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This study aimed to evaluate how the timing of transarterial chemoembolization (TACE) relative to systemic therapy (tyrosine-kinase inhibitors [TKIs] and immune checkpoint inhibitors [ICIs]) influences oncological outcomes in patients with hepatocellular carcinoma (HCC). A retrospective analysis was conducted on HCC patients treated with TACE plus TKIs and ICIs from January 2018 to February 2023. We compared objective response rate (ORR), disease control rate (DCR), overall survival (OS), and progression-free survival (PFS) between patients receiving TACE before versus after systemic therapies. Multivariate Cox regression analyses identified potential prognostic factors. Of the 194 patients enrolled, 111 received TACE before systemic therapies, and 83 after. The median age at diagnosis was 52.8 years. There were no significant differences in ORR (40.72% vs. 30.41%, p = 0.989) or DCR (48.45% vs. 35.57%, p = 0.770) between the groups. Likewise, OS (18.73 vs. 18.20 months, p = 0.091) and PFS (11.53 vs. 10.05 months, p = 0.336) were similar regardless of treatment sequence. In the result of Cox analysis, a 20% decrease in AFP from baseline at one month was associated with improved OS (HR = 0.35, 95% CI 0.17–0.70, p = 0.003) and PFS (HR = 0.69, 95% CI 0.49–0.96, p = 0.028). Large tumor size (≥ 10 cm) was a poor prognostic factor for OS (HR = 2.12, 95% CI 1.07–4.21, p = 0.032), and the presence of portal vein tumor thrombus adversely affected PFS (HR = 2.31, 95% CI 1.47–3.62, p < 0.001). The sequencing of TACE and systemic therapies does not significantly impact the prognosis of advanced HCC. A 20% reduction in AFP within one month of treatment commencement emerges as a protective prognostic factor for HCC. [ABSTRACT FROM AUTHOR]

Purpose: Metastatic non-clear cell renal cell carcinoma (nccRCC) is a heterogeneous disease with a poor prognosis and is treated with immunotherapy (IO)-based combinations according to the clear cell renal cell carcinoma. Tyrosine-kinase inhibitors (TKIs), such as cabozantinib and axitinib, are commonly used as the 2nd line therapy after 1st line IO combination therapy, but their efficacy as 2nd line TKI therapy for nccRCC is unknown. In this study, we performed a retrospective multicenter analysis of nccRCC patients who were previously treated with IO combination therapy and received 2nd line TKIs. Methods: Among 254 patients enrolled in the Japanese multicenter retrospective study, 52 patients with nccRCC histology who received second-line TKIs were included in this study. Progression-free survival and overall survival (OS) from 2nd line TKIs were analyzed by log-rank test and Cox-proportional hazard model. Objective response rate (ORR) of 2nd line TKIs were analyzed. Results: The 1-year PFS and OS rates were 25.0% (95% CI = 13.1–36.8) and 63.8% (95% CI, 48.0–75.9), respectively. No patients had a complete response, 11 had a partial response, and 18 had stable disease. ORR was 21.1%. IMDC poor risk and sunitinib as the 2nd line therapy were significantly associated with poor PFS. Conclusion: The 2nd-line TKI was effective for a small group of nccRCC patients previously treated with IO combination therapy, although this study was retrospectively analyzed with a small number of cases. [ABSTRACT FROM AUTHOR]

A 69-year-old woman presented to our department with the chief complaint of diarrhea. She had undergone left nephrectomy for renal cancer 14 years earlier. Three years earlier, metastasis was detected in the left retroperitoneal cavity, and pazopanib administration was initiated. In the 29th month after the start of chemotherapy, the patient developed diarrhea, and on the 31st month, computed tomography showed thickening of the intestinal wall. Colonoscopy revealed white villi, intramucosal hemorrhage in the terminal ileum, and rough inflammatory mucosa with inflammatory polyps extending from the transverse to the sigmoid colon. Suspecting pazopanib-induced enteritis, we discontinued the medication, and the diarrhea resolved within 3 days. On the 21st day after discontinuation, colonoscopy revealed that the inflammatory polyps had shrunk, and the inflammatory findings had improved. Biopsy of the white villi of the ileum revealed histiocytes. The patient resumed treatment with pazopanib at 400 mg/day and developed soft stool on the 7th day after resumption. Compared with other tyrosine-kinase inhibitor-induced enteritis cases, this case showed less bleeding and more extensive inflammatory findings. There are similarities as well as differences from cases of previously reported pazopanib-induced enteritis. The mechanisms and characteristics of this disease require further investigation. [ABSTRACT FROM AUTHOR]

Objective: To report the results of PADRES (Prior Axitinib as a Determinant of Outcome of Renal Surgery, NCT03438708), a study investigating neoadjuvant axitinib for tumours of high complexity with imperative indication for partial nephrectomy (PN). Methods: We conducted a single‐arm phase II clinical trial of localized (cT1b‐cT3M0) clear‐cell renal cell carcinoma (RCC) patients with imperative indications for nephron preservation, where PN is a high‐risk procedure due to complexity (RENAL score 10–12). Axitinib 5 mg was administered twice daily for 8 weeks with repeat imaging at completion, followed by surgery. The primary outcome was successful completion of planned PN following axitinib treatment. Secondary objectives included changes in tumour diameter, RENAL nephrometry score, renal function and Response Evaluation Criteria in Solid Tumours (RECIST) v1.1, and surgical complications. Results: Twenty‐seven patients were enrolled (median age 69 years). Prior to therapy, twenty patients (74.0%) had ≥ clinical T3a staged tumours. Axitinib resulted in reductions in tumour diameter (7.5 vs 6.2 cm; P < 0.001) and RENAL score (11 vs 10; P < 0.001). Nine patients (33.3%) had partial response based on RECIST and nine (33.3%) were clinically downstaged. PN was performed in twenty patients (74.0%); twenty‐five patients (96.2%) had negative margins. Six patients (22.2%) had Clavien III–IV complications. The median change in estimated glomerular filtration rate (preoperative to last follow‐up) was 8.5 mL/min/1.73 m2. Conclusion: Neoadjuvant axitnib resulted in reductions in tumour size and complexity, enabling safe and feasible PN and functional preservation in patients with complex renal masses and imperative indication. [ABSTRACT FROM AUTHOR]

Background: Approximately 50% of patients harbor the T790M mutation after developing first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance. Evidence has showed the major treatment failure is local relapses and limited metastases. Several studies have demonstrated the value of radiotherapy in metastatic non-small cell lung cancer (NSCLC) with the EGFR T790M mutation after the development of TKI resistance. The aim of this study was to explore the role of radiation in T790M-mutant NSCLC and the value of early radiotherapy for NSCLC with T790M-mediated EGFR-TKI resistance. Methods: Gefitinib-resistant NSCLC cell lines were established via stepwise exposure to increasing concentrations of gefitinib (PC-9-GR). Droplet digital PCR was used to determine the relative T790M subclone abundance. In vitro and in vivo models were established using different mixtures of PC-9-GR and PC-9 cells. Differentially expressed genes were identified using RNA sequencing. Two research models were constructed (salvage and prophylactic radiotherapy) to determine the effects of early radiotherapy on gefitinib-resistant cells. Results: PC-9-GR cells exhibited higher radiosensitivity than PC-9 cells (sensitivity enhancement ratio = 1.5). Salvage radiation reduced the number of T790M-mutant subclones, and the relative T790M abundance was significantly lower than that without radiation at 90 days (10.94% vs. 21.54%). Prophylactic radiation prevented the development of T790M subclones. These results were also confirmed in vivo. qRT-PCR revealed threefold elevation of miR-1243 in PC-9-GR cells, and the increased radiosensitivity of PC-9-GR cells was inhibited when miR-1243 was knocked down. RNA sequencing revealed that SPOCK1 was downregulated in PC-9-GR cells. Interestingly, bioinformatic analysis showed that SPOCK1 was a target gene of miR-1243. SPOCK1 knockdown markedly increased the radiosensitivity of PC-9 cells. Conclusion: Gefitinib-resistant NSCLC with the T790M mutation had higher radiosensitivity than that without the mutation, possibly mediated by SPOCK1. Early radiotherapy can eliminate T790M subclones, providing evidence for the benefit of early local treatment in patients with TKI-resistant NSCLC.

