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Background: Leptomeningeal metastasis occurs in 5% of patients with prostate cancer and indicates a very poor prognosis. Case presentation: A 60-year-old Caucasian male patient diagnosed with metastatic castration-resistant prostate cancer with sclerotic bone metastases and soft tissue metastases underwent multiple courses of chemotherapy and hormone therapy. The diagnosis of prostate cancer is based on elevated prostate-specific antigen levels and tissue biopsy. He subsequently presented with expressive aphasia. Nonspecific, diffuse irregular dural/pachymeningeal thickening enhancement was noted on magnetic resonance imaging. Upon evaluation by neurology, electroencephalogram was negative for an epileptiform correlate. The workup included a lumbar puncture to rule out infectious etiology. The patient's neurological status stabilized, and he was discharged home with a plan for continued therapy with abiraterone and prednisone. Due to advanced malignancy, the patient enrolled in hospice and died 3 weeks after hospital discharge. Conclusions: Central nervous system metastasis occurs very rarely in prostate cancer. With the increase in life expectancy and advances in oncologic therapy for prostate cancer, physicians should be aware of and consider central nervous system metastasis in men aged 50 years and above. [ABSTRACT FROM AUTHOR]

AbstractIntroductionMaterials and methodsResultsConclusionUterine cervical cancer, predominantly caused by HPV, is the fourth most common malignancy in women, rarely leading to Central Nervous System (CNS) metastases with a poor prognosis. This study analyzes 137 cases, focusing on the clinical progression, treatment efficacy, and survival outcomes, highlighting the need for a multi-disciplinary approach to extend patient survival in the face of inconsistent evidence and management practices.This systematic review meticulously adhered to PRISMA guidelines, analysing all existing evidence on CNS metastasis from Uterine Cervical Cancer (UCC) through a comprehensive literature search up to August 2023. Articles were selected based on stringent criteria, including compliance with CARE and STROBE guidelines. The study employed rigorous statistical analyses, including the Shapiro-Wilk, T-Student, and ANOVA tests, alongside Kaplan-Meier curves, to evaluate variables like patient age, lesion location, and treatment efficacy.A review of 137 UCC patients revealed CNS metastases predominantly in the cerebral lobes, with headache and hemiparesis as common symptoms. The study found no significant survival difference across histopathological subtypes, but surgery, with or without WBRT, significantly improved outcomes. Age over 50 was associated with better survival, while the FIGO stage at diagnosis correlated with recurrence-free survival. Overall, surgical intervention on CNS lesions was the most significant factor for improved survival.This study reveals that CNS metastases from UCC are critical, with younger patients at worse prognosis. It suggests surgery plus WBRT or SRS as effective treatments and calls for targeted CNS screening and more research for better outcomes. [ABSTRACT FROM AUTHOR]

Abstract Background Leptomeningeal metastasis occurs in 5% of patients with prostate cancer and indicates a very poor prognosis. Case presentation A 60-year-old Caucasian male patient diagnosed with metastatic castration-resistant prostate cancer with sclerotic bone metastases and soft tissue metastases underwent multiple courses of chemotherapy and hormone therapy. The diagnosis of prostate cancer is based on elevated prostate-specific antigen levels and tissue biopsy. He subsequently presented with expressive aphasia. Nonspecific, diffuse irregular dural/pachymeningeal thickening enhancement was noted on magnetic resonance imaging. Upon evaluation by neurology, electroencephalogram was negative for an epileptiform correlate. The workup included a lumbar puncture to rule out infectious etiology. The patient’s neurological status stabilized, and he was discharged home with a plan for continued therapy with abiraterone and prednisone. Due to advanced malignancy, the patient enrolled in hospice and died 3 weeks after hospital discharge. Conclusions Central nervous system metastasis occurs very rarely in prostate cancer. With the increase in life expectancy and advances in oncologic therapy for prostate cancer, physicians should be aware of and consider central nervous system metastasis in men aged 50 years and above.

Leptomeningeal disease (LMD) refers to the infiltration of cancer cells into the leptomeningeal compartment. Leptomeninges are the two membranous layers, called the arachnoid membrane and pia mater. The diffuse nature of LMD poses a challenge to its effective diagnosis and successful management. Furthermore, the predominant phenotype; solid masses or freely floating cells, has altering implications on the effectiveness of drug delivery systems. The standard of care is the intrathecal delivery of chemotherapy drugs but it is associated with increased instances of treatment-related complications, low patient compliance, and suboptimal drug distribution. An alternative involves administering the drugs systemically, after which they must traverse fluid barriers to arrive at their destination within the leptomeningeal space. However, this route is known to cause off-target effects as well as produce subtherapeutic drug concentrations at the target site within the central nervous system. The development of new drug delivery systems such as liposomal cytarabine has improved drug delivery in leptomeningeal metastatic disease, but much still needs to be done to effectively target this challenging condition. In this review, we discuss about the anatomy of leptomeninges relevant for drug penetration, the conventional and advanced drug delivery methods for LMD. We also discuss the future directions being set by different clinical trials.

Simple Summary: The brain is a common site of metastases from cancer. Approximately 10% of all patients develop brain metastasis during their illness. Brain metastasis used to be frequently associated with significant morbidity and short survival, measured in months. However, with advances in treatment, a significant number of patients can now expect to live for several years, with a better quality of life. We reviewed the literature published over the last 50 years, to identify patterns of care of patients diagnosed with brain metastases. Techniques such as whole brain radiotherapy are used sparingly only. A more in-depth knowledge about the cancers, and advances in radiotherapy techniques, such as focused radiation to the site of metastases, and targeted therapy which crosses the barrier between the blood and the brain have revolutionized the care, especially in patients with lung cancer, breast cancer, and melanoma. This type of literature review not only helps to summarize the evolution of clinical practice, but also helps to identify the current trends for researchers. A systematic review of the published literature was conducted to analyze the management evolution of brain metastases from different cancers. Using the keywords "brain metastasis", "brain metastases", "CNS metastasis", "CNS metastases", "phase III" AND/OR "Randomized Controlled Trial" (RCT), relevant articles were searched for on the SCOPUS database. A total of 1986 articles were retrieved, published over a 45-year period (1977–2022). Relevant articles were defined as clinical studies describing the treatment or prevention of brain metastases from any cancer. Articles on imaging, quality of life, cognitive impairment after treatment, or primary brain tumors were excluded. After a secondary analysis, reviewing the abstracts and/or full texts, 724 articles were found to be relevant. Publications significantly increased in the last 10 years. A total of 252 articles (34.8%) were published in 12 core journals, receiving 50% of the citations. The number of publications in Frontiers in Oncology, BMC Cancer, and Radiotherapy and Oncology have increased considerably over the last few years. There were 111 randomized controlled trials, 128 review articles, and 63 meta-analyses. Most randomized trials reported on brain metastases management from unselected tumors (49), lung cancer (47), or breast cancer (11). In the last 5 years (2017 to 2022), management of brain metastasis has moved on from WBRT, the use of chemotherapy, and radio-sensitization to three directions. First, Radiosurgery or Radiotherapy (SRS/SRT), or hippocampal-sparing WBRT is employed to reduce radiation toxicity. Second, it has moved to the use of novel agents, such as tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI) and third, to the use of molecularly directed therapy such as TKIs, in asymptomatic low volume metastasis, obviating the need for WBRT. [ABSTRACT FROM AUTHOR]

