cohort was 6.2 months. All patients quickly achieved MMR after resuming TKI therapy. Results appear independent of both dose reduction and potential pretreatment with interferon-α. Conclusion This retrospective study shows that TFR was not impaired by low-dose TKI regimens before TKI cessation in Patients with CML. Nevertheless, prospective randomized clinical trials must be undertaken to analyze the probability of successful TFR in patients managed with TKI dose de-escalation strategies before TKI discontinuation.

In a subgroup of Japanese patients in the ARCHER 1050 randomized phase 3 trial, we evaluated the efficacy and safety and determined the effects of dose modifications on adverse events (AE) and therapy management of first‐line oral dacomitinib 45 mg compared with oral gefitinib 250 mg, each once daily in 28‐d cycles, in patients with EGFR‐activating mutation–positive (EGFR‐positive; exon 19 deletion or exon 21 L858R substitution mutations) advanced non‐small cell lung cancer (NSCLC). The primary endpoint was progression‐free survival (PFS; RECIST, version 1.1, by blinded independent review). In 81 Japanese patients (40 dacomitinib, 41 gefitinib), PFS was longer with dacomitinib compared with gefitinib (hazard ratio [HR], 0.544 [95% confidence interval {CI}, 0.307‐0.961]; 2‐sided P = .0327; median 18.2 for dacomitinib [95% CI, 11.0‐31.3] mo, 9.3 [95% CI, 7.4‐14.7] mo for gefitinib). The most common Grade 3 AEs were dermatitis acneiform with dacomitinib (27.5%) and increased alanine aminotransferase with gefitinib (12.2%). A higher proportion of patients receiving dacomitinib (85.0%) compared with gefitinib (24.4%) had AEs leading to dose reduction. Incidence and severity of diarrhea, dermatitis acneiform, stomatitis and paronychia were generally reduced after dacomitinib dose reductions and dacomitinib treatment duration was generally longer in patients with a dose reduction in comparison with those without a dose reduction. Our results confirmed the efficacy and safety of first‐line dacomitinib in Japanese patients with EGFR‐positive advanced NSCLC., We evaluated the efficacy and safety of first‐line dacomitinib compared with gefitinib in a subgroup of Japanese patients with EGFR‐activating mutation–positive advanced non‐small cell lung cancer who were enrolled in the ARCHER 1050 randomized phase 3 trial. Results for the primary efficacy endpoint in the Japanese patients (n = 81) were consistent with the results in the overall ARCHER 1050 population; there was a clinically meaningful prolongation of median PFS by 8.9 mo favoring dacomitinib. The safety profile of dacomitinib was manageable by dose reduction or temporary dose interruption and no new safety signals were observed in the population of Japanese patients compared with the overall ARCHER 1050 study population.

Background Osimertinib is recommended for T790M mutation‐positive advanced non‐small cell lung cancer (NSCLC) resistant to first‐ and second‐generation epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs). Recently, some reports exist on the real‐world use of osimertinib; however, reports involving third/later‐line use are few. Hence, this study was conducted to evaluate the efficacy and safety of osimertinib used in various treatment lines for T790M‐positive NSCLC patients. Methods This retrospective, observational, multicenter study included T790M‐positive advanced/recurrent NSCLC patients treated with osimertinib from May 2016 to March 2018. The clinical characteristics, efficacy, and adverse events were retrospectively investigated. The Kaplan‐Meier method was used to analyze progression‐free survival (PFS) and overall survival (OS). PFS‐associated clinical characteristics were evaluated using the Cox proportional hazards model. Results The objective response rate (ORR) and disease control rate (DCR) were 60.7% and 91.1%, respectively; the median PFS was 11.0 months. There were no significant differences in the median PFS for patients treated with osimertinib as second‐line and third−/later‐line (14.5 vs. 11.0 months respectively, P = 0.327). Analysis using the Cox proportional hazards model for clinical features affecting PFS also revealed no significant factors. Adverse events of grade ≥ 3 were reported in 15 patients (26.8%); the most common were anemia (n = 3) and cutaneous toxicity (n = 3). Grade 4 neutropenia was observed in one patient; any‐grade pneumonitis was observed in six patients (10.7%), including one with grade 3 pneumonitis. Conclusions Osimertinib demonstrated efficacy even when administered as third−/later‐line treatment to NSCLC patients. Osimertinib‐related pneumonitis was observed more frequently than previously reported. Key points Significant findings of the study Osimertinib shows efficacy even as later‐line treatment in T790M mutation‐positive NSCLC patients previously treated with EGFR‐TKIs. However, the incidence of ≥ grade 3 adverse events, especially pneumonitis, was higher than that previously reported by other studies. What this study adds Osimertinib was approved for previously EGFR‐TKI‐treated EGFR T790M‐positive NSCLC. With the increasing frequency of its use as first‐line treatment, this study provides valuable evidence for the efficacy and safety of osimertinib for previously EGFR‐TKI‐treated NSCLC.

Background MET has emerged as target in head and neck squamous cell carcinoma (HNSCC). However, clinical data on MET inhibition in HNSCC are limited. Methods HNSCC biopsies and cell lines were tested for MET activity. The response of cell lines to BAY-853474 was tested in proliferation assays. The prognostic value of MET expression was also analyzed. Results HNSCC cell lines do not respond to MET inhibition. MET-dependent gastric cancer cell lines have much higher levels of MET expression and phosphorylation than HNSCC cell lines. Clinical samples of HNSCC contain much less MET than responsive models. Conclusions No clinical response to MET inhibitors in monotherapy may be expected in unselected cases of HNSCC. Only selected patients with MET amplifications should be treated with MET inhibitors. Patients with increased MET immunoreactivity have shorter overall survival. MET might be useful as marker for the detection of patients with more aggressive types of HNSCC.

Background Anlotinib is a novel, orally administered, multitarget receptor tyrosine kinase inhibitor. It functions by inhibiting tumor angiogenesis and proliferative signaling pathways. In this study, we aimed to investigate the efficacy and safety of anlotinib plus epirubicin in a sarcoma patient‐derived xenografts (PDX) model. Methods We firstly established a PDX model using fresh tumor tissues that were surgically removed from a patient diagnosed with malignant fibrous histiocytoma. Thirty‐six PDX models were divided into six groups and treated with anlotinib alone (low‐dose, 1.5 or high‐dose, 3.0 mg/kg/day, oral gavage), or with anlotinib plus epirubicin (3.0 mg/kg/once weekly, i.p.) when the tumors grew to 150‐200 mm3. After 5 weeks of treatment, the mice were sacrificed, and the tumors were measured by weight and processed for IHC and H&E staining. IHC staining was performed to detect CD31, EGFR, MVD, and Ki‐67 on paraffin sections. H&E stainings were performed to examine the microcosmic changes that occurred in the tumor tissues and myocardium, respectively. Results After 5 weeks, treatment with anlotinib or epirubicin alone significantly inhibited tumor growth in the sarcoma PDX model compared with the vehicle control. Tumor volume in the high‐dose anlotinib group was significantly smaller than the low‐dose anlotinib group (P, Soft tissue sarcoma (STS) is a rare and diverse group of solid tumors with poor survival. For the first time, we showed that anlotinib, a multikinase angiogenesis inhibitor, combined with epirubicin was an effective and safe therapy in a sarcoma patient‐derived xenografts model, which suggested combined therapy drug as a promising therapeutic strategy for STS patients.