Simple Summary: Remarkable strides have been performed in the treatment of adults diagnosed with Philadelphia-positive lymphoblastic leukemia (Ph+ ALL) through the integration of newer-generation tyrosine-kinase inhibitors and monoclonal antibodies. However, it is crucial to acknowledge that most medical centers worldwide lack access to these therapies. As a result, primary strategies employed for curing this disease continue to rely on a combination of chemotherapy and allogeneic stem-cell transplantation. Additionally, the scarcity of comprehensive literature makes it particularly challenging to provide straightforward treatment recommendations. In this narrative review, our aim is to offer a real-world perspective on the monitoring and management of Ph+ ALL patients, with an emphasis on less-resourced scenarios. Recent studies have indicated that more than half of adult patients newly diagnosed with Ph+ ALL can now achieve a cure. However, determining the most suitable protocol for less-resourced settings can be challenging. In these situations, we must consider the potential for treatment toxicity and limited access to newer agents and alloSCT facilities. Currently, it is advisable to use less intensive induction regimens for Ph+ ALL. These regimens can achieve high rates of complete remission while causing fewer induction deaths. For consolidation therapy, chemotherapy should remain relatively intensive, with careful monitoring of the BCR-ABL1 molecular transcript and minimal residual disease. AlloSCT may be considered, especially for patients who do not achieve complete molecular remission or have high-risk genetic abnormalities, such as IKZF1-plus. If there is a loss of molecular response, it is essential to screen patients for ABL mutations and, ideally, change the TKI therapy. The T315I mutation is the most common mechanism for disease resistance, being targetable to ponatinib. Blinatumomab, a bispecific antibody, has shown significant synergy with TKIs in treating this disease. It serves as an excellent salvage therapy, aside from achieving outstanding results when incorporated into the frontline. [ABSTRACT FROM AUTHOR]

Abstract Human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) is a highly aggressive subtype associated with poor prognosis. The advent of HER2-targeted drugs, including monoclonal antibodies, tyrosine-kinase inhibitors (TKIs) and antibody–drug conjugates, has yielded improved prognosis for patients. Compared with widely used monoclonal antibodies, small-molecule TKIs have unique advantages including oral administration and favorable penetration of blood–brain barrier for brain metastatic BC, and reduced cardiotoxicity. Pyrotinib is an irreversible TKI of the pan-ErbB receptor, and has recently been shown to be clinically effective for the treatment of HER2-positive BC in metastatic and neoadjuvant settings. This review highlights the development on the application of pyrotinib-based therapeutic approaches in the clinical settings of HER2-positive BC.

Introduction: Hepatocellular carcinoma (HCC) accounts for approximately 90% of primary liver cancer and can be caused by well-known risk factors, including infection with hepatitis B and C viruses, alcohol intake, and metabolic syndrome. The overall prognosis remains poor with a median survival of 1 year for symptomatic advanced-stage cases treated with systemic therapies. Case description: In July 2020, a 73-year-old male patient presented at our institution with mild abdominal pain and an attack of intense cold. After a radiological workup, the diagnosis of HCC located in the caudate lobe was established. The patient underwent atypical caudate lobe resection, and pathology confirmed the diagnosis of grade 3 HCC. Postoperative MRI showed a new metastasis in the 6th liver segment 1.3 cm in diameter, and a PVT progression which now affected the whole right lobe. The patient was started on sorafenib and demonstrated a complete response which still lasts for more than two years. Conclusion: We present a rare case of a patient who demonstrated a complete response to sorafenib treatment in advanced HCC with unfavorable prognostic factors. [ABSTRACT FROM AUTHOR]

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) is a highly aggressive subtype associated with poor prognosis. The advent of HER2-targeted drugs, including monoclonal antibodies, tyrosine-kinase inhibitors (TKIs) and antibody–drug conjugates, has yielded improved prognosis for patients. Compared with widely used monoclonal antibodies, small-molecule TKIs have unique advantages including oral administration and favorable penetration of blood–brain barrier for brain metastatic BC, and reduced cardiotoxicity. Pyrotinib is an irreversible TKI of the pan-ErbB receptor, and has recently been shown to be clinically effective for the treatment of HER2-positive BC in metastatic and neoadjuvant settings. This review highlights the development on the application of pyrotinib-based therapeutic approaches in the clinical settings of HER2-positive BC. [ABSTRACT FROM AUTHOR]

Background: Tyrosine-kinase inhibitors (TKIs) of epidermal growth factor receptor (EGFR) usually provide a potent anti-tumor efficacy with robust radiographic response for non-small cell lung cancer (NSCLC) harboring activating mutations in the EGFR gene. However, first-generation EGFR-TKIs may provide only modest pathological response in the majority of EGFR-mutated NSCLC. Here, we present a case of EGFR-mutated adenocarcinoma in which a pathological complete response was revealed in histological specimens obtained during conversion surgery following systemic treatment using a third-generation EGFR-TKI. Case presentation: A 61-year-old Japanese man was admitted to our hospital for salvage surgery. Four months prior to the admission, he had been diagnosed with unresectable adenocarcinoma (clinical stage IIIA/T4N1MO) originating from the right lower lobe. Chest computed tomography had revealed a 3.4-cm tumor and enlarged hilar nodes that invaded into the left atrium through the lower pulmonary vein. An activating EGFR-mutation (L858R) had been detected in the tumor specimen. Osimertinib monotherapy had provided a dramatic radiographic response. The patient was diagnosed with potentially resectable disease after 4 months' osimertinib treatment and was referred to our hospital. Complete resection with right lower lobectomy and combined resection of the left atrium was achieved. Pathological examination showed no viable tumor cells in the resected specimens. Postoperative course was uneventful. The patient is alive without tumor recurrence at 2 years after surgery. Conclusions: Pathological complete response was achieved with systemic treatment with osimertinib prior to surgery. Conversion surgery after osimertinib treatment may be safe and effective for NSCLC harboring activating EGFR-mutations. [ABSTRACT FROM AUTHOR]