Introduction: Osimertinib may be effective in treating central nervous system (CNS) metastasis, but its efficacy in treating radiation therapy (RT)-naive metastasis is unclear. The OCEAN study assessed the efficacy of osimertinib against RT-naive CNS metastasis in patients previously treated (T790M cohort) and untreated patients (first-line cohort) with EGFR mutation. Here, we report the results of the first-line cohort. Methods: Previously untreated patients with RT-naive CNS metastasis and EGFR mutation-positive NSCLC were treated with osimertinib. The brain metastasis response rate (BMRR), progression-free survival (PFS), and overall survival in the first-line cohort were secondary end points. Results: A total of 26 patients were enrolled in the study between September 2019 and July 2020. The median age was 72.0 years with 80.8% female. There were 20 patients who had multiple CNS metastases. BMRR assessed by PAREXEL criteria was 76.9% (90% confidence interval [CI]: 63.3%–90.5%), BMRR assessed by Response Evaluation Criteria in Solid Tumors was 76.9% (95% CI: 54.0%–99.8%), and median PFS of CNS metastasis was 22.0 months (95% CI: 9.7 mo–not reached). The overall response rate was 64.0% (95% CI: 45.2%–82.8%), median PFS was 11.5 months (95% CI: 6.9 mo–not reached), and median survival time was 23.7 months (95% CI: 16.5 mo–not reached). Paronychia and increased creatinine level were the most frequent nonhematological toxicities observed in 13 patients (50%). Grade three and higher adverse events were less than 10%, and there were no treatment-related deaths. Pneumonitis was observed in five patients (19.2%). Conclusions: These results suggest that osimertinib is effective in untreated patients with RT-naive asymptomatic CNS metastasis in a clinical practice first-line setting. Trial registration: UMIN identifier: UMIN000024218. jRCT identifier: jRCTs071180017.

Summary: Background: Central nervous system (CNS) metastases is inevitable for epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). AZD3759 is a novel EGFR-TKI with impressive CNS penetration. Methods: We initiated a phase 2, multi-center, umbrella trial (CTONG1702, NCT03574402). The eighth arm assessed the efficacy and safety of AZD3759 in untreated EGFR-mutated NSCLC with CNS metastases. The primary objective was the objective response rate (ORR). Simon’s minimax two-stage design was used to calculate the sample size. Dose optimal selection was performed using 200- and 300-mg bid cohorts. Findings: Between Oct 18, 2018 and Sep 14, 2020, 30 patients received AZD3759 at 200 mg (n = 15) or 300 mg (n = 15) bid. At data cutoff (Dec 31, 2022), median follow-up was 35.4 months. The primary endpoint was reached, with a confirmed ORR of 70% (21/30) (200 mg, 80%; 300 mg, 60%). The median progression-free survival was 12.9 months (200 mg, 15.8 months; 300 mg, 10.7 months). Grade 3 or 4 treatment-related adverse events occurred in 73% (22/30) of the patients (200 mg: 60%; 300 mg: 87%). 59% (10/17) of the patients developed a T790M mutation at disease progression. The median overall survival was 33.7 months, and 34.1 months and 25.3 months in patient treated with or without osimertinib in a later-line setting, respectively. Interpretation: AZD3759 showed promising efficacy and tolerable safety as a first-line therapy in EGFR-mutated NSCLC with CNS metastases. The 200-mg bid cohort had better clinical outcomes. Sequential use of AZD3759 and third-generation EGFR-TKIs represents a new option. Funding: Chinese Thoracic Oncology Group (CTONG).

Background: Pancreatoblastoma is a malignant neoplasm of the pancreas, occurring usually in children and rarely in adults. Treatment consists of surgery with a variable combination of adjuvant therapies. Liver metastases are common, whereas brain diffusion is exceptionally rare., Observations: The authors report the case of a 42-year-old man with a 16-year history of metastatic pancreatoblastoma, previously treated with surgery, chemotherapy, and radiotherapy, demonstrating a partial response. He presented with headache and dizziness, and brain magnetic resonance imaging (MRI) showed a cerebellar lesion. A craniotomy was performed with complete tumor removal, and the postoperative course was uneventful. Brain MRI showed gross-total resection of the lesion, and the patient was discharged with an improvement of the preoperative symptoms. Histopathological analysis confirmed the diagnosis of metastasis from pancreatoblastoma. The patient received adjuvant stereotactic radiotherapy and showed further clinical improvement at the last follow-up., Lessons: Brain metastases from pancreatoblastoma are exceptionally rare and poorly described in the literature. There is no standard therapy for this condition; hence, patients usually undergo treatments similar to those for other central nervous system metastases. All the described patients have had good clinical outcomes yet short-term follow-ups; therefore, further investigations are needed to better understand the best treatments for this condition. https://thejns.org/doi/10.3171/CASE23764.

In-depth insight into the genomic features of the uncommon EGFR p.L861Q mutant NSCLC is scarcely performed, and no consensus on the preferred treatment strategy has been established. Moreover, the therapeutic implications of EGFR-TKI stratified by clinical and molecular features remained largely unknown. A multi-center NGS database comprising 44,993 NSCLC samples was utilized for the genomic landscape profiling of EGFR p.L861Q mutation. Furthermore, a real-world cohort of 207 patients harboring EGFR p.L861Q mutation with complete treatment history was curated for comprehensive clinical analysis. L861Q is prevalent in approximately 2.1% of EGFR-mutated NSCLC and is typically co-mutated with EGFR p.G719X on the same allele (20%) and exhibits co-occurrent EGFR copy number amplification in approximately 17% of cases. In the first-line setting, afatinib and third-generation EGFR-TKI have been shown to yield notably superior treatment outcomes compared to first-generation EGFR-TKI (1st vs.2nd vs.3rd generations, ORR: 15.8% vs.56.5% vs.46.7%, P =0.01; median PFS: 6.4 vs.13.5 vs.15.1 months, P =0.002). This finding consistently held for patients without CNS metastases (1st vs.2nd vs.3rd generations, median PFS:6.0 vs.18.2 vs.14.1 months, P =0.003). In contrast, third-generation EGFR-TKI demonstrated superior efficacy compared to afatinib or first-generation TKI among the subgroup of brain metastasis (Pooled 1st/2nd-generation vs.3rd-generation TKI, brain ORR:0.00% vs.33.33%; median PFS:7.9 vs.19.3 months, P =0.021). Additional concurrent EGFR mutations or EGFR amplification did not yield a discernible impact on the efficacy of EGFR-TKI. The present study comprehensively elucidates the molecular features of EGFR p.L861Q mutation and underscores the optimal therapeutic choice of first-line EGFR-TKI based on brain metastatic status. [ABSTRACT FROM AUTHOR]