Purpose: Given the availability of TKIs with high central nervous system efficacy, the question arises as to whether upfront SRS provides additional clinical benefits. The goal of this study was to characterize the clinical outcomes of SRS as salvage therapy for TKI-uncontrolled BMs. Methods: This retrospective study included EGFR-mutant NSCLC patients presenting BMs at the time of primary tumor diagnosis. BMs were categorized into three subgroups, referred to as "Nature of TKI-treated BMs", "TKI-controlled brain metastases ± SRS", and "SRS salvage therapy". The first subgroup analysis characterized the effects of TKIs on tumor behavior. In the second subgroup, we compared outcomes of TKI-controlled BMs treated with TKI alone versus those treated with combined TKI-SRS therapy. The third subgroup characterized the outcomes of TKI-uncontrolled BMs treated with SRS as salvage therapy Clinical outcomes include local and distant tumor control. Results: This study included 106 patients with a total of 683 BMs. TKI treatment achieved control in 63% of local tumors at 24 months. Among the TKI-controlled BMs, local tumor control was significantly higher in the combined TKI-SRS group (93%) than in the TKI-alone group (65%) at 24 months (p < 0.001). No differences were observed between the two groups in terms of distant tumor control (p = 0.832). In dealing with TKI-uncontrolled BMs, salvage SRS achieved local tumor control in 58% of BMs at 24 months. Conclusions: While upfront TKI alone proved highly effective in BM control, this study also demonstrated the outcomes of SRS when implemented concurrently with TKI or as salvage therapy for TKI-uncontrolled BMs. This study also presents a strategy of the precise timing and targeting of SRS to lesions in progression. [ABSTRACT FROM AUTHOR]

Lenvatinib is a tyrosine kinase inhibitor that is being used to treat neuroendocrine tumors based on the success shown in the TALENT trial. There are two documented cases of lenvatinib-induced pancreatitis in patients being treated for thyroid cancer. This report describes the first case of pancreatitis seen in a patient with a metastatic neuroendocrine tumor being treated with lenvatinib. A 68-year-old female presented with a chief complaint of epigastric abdominal pain, nausea, and vomiting. She started on lenvatinib therapy 3 months prior to presentation and discontinued the drug 1 week prior due to worsening symptoms. This patient presented with epigastric pain radiating to the back, CT imaging findings consistent with acute pancreatitis, but only a lipase of 88. Once the diagnosis of pancreatitis was made, treatment was initiated with IV fluids, holding all oral intake and pain management. The patient was discharged after she tolerated oral intake after 5 days of hospitalization. It was concluded that the pancreatitis was likely caused by lenvatinib as other etiologies of acute pancreatitis including gallstones, alcohol use, hypertriglyceridemia, and hypercalcemia were ruled out. Clinicians who are using lenvatinib to treat neuroendocrine tumors should be aware of the occurrence of pancreatitis and may consider periodic monitoring for signs and symptoms of pancreatitis. More research regarding the mechanism and development of lenvatinib-induced pancreatitis may benefit clinical decision-making in patients being considered for lenvatinib therapy. Additionally, this therapy may need to be monitored closely in patients with a history of pancreatitis.

IntroductionHepatocellular carcinoma (HCC) accounts for approximately 90% of primary liver cancer and can be caused by well-known risk factors, including infection with hepatitis B and C viruses, alcohol intake, and metabolic syndrome. The overall prognosis remains poor with a median survival of 1 year for symptomatic advanced-stage cases treated with systemic therapies.Case descriptionIn July 2020, a 73-year-old male patient presented at our institution with mild abdominal pain and an attack of intense cold. After a radiological workup, the diagnosis of HCC located in the caudate lobe was established. The patient underwent atypical caudate lobe resection, and pathology confirmed the diagnosis of grade 3 HCC. Postoperative MRI showed a new metastasis in the 6th liver segment 1.3 cm in diameter, and a PVT progression which now affected the whole right lobe. The patient was started on sorafenib and demonstrated a complete response which still lasts for more than two years.ConclusionWe present a rare case of a patient who demonstrated a complete response to sorafenib treatment in advanced HCC with unfavorable prognostic factors.

Non-clear cell renal cell carcinoma (nccRCC) is a heterogeneous group of malignancies that represents 25% of renal cell carcinoma (RCC) cases. Treatment for non-clear cell histologies is mostly based on evidence from small phase II clinical trials or extrapolated from successful therapies in clear cell RCC because of the low incidence of non-clear cell pathology. Advances in genomic profiling have improved clinicians’ understanding of molecular targets for nccRCC, such as altered mesenchymal epithelial transition (MET) gene status and fumarate hydratase (FH) gene inactivation, but patient outcomes remain poor and optimal management of this disease remains unclear. This review assesses outcomes by histologic subtype from 27 prospective and 13 ongoing clinical trials to identify therapeutic strategies for advanced or metastatic nccRCC. Vascular endothelial growth factor tyrosine kinase inhibitors (TKI), such as sunitinib, and mammalian target of rapamycin (mTOR) inhibitors, such as everolimus, have demonstrated efficacy and remain viable treatment options, with a preference for sunitinib. However, everolimus is preferred in patients with chromophobe RCC because folliculin (FLCN) gene mutations upregulate the mTOR pathway. Novel TKIs, such as cabozantinib, show improved outcomes in patients with papillary RCC because of targeted MET inhibition. Platinum-based chemotherapy continues to be the recommended treatment strategy for collecting duct and medullary RCC. Clinically meaningful antitumor activity has been observed across all non-clear cell histologies for immune checkpoint inhibitors, such as nivolumab, pembrolizumab, and ipilimumab. Ongoing trials are evaluating novel tyrosine kinase inhibitor and immunotherapy combination regimens, with an emphasis on the promising MET-inhibitor cabozantinib and pembrolizumab plus lenvatinib.

The advancement of new therapies, including targeted therapies and immunotherapies, has improved the survival of non-small-cell lung cancer (NSCLC) patients in the last decade. Some NSCLC patients still do not benefit from therapies or encounter progressive disease during the course of treatment because they have intrinsic resistance, acquired resistance, or lack a targetable driver mutation. More investigations on the molecular biology of NSCLC are needed to find useful biomarkers for current therapies and to develop novel therapeutic strategies. Src is a non-receptor tyrosine kinase protein that interacts with cell surface growth factor receptors and the intracellular signaling pathway to maintain cell survival tumorigenesis in NSCLC. The Yes-associated protein (YAP) is one of the main effectors of the Hippo pathway and has been identified as a promoter of drug resistance, cancer progression, and metastasis in NSCLC. Here, we review studies that have investigated the activation of YAP as mediated by Src kinases and demonstrate that Src regulates YAP through three main mechanisms: (1) direct phosphorylation; (2) the activation of pathways repressing Hippo kinases; and (3) Hippo-independent mechanisms. Further work should focus on the efficacy of Src inhibitors in inhibiting YAP activity in NSCLC. In addition, future efforts toward developing potentially reasonable combinations of therapy targeting the Src-YAP axis using other therapies, including targeted therapies and/or immunotherapies, are warranted.

Purpose Brain metastasis is common in patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) at initial presentation. A previous study showed that brain radiotherapy (RT) before first-generation (first-G) EGFR-tyrosine kinase inhibitor (TKI) therapy is associated with longer overall survival than TKI therapy alone. However, there is no data regarding the role of additional brain RT before afatinib therapy. Materials and Methods Between October 2014 and June 2019, EGFR-mutant NSCLC patients with brain metastases who started first-G EGFR-TKIs (gefitinib or erlotinib) or afatinib as first-line therapy were retrospectively analyzed. This study compared overall survival and intracranial progression-free survival (PFS) between patients who received EGFR-TKIs alone and EGFR-TKIs with brain RT and either a first-G EGFR-TKI or afatinib, respectively. Results The median follow-up duration was 29.6 months (range, 1.5 to 116.9 months). In the first-G EGFR-TKI group (n=155), 94 patients (60.6%) received the first-G EGFR-TKI alone and 61 patients (39.4%) received brain RT prior to their first-G EGFR-TKI. In the afatinib group (n=204), 126 patients (61.8%) received afatinib alone and 78 patients (38.2%) received brain RT prior to afatinib. There was no difference in overall survival rates between the groups with RT (35.6 months: 95% confidence interval [CI], 27.9 to 43.3) and without RT (31.4 months: 95% CI, 23.9 to 38.9) in the afatinib group (p=0.58), but there was a significant difference in overall survival in the first-G EGFR-TKI group in a manner favoring additional brain RT (41.1 months: 95% CI, 30.5 to 51.7 vs. 25.8 months: 95% CI, 20.1 to 31.5; p=0.02). Meanwhile, median intracranial PFS was not different between patients who received EGFR-TKI therapy alone vs. EGFR-TKI therapy with brain RT in both the first-G EGFR-TKI (p=0.39) and afatinib (p=0.24) groups. Conclusion Afatinib therapy alone showed comparable survival outcomes to those of afatinib with brain RT. The current study suggests that brain RT could be an optional, not mandatory, treatment modality when afatinib therapy is considered in patients with EGFR-mutant NSCLC. [ABSTRACT FROM AUTHOR]

Lenvatinib is a tyrosine kinase inhibitor that is being used to treat neuroendocrine tumors based on the success shown in the TALENT trial. There are two documented cases of lenvatinib-induced pancreatitis in patients being treated for thyroid cancer. This report describes the first case of pancreatitis seen in a patient with a metastatic neuroendocrine tumor being treated with lenvatinib. A 68-year-old female presented with a chief complaint of epigastric abdominal pain, nausea, and vomiting. She started on lenvatinib therapy 3 months prior to presentation and discontinued the drug 1 week prior due to worsening symptoms. This patient presented with epigastric pain radiating to the back, CT imaging findings consistent with acute pancreatitis, but only a lipase of 88. Once the diagnosis of pancreatitis was made, treatment was initiated with IV fluids, holding all oral intake and pain management. The patient was discharged after she tolerated oral intake after 5 days of hospitalization. It was concluded that the pancreatitis was likely caused by lenvatinib as other etiologies of acute pancreatitis including gallstones, alcohol use, hypertriglyceridemia, and hypercalcemia were ruled out. Clinicians who are using lenvatinib to treat neuroendocrine tumors should be aware of the occurrence of pancreatitis and may consider periodic monitoring for signs and symptoms of pancreatitis. More research regarding the mechanism and development of lenvatinib-induced pancreatitis may benefit clinical decision-making in patients being considered for lenvatinib therapy. Additionally, this therapy may need to be monitored closely in patients with a history of pancreatitis. [ABSTRACT FROM AUTHOR]

Rapid tumor growth after cessation of molecularly targeted drugs, called “disease flare,” may occur and affect the prognosis of lung cancer. However, this phenomenon has never been reported in ROS proto-oncogene 1 (ROS1) fusion-positive lung adenocarcinoma. Herein, we report a disease flare in a patient with ROS1 fusion-positive lung adenocarcinoma. A 60-year-old female was diagnosed with stage IVA ROS1 fusion-positive lung adenocarcinoma via bronchoscopy. Although crizotinib, an ROS1 tyrosine kinase inhibitor, achieved a partial response, a mass lesion appeared in the patient’s right kidney 12 months after starting crizotinib, which was diagnosed pathologically as crizotinib-associated renal cysts (CARCs). Given that readministration of crizotinib repeatedly induced CARC-like aseptic inflammation that appeared to be disseminated around surgical site, crizotinib treatment had to be abandoned. Around 25 days after crizotinib cessation, she was referred to the emergency department with a convulsive seizure and hemiparesis due to new, rapidly growing brain metastases. Whole-brain irradiation and administration of another ROS1 tyrosine kinase inhibitor, entrectinib, markedly ameliorated the metastases and improved hemiparesis. This has been the first report of a disease flare after crizotinib cessation due to CARCs in a patient with ROS1 fusion-positive lung adenocarcinoma. Attention should be paid to disease flare, especially in the brain, when molecularly targeted medication is stopped due to adverse events in ROS1 fusion-positive lung adenocarcinoma. Switching to drugs that penetrate the blood-brain barrier could overcome disease flare in the brain.

Metastatic urothelial cancer, associated with a poor prognosis, is still major cause of cancer-related death, with scarce options of effective treatment after progression to platinum-based chemotherapy and immunotherapy. The human epithelial growth factor receptor 2 (Her-2) has been identified as a new therapeutic target in medical oncology. However, despite the encouraging results in breast and gastric cancers, clinical trials with anti-Her-2 monoclonal antibodies and tyrosine-kinase inhibitors have shown limited efficacy of this strategy in urothelial tumors. Notably, more favorable data have been recently shown that antibody-drug conjugates are currently emerging as a novel promising approach for Her-2 targeted therapy in advanced urothelial cancer. [ABSTRACT FROM AUTHOR]

Objective: Tyrosine kinase inhibitors (TKIs) is the first-line treatment for EGFR-positive non-small cell lung cancer (NSCLC); however, its applicability to patients with wild-type NSCLC remains an issue of contention. This study compared the effects of gamma knife radiosurgery (GKRS) alone versus combining GKRS and TKIs in treating two genetic forms of NSCLC. Methods: This retrospective study examined 479 NSCLC patients with 1982 brain metastases who underwent GKRS and for whom imaging follow-up data or death records were available. All our patients were consecutive. All gene mutations were confirmed by lung biopsy. The three main endpoints in this study were overall survival (OS), local intracranial tumor control (LC), and distal intracranial tumor control (DC). Results: There were 296 NSCLC patients with EGFR positive: TKI treatment (n = 262) and without TKI treatment (n = 34). GKRS + TKIs was more effective than GKRS alone in terms of OS (HR 0.53, p = 0.085) and DC (HR 0.51, p < 0.001). There were 150 NSCLC patients with wild-type EGFR: TKI treatment (n = 50) and without TKI treatment (n = 100). GKRS + TKIs was less effective than GKRS alone in terms of OS (HR 1.82, p = 0.049) and DC (HR: 1.40, p = 0.011). We observed no difference in terms of LC in both genetic groups. Conclusions: Combining GKRS with TKIs proved effective in EGFR positive NSCLC patients; however, we do not observe the similar results when combining GKRS with TKIs for patients with wild-type NSCLC. [ABSTRACT FROM AUTHOR]

The spectrum of TKI-related adverse events (AEs) is variable. Pleural effusion (PE) is a frequent AE attributable to dasatinib treatment, while it is only rarely associated with nilotinib. The pathogenetic mechanism leading to PE during nilotinib therapy is still unknown and its management has not yet been defined. To the best of our knowledge, only a limited number of similar case reports have already been reported in the literature so far. Here, we describe the case of a 41-year-old CML patient who developed PE during first-line nilotinib, successfully treated with steroids and nilotinib permanent discontinuation. We highlight the differences among our patient and the others, proposing therapeutic strategies to solve this rare but still possible AE, of which physicians should be aware.