• EGFR mutation was not an independent prognostic factor for postoperative recurrence. • EGFR-mutated LUADs did not have a clinical course with a higher incidence of CNS metastasis. • The peak hazards for recurrence of CNS metastasis occur at a later time point in the EGFR mutant group compared with the EGFR wild type group. For NSCLC patients with complete resection, the prognostic role of EGFR mutation for recurrence, especially for CNS metastasis, is still controversial. In this study, we aimed to identify the characteristics of the recurrence pattern of lung adenocarcinoma based on EGFR mutation status. Overall, 888 patients with completely surgically resected LUAD who underwent EGFR mutation status analysis from two Chinese institutions were included. Sites and data of initial recurrence were recorded. The recurrence patterns according to EGFR mutation status were estimated by Kaplan-Meier analysis, and hazard rate curves were generated. 245 (27.6%) of 888 patients suffered from recurrence. Before and after PSM, there were no statistically significant differences between the EGFR mutation and EGFR WT groups for all types of recurrence, including CNS metastasis. Multivariable Cox analysis revealed that EGFR status was not a risk factor for all types of recurrence, including CNS metastasis (HR 0.88, 95% CI 0.54–1.46, p = 0.632). The CNS metastasis hazard curve in the EGFR mutation group showed that the first peak occurred at approximately 24–26 months after surgery, which was 10 months later than that in the EGFR WT group. In addition, the second peak time in the EGFR mutation group was approximately 2 years later than that in the EGFR WT group. EGFR mutation was not an independent prognostic factor for postoperative recurrence. EGFR-mutated LUADs did not have a clinical course with a higher incidence of CNS metastasis. However, the peak hazards for recurrence of CNS metastasis occur at a later time point in the EGFR mutant group compared with the EGFR wild type group. [ABSTRACT FROM AUTHOR]

We present an unusual case of metastatic melanoma in a young patient with imaging appearance resembling neurofibromatosis. A 36-year-old-man with a history of cervical radiculopathy presented with cauda equina syndrome. An MRI was performed for further evaluation demonstrating multiple intradural, extramedullary enhancing lesions in the thoracic and lumbar spine, as well as extra-axial enhancing lesions with involvement of the lateral ventricles and posterior fossa. Bilateral pulmonary masses were found on chest CT. Lung lesions were biopsied and positive for metastatic melanoma. Melanoma is the third most common primary neoplasm to produce brain metastasis and should be considered on the differential as a cause of newly detected intracranial and intraspinal masses in young patients.

Leptomeningeal disease (LMD) refers to the infiltration of cancer cells into the leptomeningeal compartment. Leptomeninges are the two membranous layers, called the arachnoid membrane and pia mater. The diffuse nature of LMD poses a challenge to its effective diagnosis and successful management. Furthermore, the predominant phenotype; solid masses or freely floating cells, has altering implications on the effectiveness of drug delivery systems. The standard of care is the intrathecal delivery of chemotherapy drugs but it is associated with increased instances of treatment-related complications, low patient compliance, and suboptimal drug distribution. An alternative involves administering the drugs systemically, after which they must traverse fluid barriers to arrive at their destination within the leptomeningeal space. However, this route is known to cause off-target effects as well as produce subtherapeutic drug concentrations at the target site within the central nervous system. The development of new drug delivery systems such as liposomal cytarabine has improved drug delivery in leptomeningeal metastatic disease, but much still needs to be done to effectively target this challenging condition. In this review, we discuss about the anatomy of leptomeninges relevant for drug penetration, the conventional and advanced drug delivery methods for LMD. We also discuss the future directions being set by different clinical trials.

Abstract Background Patients with activating epidermal growth factor receptor (EGFR) mutations are highly responsive to EGFR-tyrosine kinase inhibitors (TKIs). However, it has been reported that approximately 15–30% of patients treated with EGFR-TKIs experience central nervous system (CNS) progression, and patients with EGFR mutations exhibit a higher incidence of brain metastasis than those without such mutations. The efficacy of osimertinib for treating CNS metastasis has been reported, but its efficacy for CNS metastasis in radiotherapy-naïve patients is unclear. Methods In the present prospective two-cohort phase II trial, 65 patients (T790M cohort, 40 patients; first-line cohort, 25 patients) with radiotherapy-naïve CNS metastasis of EGFR mutation-positive non-small cell lung cancer (NSCLC) will be included. Patients will be treated once-daily with osimertinib 80 mg. The primary endpoint is the response rate of brain metastasis as assessed using the PAREXEL criteria. Key secondary endpoints are progression-free survival and the response rate of brain metastasis as assessed using the RECIST criteria. We will exploratorily analyze the relationships of the blood concentration of osimertinib with its efficacy against brain metastasis of NSCLC and the accumulation of osimertinib in cerebrospinal fluid and evaluate tumor-derived DNA from plasma specimens for mutations in EGFR and other genes. Recruitment, which in October 2016, is ongoing. Discussion Although previous reports revealed the efficacy of osimertinib for CNS metastasis, these reports only involved subgroup analysis, and the efficacy of osimertinib for patients with previously untreated CNS metastasis remains unclear. The OCEAN study is the only trial of osimertinib for patients with untreated brain metastasis of NSCLC. This study should provide novel data about osimertinib. If the results of the OCEAN study are positive, then avoidance of radiotherapy will be recommended to patients harboring EGFR mutations and brain metastasis. Trial registration UMIN identifier: UMIN000024218 (date of initial registration: 29 September 2016). jRCT identifier: jRCTs071180017 (date of initial registration: 13 February 2019).

Abstract Brain metastasis (BM) predominantly occurs in triple-negative (TN) and epidermal growth factor 2 (HER2)-positive breast cancer (BC) patients, and currently, there is an unmet need for the treatment of these patients. BM is a complex process that is regulated by the formation of a metastatic niche. A better understanding of the brain metastatic processes and the crosstalk between cancer cells and brain microenvironment is essential for designing a novel therapeutic approach. In this context, the aberrant expression of miRNA has been shown to be associated with BM. These non-coding RNAs/miRNAs regulate metastasis through modulating the formation of a metastatic niche and metabolic reprogramming via regulation of their target genes. However, the role of miRNA in breast cancer brain metastasis (BCBM) is poorly explored. Thus, identification and understanding of miRNAs in the pathobiology of BCBM may identify a novel candidate miRNA for the early diagnosis and prevention of this devastating process. In this review, we focus on understanding the role of candidate miRNAs in the regulation of BC brain metastatic processes as well as designing novel miRNA-based therapeutic strategies for BCBM.

Despite the fact that prostate cancer is the most prevalent cancer in men, metastases to the central nervous system including leptomeningeal involvement by prostate carcinoma is a rare event. The prognosis of metastatic prostate cancer is very poor due to lack of CNS penetrating therapeutic agents. [ABSTRACT FROM AUTHOR]

Abstract Despite the fact that prostate cancer is the most prevalent cancer in men, metastases to the central nervous system including leptomeningeal involvement by prostate carcinoma is a rare event. The prognosis of metastatic prostate cancer is very poor due to lack of CNS penetrating therapeutic agents.