New strategies for molecular-targeted drug therapy for advanced hepatocellular carcinoma (HCC) ignore the contribution of the nutritional status of patients and nutritional support to improve physical status and immunity. We aimed to elucidate the role of a single nucleotide mixture (SNM) in the anti-tumor therapy of HCC, and to explore the importance of a SNM as adjuvant therapy for HCC. Compared with a lipid emulsion (commonly used nutritional supplement for HCC patients), the SNM could not induce metabolic abnormalities in HCC cells (Warburg effect), and did not affect expression of metabolic abnormality-related factors in HCC cells. The SNM could also attenuate the lymphocyte injury induced by antitumor drugs in vitro and in vivo , and promote the recruitment and survival of lymphocytes in HCC tissues. Using HCC models in SCID (server combined immune-deficiency) mice or BalB/c mice, the SNM had anti-tumor activity, and could significantly upregulate the antitumor activity of molecular-targeted drugs (tyrosine-kinase inhibitors [TKI] and immune-checkpoint inhibitors [ICI]) against HCC. We employed research models in vivo and in vitro to reveal the anti-tumor activity of the SNM on HCC. Our findings expand understanding of the SNM and contribute to HCC (especially nutritional support) therapy. [ABSTRACT FROM AUTHOR]

New strategies for molecular-targeted drug therapy for advanced hepatocellular carcinoma (HCC) ignore the contribution of the nutritional status of patients and nutritional support to improve physical status and immunity. We aimed to elucidate the role of a single nucleotide mixture (SNM) in the anti-tumor therapy of HCC, and to explore the importance of a SNM as adjuvant therapy for HCC. Compared with a lipid emulsion (commonly used nutritional supplement for HCC patients), the SNM could not induce metabolic abnormalities in HCC cells (Warburg effect), and did not affect expression of metabolic abnormality-related factors in HCC cells. The SNM could also attenuate the lymphocyte injury induced by antitumor drugs in vitro and in vivo, and promote the recruitment and survival of lymphocytes in HCC tissues. Using HCC models in SCID (server combined immune-deficiency) mice or BalB/c mice, the SNM had anti-tumor activity, and could significantly upregulate the antitumor activity of molecular-targeted drugs (tyrosine-kinase inhibitors [TKI] and immune-checkpoint inhibitors [ICI]) against HCC. We employed research models in vivo and in vitro to reveal the anti-tumor activity of the SNM on HCC. Our findings expand understanding of the SNM and contribute to HCC (especially nutritional support) therapy.

Simple Summary: An increasing number of new systemic therapies have significantly enhanced treatment opportunities for patients with advanced liver cancer. Yet, it is unclear which sequence of systemic therapies is best for individual patients. In the present study, we compared systemic treatment lines in patients who received either first-line therapy with sorafenib or lenvatinib, two important tyrosine-kinase inhibitors for the treatment of liver cancer. Overall, baseline liver function rather than choice of first-line tyrosine kinase inhibitor (TKI) had an impact on median overall survival (mOS). The optimal treatment sequence of tyrosine kinase inhibitor (TKI)-based therapy in patients with hepatocellular carcinoma (HCC) remains unclear. Therefore, sequential systemic therapy after first-line therapy with sorafenib or lenvatinib was compared in a retrospective real-world cohort. In total, 164 patients with HCC were included. Child B cirrhosis was present in 26 patients (16.5%), whereas 132 patients (83.5%) had preserved liver function. In total, 72 patients (44%) discontinued systemic therapy after first-line therapy while 51 (31%) and 31 (19%) patients received 2 or more treatment lines. Most notably, median overall survival (mOS) was influenced by liver functional status and patient performance status at the beginning of first-line therapy. Patients receiving a sequential therapy regimen had significantly longer mOS compared to patients that discontinued systemic therapy after omitting first-line treatment. The choice of the initial TKI did not impact mOS. A clear deterioration of liver function could be observed during the course of TKI-based treatment. [ABSTRACT FROM AUTHOR]

An 82-year-old woman treated for advanced lung cancer with gefitinb was admitted to the emergency unit complaining of dyspnea. Chest computed tomography found abnormalities classified as possible diffuse COVID-19 pneumonia. RT-PCR for Sars-Cov-2 was twice negative. PCR for Pneumocystis jirovecii was positive on bronchoalveolar lavage. The final diagnosis was Pneumocystis jirovecii pneumonia. Therefore, physicians must be careful not to misdiagnose COVID-19, especially in cancer patients on small-molecule therapeutics like gefitinib and corticosteroids.

Rapid tumor growth after cessation of molecularly targeted drugs, called "disease flare," may occur and affect the prognosis of lung cancer. However, this phenomenon has never been reported in ROS proto-oncogene 1 (ROS1) fusion-positive lung adenocarcinoma. Herein, we report a disease flare in a patient with ROS1 fusion-positive lung adenocarcinoma. A 60-year-old female was diagnosed with stage IVA ROS1 fusion-positive lung adenocarcinoma via bronchoscopy. Although crizotinib, an ROS1 tyrosine kinase inhibitor, achieved a partial response, a mass lesion appeared in the patient's right kidney 12 months after starting crizotinib, which was diagnosed pathologically as crizotinib-associated renal cysts (CARCs). Given that readministration of crizotinib repeatedly induced CARC-like aseptic inflammation that appeared to be disseminated around surgical site, crizotinib treatment had to be abandoned. Around 25 days after crizotinib cessation, she was referred to the emergency department with a convulsive seizure and hemiparesis due to new, rapidly growing brain metastases. Whole-brain irradiation and administration of another ROS1 tyrosine kinase inhibitor, entrectinib, markedly ameliorated the metastases and improved hemiparesis. This has been the first report of a disease flare after crizotinib cessation due to CARCs in a patient with ROS1 fusion-positive lung adenocarcinoma. Attention should be paid to disease flare, especially in the brain, when molecularly targeted medication is stopped due to adverse events in ROS1 fusion-positive lung adenocarcinoma. Switching to drugs that penetrate the blood-brain barrier could overcome disease flare in the brain. [ABSTRACT FROM AUTHOR]

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Metastatic urothelial cancer, associated with a poor prognosis, is still major cause of cancer-related death, with scarce options of effective treatment after progression to platinum-based chemotherapy and immunotherapy. The human epithelial growth factor receptor 2 (Her-2) has been identified as a new therapeutic target in medical oncology. However, despite the encouraging results in breast and gastric cancers, clinical trials with anti-Her-2 monoclonal antibodies and tyrosine-kinase inhibitors have shown limited efficacy of this strategy in urothelial tumors. Notably, more favorable data have been recently shown that antibody-drug conjugates are currently emerging as a novel promising approach for Her-2 targeted therapy in advanced urothelial cancer.

Metastasis from salivary gland tumors to liver is exceedingly uncommon. Reported is the first case of a mammary analog secretory carcinoma (MASC) of salivary gland origin metastasized to the liver, even after complete surgical resection. A 76 year old female, with past history of a completely extirpated right parotid gland MASC, presented 2 years after right superficial parotidectomy and right neck dissection, with back and flank pain. Subsequent abdominal and pelvic CT revealed multiple small hepatic lesions. Biopsy of the largest hepatic lesion confirmed metastatic MASC of primary parotid gland origin. Both the parotid primary and the hepatic metastases had the confirmatory ETV6 rearrangement by fluorescence in situ hybridization. Although high-grade malignancy and distant metastases of MASC of salivary gland origin to liver is rare, recognizing metastatic MASC potentially alters prognosis and determines therapeutic options.

Zhichao Tian,1 Xin Wang,1 Zhiyong Liu,1 Jiaqiang Wang,1 Weitao Yao,1 Yao Zhao,2 Songtao Gao,3 Peng Zhang,1 Hong Ge41Department of Orthopedics, the Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008, Henan Province, People’s Republic of China; 2Department of Orthopedics, the First Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, Henan Province, People’s Republic of China; 3Department of Orthopedics, the Affiliated People’s Hospital of Zhengzhou University, Zhengzhou 450003, Henan Province, People’s Republic of China; 4Department of Radiation Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan Province, 450008, People’s Republic of ChinaPurpose: Apatinib has shown effectiveness in treating sarcoma. This study aimed to assess the safety and efficacy of apatinib and doxorubicin combination therapy in metastatic soft tissue sarcomas (STS) and to compare the therapeutic effects of two treatments (apatinib after doxorubicin vs apatinib plus doxorubicin) on STS.Patients and methods: A total of 76 patients with metastatic STS who received apatinib and doxorubicin between May 2016 and June 2017 were retrospectively reviewed. Patients were divided into either the apatinib after doxorubicin group (in which apatinib was used after six cycles of doxorubicin chemotherapy) or the apatinib plus doxorubicin group (in which apatinib was used in combination with doxorubicin chemotherapy).Results: There were 55 patients in the apatinib after doxorubicin group and 21 patients in the apatinib plus doxorubicin group. There were significant differences between the apatinib plus doxorubicin group and the apatinib after doxorubicin group in the objective response rate (57.14% vs 25.45%, respectively, p=0.016) and average change from baseline in the target lesion size (−41.71±43.75% vs −1.89±51.61%, respectively, p=0.03). There were no significant differences in disease control rate (85.71% vs 63.64%, p=0.093) and median progression-free survival (8.8 months vs 10.3 months, p=1). Grade 3–4 adverse events were more common with apatinib plus doxorubicin than with apatinib after doxorubicin, and these included leukopenia (5.45% vs 38.1%, respectively, p=0.001), anemia (7.27% vs 28.57%, respectively, p=0.023), oral mucositis (3.64% vs 19.05%, respectively, p=0.046), transaminase increases (0% vs 14.29%, respectively, p=0.011).Conclusion: Our results do not support the use of apatinib plus doxorubicin for metastatic STS unless the specific objective is tumor shrinkage.Keywords: chemotherapy, apatinib, tyrosine-kinase inhibitor, sarcoma, adverse events

Embryonal tumor with multilayered rosettes (ETMR) are rare pediatric brain tumors with increased malignant potential. Despite the advances in multimodal treatment schemes the overall 5-year event free survival rates for ETMR are not favorable. Further, therapeutic regimes are limited to a case by case basis due to the limited amount of literature and guidelines available for treating childhood ETMR. We report one patient with refractory ETMR who was successfully treated by implementing a molecular profiling approach which identified the tyrosine kinase inhibitor dasatinib as a viable therapy. Our results suggest that utilizing this precision medicine approach might prove useful in treating patients with refractory ETMR.

Although tyrosine Kinase Inhibitors (TKI) has revolutionized the treatment of chronic myeloid leukemia (CML), patients are not cured with the current therapy modalities. Also, the more recent goal of CML treatment is to induce successful treatment-free remission (TFR) among patients achieving durable deep molecular response (DMR). Together, it is necessary to develop novel, curative treatment strategies. With advancements in understanding the biology of CML, such as dormant Leukemic Stem Cells (LSCs) and impaired immune modulation, a number of agents are now under investigation. This review updates such agents that target LSCs, and together with TKIs, have the potential to eradicate CML. Moreover, we describe the developing immunotherapy for controlling CML.

Although tyrosine Kinase Inhibitors (TKI) has revolutionized the treatment of chronic myeloid leukemia (CML), patients are not cured with the current therapy modalities. Also, the more recent goal of CML treatment is to induce successful treatment-free remission (TFR) among patients achieving durable deep molecular response (DMR). Together, it is necessary to develop novel, curative treatment strategies. With advancements in understanding the biology of CML, such as dormant Leukemic Stem Cells (LSCs) and impaired immune modulation, a number of agents are now under investigation. This review updates such agents that target LSCs, and together with TKIs, have the potential to eradicate CML. Moreover, we describe the developing immunotherapy for controlling CML. [ABSTRACT FROM AUTHOR]

Tyrosine kinase inhibitors (TKIs), the backbone of treatment for chronic phase chronic myeloid leukemia patients (CP-CML), have changed the long-term outcome of the disease. Nonetheless, over 20% of patients fail front-line therapy due to intolerance or resistance. A head-to-head comparison of dasatinib and nilotinib as second-line treatment outside of sponsored clinical trials has not been reported. We retrospectively analyzed 131 CP-CML patients who, after front-line imatinib failure, switched to a second-line therapy with nilotinib (59, 45%) or dasatinib (72, 55%). Median duration of second-line treatment was 33 months (range 2-100). The reason for switching therapy was resistance in 83.2% and intolerance in 16.8% of patients. The overall survival of the entire cohort at 7 years was 78.9%, while it was 72% and 85.6% for patients treated with dasatinib and nilotinib, respectively (p=0.287). With regard to efficacy after 12 months of treatment, 108 patients were evaluable for molecular response: 47% achieved a major molecular response and 18.2% a deep molecular response with dasatinib, compared to 38% and 16.2% with nilotinib (p=ns). We observed 35% of grade 3-4 adverse events, more frequently in the dasatinib group (47%) compared to the nilotinib group (22%), without affecting molecular responses. Our study suggests that, in the real-life setting, dasatinib and nilotinib used as second-line treatment in CP-CML are equally effective, with high molecular response rates and an acceptable tolerability. [ABSTRACT FROM AUTHOR]

Purpose: Lenvatinib (LEN) has been approved for the treatment of patients with progressive radioiodine-refractory differentiated thyroid cancer (RAI-R DTC). Real-life studies reported a lower progression-free survival (PFS) than the registration study, likely due to the more advanced stage of tumors, the more frequent pretreatment with other TKIs, the limited follow-up, and the worse clinical condition of the patients included. Methods: We evaluated the clinical data of our cohort of 13 consecutive patients, all receiving LEN as a first-line TKI treatment, and followed-up in a single tertiary Center. Results: All patients had an ECOG of 0–1 and regional or distant metastases were documented in 61.5% and 77% of patients, respectively. Median PFS was 22 months (95% CI 14–35) with partial response in 69% and stable disease in 31% of patients. All patients experienced at least one adverse event (AE), the most frequent being fatigue, anorexia, diarrhea, and hypertension. The daily dose was reduced in 70% of patients and only one patient (7.7%) discontinued the drug for AEs. Conclusion: In this series of RAI-R DTC patients, with the unique features to have an ECOG 0 or 1 and to be naive for TKI treatments, PFS was the longest among all real-life published so far, with the highest rate of patients with partial response and one of the lowest drug discontinuation rate for AEs. The correct timing of treatment start, the tailoring of the dose, and a proper management of the AEs may have a significant impact on the treatment response to LEN. [ABSTRACT FROM AUTHOR]