Central nervous system (CNS) metastases from epithelial ovarian cancer (EOC) are rare. We investigated the clinico-pathological prognostic factors of patients with CNS metastases from EOC and compared the outcomes of various treatment modalities. We retrospectively reviewed the records of patients with CNS metastases from EOC between 2000 and 2020. Information on the clinical and pathological characteristics, treatment, and outcomes of these patients was retrieved from Samsung Medical Center and National Taiwan University Hospital. A total of 94 patients with CNS metastases were identified among 6,300 cases of EOC, resulting in an incidence of 1.49%. Serous histological type [hazard ratio (HR): 0.49 (95% confidence interval [CI] 0.25-0.95), p=0.03], progressive disease [HR: 2.29 (95% CI 1.16-4.54), p=0.01], CNS involvement in first disease relapse [HR: 0.36 (95% CI 0.18-0.70), p=0.002], and gamma knife radiosurgery (GKS)-based combination treatment for EOC patients with CNS lesions [HR: 0.59 (95% CI 0.44-0.79), p

Central nervous system (CNS) metastases from epithelial ovarian cancer (EOC) are rare. We investigated the clinico-pathological prognostic factors of patients with CNS metastases from EOC and compared the outcomes of various treatment modalities. We retrospectively reviewed the records of patients with CNS metastases from EOC between 2000 and 2020. Information on the clinical and pathological characteristics, treatment, and outcomes of these patients was retrieved from Samsung Medical Center and National Taiwan University Hospital. A total of 94 patients with CNS metastases were identified among 6,300 cases of EOC, resulting in an incidence of 1.49%. Serous histological type [hazard ratio (HR): 0.49 (95% confidence interval [CI] 0.25-0.95), p =0.03], progressive disease [HR: 2.29 (95% CI 1.16-4.54), p =0.01], CNS involvement in first disease relapse [HR: 0.36 (95% CI 0.18-0.70), p =0.002], and gamma knife radiosurgery (GKS)-based combination treatment for EOC patients with CNS lesions [HR: 0.59 (95% CI 0.44-0.79), p <0.001] significantly impacted survival after diagnosis of CNS metastases. In a subgroup analysis, superior survival was observed in patients with CNS involvement not in first tumor recurrence who underwent GKS-based combination therapeutic regimens. The survival benefit of GKS-based treatment was not significant in patients with CNS involvement in first disease relapse, but a trend for longer survival was still observed. In conclusion, GKS-based combination treatment can be considered for the treatment of EOC patients with CNS metastases. The patients with CNS involvement not in first disease relapse could significantly benefit from GKS-based combination strategies. [ABSTRACT FROM AUTHOR]

Central nervous system (CNS) metastasis from prostate cancer (PCA) is a rare event, but one with significant prognostic impact. We retrospectively identified 6596 cases of PCA, with 29 confirmed cases of CNS metastases from PCA. The incidence of CNS metastases in PCA is considerably increased in patients who receive medical therapy beyond first-line androgen deprivation therapy. Introduction: Central nervous system (CNS) metastasis from prostate cancer (PCA) is a rare event, but one with significant prognostic impact for those affected. There are limited data on its impact in contemporary cohorts treated with modern agents. Patients and Methods: A retrospective institutional review was performed to characterize the occurrence/outcome of PCA CNS metastasis on all cases of PCA from 2011 to 2017. A manual chart review was performed to confirm PCA CNS metastases in all cases identified through a diagnostic code screening of the health data. Results: A total of 6596 cases of PCA were identified, with 29 (20 dural and 9 intraparenchymal) confirmed cases of CNS metastases from PCA. The median survival from the time of diagnosis of CNS metastasis was 2.6 months (95% confidence interval, 2.04-10.78 months) and 5.41 months (95% confidence interval, 3.03 months to not reached) for dural and parenchymal metastases, respectively. Among those who developed CNS metastases, approximately 79% of patients had prior exposure to abiraterone and/or enzalutamide, of whom 50% had ≥ 6 months of exposure. Four (0.07%) of the 5841 patients developed CNS metastases prior to the initiation of therapy or on androgen deprivation therapy alone. In contrast, 24 (8.6%) of the 279 patients with 2 or more lines of medical therapy developed CNS metastases. Conclusions: Our analysis highlights the continued poor prognosis of parenchymal and dural CNS metastases from PCA. CNS metastases in PCA remain a rare event with a 0.4% incidence in this series, but this incidence is considerably increased in patients who receive medical therapy beyond first-line androgen deprivation therapy. [ABSTRACT FROM AUTHOR]

Purpose: Leptomeningeal carcinomatosis (LMC) is a form of CNS cancer metastasis with severe morbidity. Intrathecal chemotherapy (ITC) administration through an implanted ventricular catheter reservoir (IVCR) is often utilized. Additionally, a nuclear imaging flow study can be performed prior to ITC administration to assess cerebrospinal fluid (CSF) flow. The clinical impact of a CSF flow study is unclear. Methods: A retrospective chart review identified 31 patients with LMC that underwent IVCR placement between 2011 and 2019. Data extracted included patient demographics, nuclear imaging flow study, surgical complications, ITC toxicities and outcomes. Results: Potential drug-induced neurologic toxicities (headache, nausea/vomiting, altered mental status, etc.) were noted in (n = 4/16) 25% of patients who underwent a flow study prior to initiation of ITC, compared to (n = 1/15) 6.6% of patients who did not undergo a flow study. Median overall survival (OS) was 4.0 and 32.8 months for the patients that underwent a flow study versus patients who did not, respectively (p < 0.01). The mean interval from IVCR implantation to initiation of ITC was 15.2 ± 8.5 days and 3.3 ± 3.0 days in patients who underwent CSF flow study and patients that did not, respectively (p < 0.0001). Conclusions: A flow study can provide information regarding CSF flow dynamics prior to initiation of ITC; however this might delay initiation of ITC which may negatively impact OS. Additionally, in our study patients that underwent a flow study had more ITC induced drug toxicity events compared to those that did not. Further studies are needed to clarify the role of CSF flow study in these patients. [ABSTRACT FROM AUTHOR]

To our knowledge, we report the first case of a cholangiocarcinoma brain metastasis successfully treated with magnetic resonance imaging (MRI)-guided laser interstitial thermal therapy. In 2017, a 71-year-old man was diagnosed with unresectable intrahepatic cholangiocarcinoma. In August 2018, a brain MRI scan was performed after a transient episode of altered mental status and revealed a subcentimeter enhancing lesion in the deep white matter of the right cerebellum. Due to lack of symptoms and the small size of the lesion, it was initially observed. However, a follow-up MRI scan at 2.5 months demonstrated increased lesion size with worsening perilesional edema. Given the rarity of cholangiocarcinoma brain metastases and the deep location, the patient underwent stereotactic needle biopsy to confirm the diagnosis followed by laser ablation as a primary treatment for the metastasis. The patient tolerated the surgery well with no complications, and the postoperative course was uneventful. At 16 months postablation, there has been no recurrence or disease progression. Although prognosis for these tumors is poor, our result suggests that laser ablation can be an effective treatment for this rare entity and is a representative example of the expanding indications for laser interstitial thermal therapy. [ABSTRACT FROM AUTHOR]

Background: Patients with activating epidermal growth factor receptor (EGFR) mutations are highly responsive to EGFR-tyrosine kinase inhibitors (TKIs). However, it has been reported that approximately 15-30% of patients treated with EGFR-TKIs experience central nervous system (CNS) progression, and patients with EGFR mutations exhibit a higher incidence of brain metastasis than those without such mutations. The efficacy of osimertinib for treating CNS metastasis has been reported, but its efficacy for CNS metastasis in radiotherapy-naïve patients is unclear.Methods: In the present prospective two-cohort phase II trial, 65 patients (T790M cohort, 40 patients; first-line cohort, 25 patients) with radiotherapy-naïve CNS metastasis of EGFR mutation-positive non-small cell lung cancer (NSCLC) will be included. Patients will be treated once-daily with osimertinib 80 mg. The primary endpoint is the response rate of brain metastasis as assessed using the PAREXEL criteria. Key secondary endpoints are progression-free survival and the response rate of brain metastasis as assessed using the RECIST criteria. We will exploratorily analyze the relationships of the blood concentration of osimertinib with its efficacy against brain metastasis of NSCLC and the accumulation of osimertinib in cerebrospinal fluid and evaluate tumor-derived DNA from plasma specimens for mutations in EGFR and other genes. Recruitment, which in October 2016, is ongoing.Discussion: Although previous reports revealed the efficacy of osimertinib for CNS metastasis, these reports only involved subgroup analysis, and the efficacy of osimertinib for patients with previously untreated CNS metastasis remains unclear. The OCEAN study is the only trial of osimertinib for patients with untreated brain metastasis of NSCLC. This study should provide novel data about osimertinib. If the results of the OCEAN study are positive, then avoidance of radiotherapy will be recommended to patients harboring EGFR mutations and brain metastasis.Trial Registration: UMIN identifier: UMIN000024218 (date of initial registration: 29 September 2016). jRCT identifier: jRCTs071180017 (date of initial registration: 13 February 2019). [ABSTRACT FROM AUTHOR]

Brain metastasis (BM) predominantly occurs in triple-negative (TN) and epidermal growth factor 2 (HER2)-positive breast cancer (BC) patients, and currently, there is an unmet need for the treatment of these patients. BM is a complex process that is regulated by the formation of a metastatic niche. A better understanding of the brain metastatic processes and the crosstalk between cancer cells and brain microenvironment is essential for designing a novel therapeutic approach. In this context, the aberrant expression of miRNA has been shown to be associated with BM. These non-coding RNAs/miRNAs regulate metastasis through modulating the formation of a metastatic niche and metabolic reprogramming via regulation of their target genes. However, the role of miRNA in breast cancer brain metastasis (BCBM) is poorly explored. Thus, identification and understanding of miRNAs in the pathobiology of BCBM may identify a novel candidate miRNA for the early diagnosis and prevention of this devastating process. In this review, we focus on understanding the role of candidate miRNAs in the regulation of BC brain metastatic processes as well as designing novel miRNA-based therapeutic strategies for BCBM. [ABSTRACT FROM AUTHOR]

Purpose of Review: This review will discuss recent important trials for the treatment of HER2-positive breast cancer, emphasize ongoing areas of development, and highlight areas of unmet need. Recent Findings: Advances for early-stage treatment have been driven by key clinical trials with pertuzumab, neratinib, and TDM-1. In the adjuvant setting, dual HER2 targeting with trastuzumab and pertuzumab has demonstrated modest improvement in disease-free survival. Neratinib also showed modest benefit in the extended adjuvant setting after prior trastuzumab. Finally, for patients who did not achieve pathologic complete response to neoadjuvant therapy, adjuvant therapy with TDM-1 showed significant disease-free survival benefit over trastuzumab. In advanced disease, neratinib appears to have activity beyond standard second line treatment. Promising compounds with early-phase data reviewed are tucatinib, margetuximab, and antibody-drug complexes. Immunotherapy in HER2-positive disease also has early-phase data. Endocrine therapy in combination with CDK4/6 inhibition and HER2-targeted therapy is in evaluation. Two areas of unmet need include CNS disease and disease treatment in the elderly population. Summary: In the wake of recent practice changing clinical trials, HER2-directed therapy is rapidly evolving. Future advances in therapy are anticipated with ongoing studies. [ABSTRACT FROM AUTHOR]

Despite the important evolution of immunotherapeutic agents, brain tumors remain, in general, refractory to immune therapeutics. Recent discoveries have revealed that the glioma microenvironment includes a wide variety of immune cells in various states that play an important role in the process of tumorigenesis. Anti-tumor immune activity may be occurring or induced in immunogenic hot spots or at the invasive edge of central nervous system (CNS) tumors. Understanding the complex heterogeneity of the immune microenvironment in gliomas will likely be the key to unlocking the full potential of immunotherapeutic strategies. An essential consideration will be the induction of immunological effector responses in the setting of the numerous aspects of immunosuppression and evasion. As such, immune therapeutic combinations are a fundamental objective for clinical studies in gliomas. Through immune profiling conducted on immune competent murine models of glioma and ex vivo human glioma tissue, we will discuss how the frequency, distribution of immune cells within the microenvironment, and immune modulatory processes, may be therapeutically modulated to lead to clinical benefits.

Limited data are available on nivolumab in challenging subgroups with advanced melanoma. We report outcomes of nivolumab after prior ipilimumab in patients who are typically excluded from clinical trials. In this phase II, single-arm, open-label, multicentre study (CheckMate 172), patients with advanced melanoma who progressed on or after ipilimumab received nivolumab 3 mg/kg, every 2 weeks for up to 2 years. The primary objective was incidence of grade ≥3, treatment-related select adverse events (AEs). At a minimum follow-up of 18 months, grade ≥3 treatment-related select AEs with the most variation across subgroups were diarrhoea and colitis (1.1% [n = 11] and 0.3% [n = 3] for the total population [n = 1008]; 0.6% [n = 1] and 0.6% [n = 1] for patients with an asymptomatic central nervous system [CNS] metastasis [n = 165; 16.4%]; 4.5% [n = 3] and 3.0% [n = 2] for patients with an Eastern Cooperative Oncology Group performance status [ECOG PS] of 2 [n = 66; 6.5%]; 2.4% [n = 2] and 0% for those who experienced a grade 3/4 immune-related AE [irAE] with prior ipilimumab [n = 84; 8.3%]; and 0% and 0% for autoimmune disease [n = 25; 2.5%], respectively). Median overall survival was 21.4 months in the total population and was 11.6, 2.4, 21.5, and 18.6 months in patients with a CNS metastasis, ECOG PS 2, a grade 3/4 irAE with prior ipilimumab, and autoimmune disease, respectively. In this large, phase II clinical trial of patients with advanced melanoma who progressed on or after ipilimumab, nivolumab demonstrated a safety profile consistent with that of prior clinical trials. ClinicalTrials.gov ID: NCT02156804. • The safety profile of nivolumab was consistent with that observed in prior studies. • Adverse events with the most variation across subgroups were diarrhoea and colitis. • Median overall survival was lowest in patients with poor performance status. [ABSTRACT FROM AUTHOR]

aimed to identify the biomarkers in cerebrospinal fluid (CSF) that facilitate the diagnosis of lymphomas with central nervous system (CNS) involvement. Methods: Four cases of non-Hodgkin's lymphoma (NHL) patients with/without CNS involvement were enrolled respectively, and non-CNS tumor patients (n=3) were selected to be the controls. Lab biomarkers, cytokines, and tight junction proteins (TJs) in CSF and serum were measured. Results: When comparing the CNS to non-CNS group, cytokine including MMP-9 (15.24 vs 0.36 ng/mL), CCL-2 (1922.04 vs 490.68 pg/mL), and sVCAM-1 (61.36 vs 9.00 pg/mL), TJs including OCLN (6.68 vs 2.59 pg/mL), and ZO-1 (710.04 vs 182.98 pg/mL) in CSF were significantly higher in lymphomas patients with CNS involvement than those without CNS involvement. However, serum biomarkers were not significantly elevated. Contrary to the major findings, all conventional biomarkers and MRI results showed no significant change. Conclusion: CSF biomarkers affecting BBB disruption are valuable in mirroring the risk of lymphoma CNS metastasis. Further study with a larger sample size is needed to verify these biomarkers in predicting lymphoma CNS involvement. [ABSTRACT FROM AUTHOR]