An 82-year-old woman treated for advanced lung cancer with gefitinb was admitted to the emergency unit complaining of dyspnea. Chest computed tomography found abnormalities classified as possible diffuse COVID-19 pneumonia. RT-PCR for Sars-Cov-2 was twice negative. PCR for Pneumocystis jirovecii was positive on bronchoalveolar lavage. The final diagnosis was Pneumocystis jirovecii pneumonia. Therefore, physicians must be careful not to misdiagnose COVID-19, especially in cancer patients on small-molecule therapeutics like gefitinib and corticosteroids. [ABSTRACT FROM AUTHOR]

Background: Approximately 50% of patients harbor the T790M mutation after developing first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance. Evidence has showed the major treatment failure is local relapses and limited metastases. Several studies have demonstrated the value of radiotherapy in metastatic non-small cell lung cancer (NSCLC) with the EGFR T790M mutation after the development of TKI resistance. The aim of this study was to explore the role of radiation in T790M-mutant NSCLC and the value of early radiotherapy for NSCLC with T790M-mediated EGFR-TKI resistance., Methods: Gefitinib-resistant NSCLC cell lines were established via stepwise exposure to increasing concentrations of gefitinib (PC-9-GR). Droplet digital PCR was used to determine the relative T790M subclone abundance. In vitro and in vivo models were established using different mixtures of PC-9-GR and PC-9 cells. Differentially expressed genes were identified using RNA sequencing. Two research models were constructed (salvage and prophylactic radiotherapy) to determine the effects of early radiotherapy on gefitinib-resistant cells., Results: PC-9-GR cells exhibited higher radiosensitivity than PC-9 cells (sensitivity enhancement ratio = 1.5). Salvage radiation reduced the number of T790M-mutant subclones, and the relative T790M abundance was significantly lower than that without radiation at 90 days (10.94% vs. 21.54%). Prophylactic radiation prevented the development of T790M subclones. These results were also confirmed in vivo . qRT-PCR revealed threefold elevation of miR-1243 in PC-9-GR cells, and the increased radiosensitivity of PC-9-GR cells was inhibited when miR-1243 was knocked down. RNA sequencing revealed that SPOCK1 was downregulated in PC-9-GR cells. Interestingly, bioinformatic analysis showed that SPOCK1 was a target gene of miR-1243. SPOCK1 knockdown markedly increased the radiosensitivity of PC-9 cells., Conclusion: Gefitinib-resistant NSCLC with the T790M mutation had higher radiosensitivity than that without the mutation, possibly mediated by SPOCK1. Early radiotherapy can eliminate T790M subclones, providing evidence for the benefit of early local treatment in patients with TKI-resistant NSCLC., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier B.V.)

Since July 2017, different generic imatinib formulations have been introduced in Italy for the treatment of patients with chronic myeloid leukemia (CML). We analyzed 168 chronic phase CML patients treated with branded imatinib for a median of 12 years (range 1–16) at a single institution who switched to a single generic formulation in order to assess the safety and impact on molecular response. The Sokal risk was low/intermediate/high in 63%, 33%, and 4% of patients, respectively. The median duration of generic imatinib treatment was 19 months (range 4–22). Twenty-seven percent of patients were in MMR and 73% were in deep molecular responses (MR4–4.5) at the time of the switch. After 12 months of treatment with generic imatinib, 140 patients were evaluable for response: 23.6% and 76.4% were respectively in MMR and in deep molecular response. When the degree of response was compared with the best molecular response observed with branded imatinib, it was found that 84% of patients maintained the response previously achieved, 6% improved it, and 10% of patients had a molecular fluctuation from the previous deep molecular response to MMR. Only 1 patient lost the MMR and no patient switched to another TKI for inefficacy. In terms of safety, 20% of patients reported new or worsening side effects, but only 2 patients returned to branded imatinib for toxicity. Our data show that the switch to generic imatinib in patients who have been previously treated with branded imatinib appears to maintain efficacy, although a proportion of patients experience new or worsening side effects. [ABSTRACT FROM AUTHOR]

Interstitial lung diseases (ILDs) are a heterogenous group of disorders and pathological conditions of known and unknown nature characterized by extensive and, generally, bilateral damage of the respiratory part of the lungs (alveoli, respiratory bronchioles). Until recently, there weren’t any effective therapies for patients with progressive pulmonary fibrosis, partly because of limited knowledge of the disease pathogenesis. However, in the last decade, new data of etiological, genetic factors and pathogenetic mechanisms of ILD were obtained. Currently, only two drugs were proven effective for treatment of patients with interstitial pulmonary fibrosis: pirfenidone and nintedanib which affect the rate of progression of restrictive changes in the lungs. The search for drugs is continuing in accordance with the growing understanding of pathogenetic mechanisms of ILDs. Notably, recent years saw an “explosion” of pre-clinical studies.

Abstract Background Anti-angiogenesis Tyrosine kinase inhibitors (TKIs) have been proved to show promising effects on prolonging progression-free survival (PFS) for advanced sarcoma after failure of standard multimodal Therapy. Methylsulfonic apatinib is one of those TKIs which specifically inhibits VEGFR-2. This paper summarizes the experience of three Peking University affiliated hospitals in off-label use of apatinib in the treatment of extensively pre-treated sarcoma. Methods We retrospectively analysed files of patients with advanced sarcoma not amenable to curative treatment, who were receiving an apatinib-containing regimen between June 1, 2015 and December 1, 2016. Fifty-six patients were included: 22 osteosarcoma, 10 Ewing’s sarcoma, 3 chondrosarcoma and 21 soft tissue sarcoma. Results With median follow-up time of 6 months (range, 0.7–18.0 m), thirty-five (62.5%) patients had partial response, and disease was stable in 11 (19.6%). The 4-month and 6-month progression-free survival rates were 46.3 and 36.5%, respectively. The median duration of response was 3.8 months (95% CI 1.9–5.6 m), with much variability among disease subtypes. The median overall survival was 9.9 months (95% CI 7.6–12.2 m). Grade 3 and 4 toxicities were observed in 8 (14.3%) patients, the most common being hypertension, pneumothorax, wound-healing problems, anorexia, and rash or desquamation. Conclusions Apatinib might be effective, with a high objective response rate, in an off-label study of sarcoma patients with advanced, previously treated disease. The duration of response was consistent with reports in different subtypes of sarcomas. Prospective trials of apatinib in the treatment of selected subtypes of sarcomas are needed. Trial registration Retrospectively registered in the Medical Ethics Committee of Peking University People’s Hospital, Peking University Shougang Hospital and Peking University International Hospital. The trial registration number is 2017PHB176–03 and the date of registration is January 20th 2017.