Highlights • Incidence of CNS metastasis in ROS1+NSCLC varies from studies. • CNS metastasis is a major mode of progression while on long term treatment. • ROS1 fusion variant CD74-ROS1 may have increased predilection for CNS metastasis. • ROS1 TKIs has varying degree of efficacy in CNS metastasis in ROS1+NSCLC. • Better appreciation of treatment outcome of CNS metastasis is urgently needed. Abstract The incidence of CNS metastasis at the time of diagnosis of and during the natural disease history of advanced ROS1+ NSCLC is largely unknown. It is generally believed that the incidence of CNS metastasis is lower in ROS1+ NSCLC than ALK+ NSCLC as ROS1 fusions are regarded as a less powerful driver mutation than ALK fusions in ALK+ NSCLC based on the longer progression-free survival of ROS1+ NSCLC patients than ALK+ NSCLC patients treated with crizotinib. Here we reviewed the incidence of CNS metastasis from prospective clinical trials and retrospective case series from primarily single institution. The incidence of CNS metastasis in ROS1+ NSCLC patients at the time of diagnosis ranged from 20% to mid 30% while the incidence of CNS metastasis can be as high as in the mid 50% range post-crizotinib indicating CNS metastasis is indeed a major morbidity for ROS1+ NSCLC patients throughout the course of treatment. To date 22 fusion partners in ROS1+ NSCLC have been reported in the literature and one report has indicated CD74-ROS1 fusion variant increased the predilection for CNS metastasis than non-CD74-ROS1 fusion variants. We reviewed reported intra-cranial activity of all preclinical and clinical development stage ROS1 TKIs and pemetrexed-based chemotherapy in ROS1+ NSCLC patients. While several ROS1 TKIs (i.e. entrectinib, cabozantinib, lorlatinib, repotrectinib) have reported intra-cranial response rates, there is no literature reporting on the intra-cranial activity of pemetrexed-based chemotherapy in ROS1+ NSCLC patients. In summary, better understanding the high incidence of CNS metastasis in ROS1+ NSCLC patients, how certain ROS1 fusion variant may increase the incidence of CNS metastasis, and any intra-cranial efficacy data of pemetrexed in ROS1+ NSCLC are all urgently needed. [ABSTRACT FROM AUTHOR]

Infiltration of acute lymphoblastic leukemia (ALL) blasts into the CNS remains as a major clinical problem, with high risk for chemotherapy‐resistant relapse and treatment‐related morbidity. Despite the common inclusion of CNS prophylaxis treatments in therapy regimens, there are significant gaps in understanding the mechanisms that mediate leukemia cell entry into the CNS as well as roles for resident cells in the brain. In this study, we employ a xenograft model of human B cell precursor (BCP)‐ALL in immunocompromised mice. This model system recapitulates key pathological characteristics of leptomeningeal involvement seen in patients and provides insights into rare cases that involve parenchymal invasion. We examine the infiltration of engrafted leukemia blasts into brains of recipient mice and provide evidence that the interaction between blasts and brain resident cells causes aberrant activation of host cells in the brain microenvironment. BCP‐ALL blasts also release multiple cytokines and exosomes containing IL‐15 that bind and are internalized by astrocytes and brain vessel endothelial cells. Leukemic invasion is linked to production of VEGF‐AA by astrocytes and disruption of the blood‐brain‐barrier (BBB) integrity. Knockdown of either IL‐15 or IL‐15Rα in the NALM6 cell line decreases CNS infiltration in engrafted mice. These results provide important insights into the multiple mechanisms by which lymphoblasts modulate the brain microenvironment to breach the BBB for metastatic invasion. CNS infiltration of leukemia through the modulation of the blood‐brain barrier by blast‐derived exosomes. [ABSTRACT FROM AUTHOR]

While the CNS has long been viewed as an immune-privileged environment, a paradigm shift in neuro-immunology has elevated the role of systemic immunotherapy for the treatment of metastatic disease. Increasing knowledge regarding the presence of a CNS lymphatic system and the physical and biochemical alteration of the blood brain barrier (BBB) by the tumor microenvironment suggests immune cell trafficking in and out of the CNS is possible. Emerging clinical data suggest immune checkpoint inhibitors (ICIs) can stimulate T cells peripherally to in turn have anti-tumor effects in the CNS. For example, anti-programmed cell death-1 (PD-1) monotherapy with pembrolizumab has shown intracranial response rates of 20–30% in patients with melanoma or non-small cell lung cancer (NSCLC) brain metastases. The combination of nivolumab and ipilimumab [anti-PD-1 and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)] showed an intracranial response rate of 55% in patients with melanoma brain metastases. More data are needed to confirm these response rates and to determine mechanisms of efficacy and resistance. While local therapies such as stereotactic radiosurgery (SRS), whole-brain radiation therapy (WBRT), and surgery remain current mainstays, ICIS offer potential decreased neurotoxicity. This review summarizes the biological rationale for systemic immunotherapy to treat CNS metastatic disease, existing clinical data on ICIs in this setting and ongoing clinical trials exploring areas of unmet need.

Introduction: Osimertinib may be effective in treating central nervous system (CNS) metastasis, but its efficacy in treating radiation therapy (RT)-naive metastasis is unclear. The OCEAN study assessed the efficacy of osimertinib against RT-naive CNS metastasis in patients previously treated (T790M cohort) and untreated patients (first-line cohort) with EGFR mutation. Here, we report the results of the first-line cohort., Methods: Previously untreated patients with RT-naive CNS metastasis and EGFR mutation-positive NSCLC were treated with osimertinib. The brain metastasis response rate (BMRR), progression-free survival (PFS), and overall survival in the first-line cohort were secondary end points., Results: A total of 26 patients were enrolled in the study between September 2019 and July 2020. The median age was 72.0 years with 80.8% female. There were 20 patients who had multiple CNS metastases. BMRR assessed by PAREXEL criteria was 76.9% (90% confidence interval [CI]: 63.3%-90.5%), BMRR assessed by Response Evaluation Criteria in Solid Tumors was 76.9% (95% CI: 54.0%-99.8%), and median PFS of CNS metastasis was 22.0 months (95% CI: 9.7 mo-not reached). The overall response rate was 64.0% (95% CI: 45.2%-82.8%), median PFS was 11.5 months (95% CI: 6.9 mo-not reached), and median survival time was 23.7 months (95% CI: 16.5 mo-not reached). Paronychia and increased creatinine level were the most frequent nonhematological toxicities observed in 13 patients (50%). Grade three and higher adverse events were less than 10%, and there were no treatment-related deaths. Pneumonitis was observed in five patients (19.2%)., Conclusions: These results suggest that osimertinib is effective in untreated patients with RT-naive asymptomatic CNS metastasis in a clinical practice first-line setting., Trial Registration: UMIN identifier: UMIN000024218. jRCT identifier: jRCTs071180017., (© 2023 The Authors.)

Background: Central nervous system (CNS) metastases is inevitable for epidermal growth factor receptor ( EGFR )-mutant non-small cell lung cancer (NSCLC). AZD3759 is a novel EGFR-TKI with impressive CNS penetration., Methods: We initiated a phase 2, multi-center, umbrella trial (CTONG1702, NCT03574402). The eighth arm assessed the efficacy and safety of AZD3759 in untreated EGFR -mutated NSCLC with CNS metastases. The primary objective was the objective response rate (ORR). Simon's minimax two-stage design was used to calculate the sample size. Dose optimal selection was performed using 200- and 300-mg bid cohorts., Findings: Between Oct 18, 2018 and Sep 14, 2020, 30 patients received AZD3759 at 200 mg (n = 15) or 300 mg (n = 15) bid. At data cutoff (Dec 31, 2022), median follow-up was 35.4 months. The primary endpoint was reached, with a confirmed ORR of 70% (21/30) (200 mg, 80%; 300 mg, 60%). The median progression-free survival was 12.9 months (200 mg, 15.8 months; 300 mg, 10.7 months). Grade 3 or 4 treatment-related adverse events occurred in 73% (22/30) of the patients (200 mg: 60%; 300 mg: 87%). 59% (10/17) of the patients developed a T790M mutation at disease progression. The median overall survival was 33.7 months, and 34.1 months and 25.3 months in patient treated with or without osimertinib in a later-line setting, respectively., Interpretation: AZD3759 showed promising efficacy and tolerable safety as a first-line therapy in EGFR -mutated NSCLC with CNS metastases. The 200-mg bid cohort had better clinical outcomes. Sequential use of AZD3759 and third-generation EGFR-TKIs represents a new option., Funding: Chinese Thoracic Oncology Group (CTONG)., Competing Interests: Prof. Yi-Long Wu reports grants and personal fees from AstraZeneca, BMS, Pfizer; and personal fees from Boehringer Ingelheim, Eli Lilly, Hengrui, MSD, Sanofi, Roche, outside the submitted work. Prof. Qing Zhou reports honoraria from AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Pfizer, Roche, and Sanofi. Prof. Wen-Zhao Zhong reports speech honoraria from AstraZeneca, Roche, Eli Lilly and Pfizer. Dr. Chong-Rui Xu reports grants from Hengrui Pharmaceutical and Pfizer. The other authors have no competing interests to declare., (© 2023 The Author(s).)

While the CNS has long been viewed as an immune-privileged environment, a paradigm shift in neuro-immunology has elevated the role of systemic immunotherapy for the treatment of metastatic disease. Increasing knowledge regarding the presence of a CNS lymphatic system and the physical and biochemical alteration of the blood brain barrier (BBB) by the tumor microenvironment suggests immune cell trafficking in and out of the CNS is possible. Emerging clinical data suggest immune checkpoint inhibitors (ICIs) can stimulate T cells peripherally to in turn have anti-tumor effects in the CNS. For example, anti-programmed cell death-1 (PD-1) monotherapy with pembrolizumab has shown intracranial response rates of 20-30%in patients with melanoma or non-small cell lung cancer (NSCLC) brain metastases. The combination of nivolumab and ipilimumab [anti-PD-1 and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)] showed an intracranial response rate of 55%in patients withmelanoma brainmetastases.More data are needed to confirmthese response rates and to determinemechanisms of efficacy and resistance. While local therapies such as stereotactic radiosurgery (SRS), whole-brain radiation therapy (WBRT), and surgery remain current mainstays, ICIS offer potential decreased neurotoxicity. This review summarizes the biological rationale for systemic immunotherapy to treat CNS metastatic disease, existing clinical data on ICIs in this setting and ongoing clinical trials exploring areas of unmet need. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: The influence of blood group antigens on cancerogenesis is shown for distinct tumor types, yet the impact of Rhesus blood group antigens in lung cancer is not clarified. Materials and Methods: To investigate the impact of Rhesus blood groups a non‐small cell lung cancer (NSCLC) collective (n = 1047) was analyzed retrospectively. Using a second cohort of n = 340 primarily operated stage I‐III NSCLC patients, we evaluated immunohistochemistry of CD47‐antibody stained tissue samples in correlation to histopathologic subtype and Rhesus blood group. Results and Conclusion: In 516 of 1047 patients blood group data were available. Seven different RhCE phenotypes were grouped as “··ee,” “ccE·,” and “C·E·.” Adenocarcinoma patients with Rh “··ee” revealed improved overall survival (29 (21.2‐36.8) m; HR 1.00 [index]) compared with Rh “ccE·” (19 (1.9‐36.1) m; HR 1.76 [1.15‐2.70]) and Rh “C·E·” (10 (7.4‐12.6) m; HR 2.65 [1.70‐4.12]) univariately (P < .001) and multivariately (P < .001). Rh “··ee” showed reduced incidence of CNS‐metastasis (P = .014) and metastasis count (P = .032) in stage IV adenocarcinoma. Immunohistochemistry associated CD47‐positivity with adenocarcinomas (n = 340, P = .048). In n = 51 cases blood group data were available. The prognostic effect of Rh “··ee” compared with Rh “ccE·” and Rh “C·E·” was stated (P = .001), foremost in CD47‐positive adenocarcinomas (Rh “··ee” vs. Rh “ccE·” and Rh “C·E·,” P = .008). Inversely Rh “ccE·” or Rh “C·E·” was found beneficial in CD47‐negative non‐adenocarcinomas (P = .046). Phenotypic RhCE expression may be an independent prognostic factor for overall survival in adeno‐NSCLC. We hypothesize an erythrocytic‐immunologic interaction with tumor tissue, possibly altered by RhCE and CD47, resulting in a metastatic prone condition. [ABSTRACT FROM AUTHOR]