Cutaneous adverse effects (AE) related to tyrosine‐kinase inhibitor (TKI) drugs have been mainly described as case reports. We have characterized their appearance and correlation with patient's photoexposition habits and, further, with treatment response, in 61 patients with chronic myelogenous leukemia (CML) treated with TKI drugs. We have found hypopigmentation in 49.2% of the cases and a statistically significant association with interferon (IFN) intake. Eyelid edema's frequency was 45.4%. Mean photo‐exposure was 1.95 h/day and only 8.3% of the patients used sunscreen daily. 44.3% of the patients reported a lighter skin color with the treatment and a statistically significant relationship with conjunctival hemorrhage was also found. Concordance between patients and dermatologist was moderate (kappa index 0.41). We found xerosis (21.3%), eczematous eruptions (21.3%), melasma (4.9%) and other isolated skin problems (ie, granulomatous panniculitis) in up to 16.4% of cases. Appearance of hypopigmented macules is associated to vascular conjunctival fragility and these patients need a slightly longer time to reach a complete molecular response, but without additional changes in survival or relapse frequency. We have stablished a specific dermatologic diagnosis in all the cases and we have not found the previously published as maculopapular rashes. Hypopigmentation, the more frequent AE, was not perceived as a relevant side effect. Photosensitivity, in our cases, was not reported, although imatinib‐treated patients avoided sun‐exposure. In addition, we identified some nonpreviously described dermatologic conditions in patients taking TKI drugs, like granulomatous panniculitis tufted folliculitis or oral spindle cell lipoma. [ABSTRACT FROM AUTHOR]

Tyrosine kinase inhibitors are considered for use in patients with hepatocellular carcinoma (HCC) refractory to transarterial chemoembolization (TACE). The aim of the present retrospective study was to identify factors associated with progression-free survival (PFS) and to evaluate the indications for lenvatinib treatment in patients with intermediate-stage HCC refractory to TACE using a data-mining analysis. A total of 171 patients with intermediate-stage HCC refractory to TACE were included. All patients were classified into three groups according to their HCC treatment: Lenvatinib (n=45), sorafenib (n=53) and TACE (n=73) groups. PFS time was calculated using the Kaplan-Meier method and analyzed using a log-rank test. Factors associated with PFS time were evaluated using multivariate and decision-tree analyses. The median PFS time was 5.8, 3.2 and 2.4 months in the lenvatinib, sorafenib and TACE groups, respectively (P<0.001). In the Cox regression analysis, lenvatinib treatment and being within the up-to-seven criteria were identified as independent factors for PFS (lenvatinib, P<0.0001; within up-to-seven, P=0.001). The decision-tree analysis revealed that patients beyond the up-to-seven criteria, treated with lenvatinib and with albumin-bilirubin (ALBI) grade 1 had a longer PFS time (245.2±107.9 days) than patients beyond the up-to-seven criteria, treated with lenvatinib and with ALBI grade 2 (147.1±78.6 days). Additionally, lenvatinib was independently associated with longer PFS time in patients with intermediate-stage HCC refractory to TACE. Therefore, lenvatinib may be recommended for patients who have intermediate-stage HCC refractory to TACE, ALBI grade 1 and who are within the up-to-seven criteria. [ABSTRACT FROM AUTHOR]

Chronic myeloid leukemia (CML) is a clonal hematopoietic disorder caused by an acquired genetic defect in a pluripotent stem cell. A series of discoveries led to the recognition that the BCR-ABL protein, which results from a reciprocal translocation involving chromosomes 9 and 22, has a central role in the pathogenesis of chronic myelogenous leukemia. The BCR-ABL protein functions as a constitutively activated tyrosine kinase (TK) and this knowledge led to the development of imatinib (STI-571), a drug that specifically inhibits the BCR-ABL TK. Common side effects of imatinib are low blood counts, nausea and vomiting, edema (swelling of the face, feet, and hands), muscle cramps and bone pain, diarrhea, hemorrhage, skin rash, and fever. Headache, fatigue, joint pain, indigestion, and abdominal pain are occasionally seen, and liver toxicity is a rare complication. We here report a case of multiple small bowel perforations in a patient of Ph+ve chronic myeloid leukemia-chronic phase on imatinib. Bowel perforation is a known complication for targeted therapy agents like bevacizumab, sunitinib, and sorafenib, which act on vascular endothelial growth factor receptor but imatinib having no anti VEGF receptor activity leading to such complication is a mystery. Physician treating their patient with imatinib should be aware of this complication and should act accordingly. [ABSTRACT FROM AUTHOR]

Summary: This observational, prospective study assessed, in a daily clinical practice, the molecular response, safety, quality of life (QoL) and treatment adherence in 183 patients with chronic myeloid leukaemia in chronic phase (CML‐CP), receiving nilotinib as first‐line treatment. Premature study termination before 24 months of follow‐up occurred in 61 patients (33·3%), and was essentially due to nilotinib treatment discontinuation (n = 53; 29%), motivated by treatment intolerance (n = 29; 15·8%) and inefficacy (n = 19; 10·4%). After 24 months of treatment, 112/122 patients (91·8%) had a molecular assessment, 95·5% of whom achieved a major molecular response (MMR), 32·1% achieved uMR4, defined as an undetectable molecular disease with 4‐log molecular response sensitivity (≥10 000 ABL1 transcripts). The Morisky Green Levine Medication Adherence Scale was completed by 94/122 patients (77·0%), and 89·4% of these patients obtained a satisfactory level of treatment adherence, defined as a score ≥3. Patients' QoL was good at baseline and stable during the follow‐up period. The two most common nilotinib‐related adverse events (AEs) were pruritus (14·8%) and asthenia (13·7%). Seven patients (3·8%) experienced at least one cardiovascular ischaemic AE. This French nationwide cohort study provides relevant information in daily clinical practice indicating that nilotinib is a valuable first‐line treatment option for CML‐CP patients. [ABSTRACT FROM AUTHOR]

Currently, about 50% of patients with metastatic renal cell carcinoma (mRCC) receive a second-line therapy. Therefore, the choice at each subsequent treatment line remains an important issue. In this retrospective study, we sought to identify pretreatment clinical parameters that could predict the likelihood of a patient receiving a second-line therapy. One hundred and sixty-one mRCC patients who received targeted therapy were evaluated. Descriptive statistics, Kaplan–Meier overall survival (OS), Cox regression, and binary logistic regression models were used for data analysis. Second-line therapy was given to 105 patients (65%). Patients with grade 1 tumor received second-line therapy more frequently than those with grade 2/3 tumors (P = 0.03). Only tumor grade was significantly different between patients receiving, or not receiving, second-line treatment. Median OS was significantly superior in patients receiving second-line therapy (32 versus 14 months; P = 0.007; hazard ratio [HR], 1.75; P = 0.008), patients with grade 1 tumors (130 versus 29 months in G2/3 tumors; HR, 3.85; P = 0.009), and in patients without early tumor progression (41 versus 11 months; HR, 5.04; 95% confidence interval [CI], 3.06–8.31; P < 0.001). In binary logistic regression, we identified early progression to be significantly associated with a higher probability of not receiving a second-line therapy (HR, 2.50; 95% CI, 1.01–6.21; P = 0.048). This study hypothesizes that pretreatment grade and early progression are predictive parameters for the selection of patients for second-line therapy.