Six ALK TKIs (crizotinib, ceritinib, alectinib, brigatinib, lorlatinib, ensartinib) have received first-line treatment indication of advanced ALK+ NSCLC in various countries. In Ba/F3 cells, lorlatinib achieved lowest IC 50 among these 6 ALK TKIs against EML4-ALK variant 1 or 3. In 2022, 7 abstracts reported updated efficacy and safety data from CROWN. With a median follow-up time of 36.7 months, the 3-year progression-free survival (PFS) rate was 63.5% for lorlatinib-treated patients and the median PFS of lorlatinib still has not been reached. Importantly, post-lorlatinib treatment median PFS2 was 74.0% at 3-years. Lorlatinib-treated Asian patients achieved similar 3-year PFS rate as overall lorlatinib-treated patients. Median PFS was 33.3 months among lorlatinib-treated EML4-ALK v3 patients. CNS AE occurred fewer than 1 event per patient over the median follow-up time of 36.7 months and most resolved without intervention. Altogether these data affirm our belief that lorlatinib should be the treatment of choice of advanced ALK+ NSCLC. [Display omitted] • At 36.7 months follow up time, 3-year PFS rate for lorlatinib was 63.5 % with median PFS not reached. • Post-lorlatinib progression treatment resulted in a 3-year PFS2 rate of 74 %. • Lorlatinib was efficacious (3-yr PFS rate = 61 %) and tolerable (5 % discontinuation) among Asians. • EML4-ALK variant 3 achieved a mPFS of 33 months on lorlatinib. • CNS adverse event was < 1 per patient over a median 36.7 months and 59 % resolved without intervention. [ABSTRACT FROM AUTHOR]

Background: Crizotinib has been approved for C-ros oncogene 1 ( ROS1) - and anaplastic lymphoma kinase (ALK) -rearranged non-small cell lung cancer (NSCLC) patients. Few studies have examined the differences in crizotinib treatment outcomes between these patients and the progression sites during treatment. We investigated the metastatic spread, crizotinib efficacy, and progression patterns during crizotinib treatment in ROS1 - and ALK- rearranged NSCLC patients., Methods: We retrospectively reviewed crizotinib-treated ROS1 - and ALK -rearranged NSCLC patients between January 2011 and March 2021. Patient characteristics, clinical outcomes, and progression patterns during treatment were collected from medical records. The metastasis extent, crizotinib response, and progression patterns between the groups were compared., Results: We identified 26 patients with ROS1 - and 42 with ALK -positive NSCLC. The baseline proportion of central nervous system (CNS) metastases did not differ between the groups (12% vs. 29%, P=0.10), but the proportion of extrathoracic metastases, including CNS metastases, was significantly higher in ALK -positive than in ROS1 -positive NSCLC patients (35% vs. 71%, P=0.003). Regarding the response to crizotinib, the objective response rate (ORR), progression-free survival (PFS), or overall survival (OS) did not significantly differ between the groups ( ROS1 vs. ALK , ORR: 69% vs. 69%, P=0.987; PFS: median 10.9 vs. 10.7 months, P=0.232; median OS: not reached vs. 46% (17/37), P=0.127], and the cumulative incidence of CNS metastasis did not differ between the groups (P=0.914).ROS1 vs. ALK , 69% (11/16) vs. 46% (17/37), P=0.127], and the cumulative incidence of CNS metastasis did not differ between the groups (P=0.914)., Conclusions: Crizotinib treatment outcomes, including progression patterns, were similar between ROS1 - and ALK -positive NSCLC patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-23-10/coif). TY reports receiving grants and personal fees from Amgen, AstraZeneca, Ono, Merck Sharp & Dohme, Novartis, Chugai, and Bristol-Myers Squibb; grants from Takeda, Daiichi Sankyo, and AbbVie; and personal fees from Taiho, Eli Lilly, Roche, and ArcherDX outside of the submitted work. KM reports receiving personal fees from Ono Pharmaceutical Co., Ltd., AstraZeneca, Chugai, and Bristol-Myers Squibb, outside of the submitted work. YS reports receiving personal fees from Bristol-Myers Squibb, Chugai, AstraZeneca, and Eli Lilly; grants and personal fees from Ono; and grants from Janssen and Japan Clinical Research Operations K.K. outside of the submitted work. YM reports receiving grants from the National Cancer Center Research and Development Fund, Grant-in-Aid for Scientific Research on Innovative Areas, and Hitachi, Ltd.; grants and personal fees from Olympus; and personal fees from AstraZeneca, Novartis, COOK, AMCO Inc., Thermo Fisher Scientific, Erbe Elektromedizin GmbH, Fujifilm, Chugai, and Eli Lilly outside of the submitted work. Yusuke Okuma reports receiving grants from Roche and AbbVie K.K.; and personal fees from AstraZeneca, Ely Lilly K.K., Bristol-Myers Squibb, Pfizer Taiho Pharma Co. Ltd., AstraZeneca Nippon Boehringer Ingelheim, Chugai Pharma Co. Ltd., Ono Pharma Co. Ltd., and Taiho Pharma Co. Ltd. outside of the submitted work. YG reports receiving grants from AZK, AbbVie, Kyorin, and Preferred Network; grants and personal fees from Pfizer, Eli Lilly, Bristol-Myers Squibb, Ono, Novartis, and Daiichi Sankyo; and personal fees from Chugai, Taiho, Boehringer Ingelheim, Merck Sharp & Dohme, Merck, Thermo Fisher, AstraZeneca, Chugai, Guardant Health Inc., and Illumina outside of the submitted work. HH reports receiving grants and personal fees from Merck Sharp & Dohme, AstraZeneca, Ono, Chugai, Roche, and Novartis; grants from AbbVie, Bristol-Myers Squibb, Merck Biopharma, Daiichi Sankyo, Janssen, and Genomic Health; and personal fees from Eli Lilly and Kyowa-Kirin, outside of the submitted work. NY reports receiving grants from Chugai, Taiho, Eisai, Eli Lilly, Quintiles, Astellas, Bristol-Myers Squibb, Novartis, Daiichi Sankyo, Pfizer, Boehringer Ingelheim, Kyowa-Hakko Kirin, Bayer, Ono Pharmaceutical Co., Ltd., Takeda, Janssen Pharma, Merck Sharp & Dohme, Merck, GlaxoSmithKline, Sumitomo Dainippon, Chiome Bioscience Inc., Otsuka, Carna Biosciences, Genmab, and Shionogi; and personal fees from Ono Pharmaceutical Co., Ltd., Chugai, AstraZeneca, Pfizer, Lilly, Bristol-Myers Squibb, Eisai, Otsuka, Takeda, Boehringer Ingelheim, Cimic, Sysmex, and Eisai, outside of the submitted work. Yuichiro Ohe reports receiving grants, personal fees, and nonfinancial support from AstraZeneca, Chugai, Ono Pharmaceutical Co., Ltd., and Bristol-Myers Squibb; grants and personal fees from Eli Lilly and Pfizer; grants and nonfinancial support from Kyorin; grants from Dainippon-Sumitomo, Taiho, Novartis, Takeda, Kissei, Daiichi Sankyo, Janssen, and LOXO; and personal fees from Boehringer Ingelheim, Bayer, Merck Sharp & Dohme, Taiho, Nippon Kayaku, Kyowa-Hakko Kirin, Celltrion, Amgen, and AnHeeart Therapeutics Inc. outside of the submitted work. The other authors have no conflicts of interest to declare., (2023 Translational Lung Cancer Research. All rights reserved.)

Brain metastases are a much-feared complication of cancer. The development of brain metastases requires a malignant cell to acquire characteristics that facilitate dissemination away from the primary site, entrance into the nervous system, and establishment in the brain. This review summarizes recent work focused on the molecular derangements leading to brain metastases and outlines areas in need of greater understanding.

Primary Testicular Lymphoma (PTL) is a rare intermediate to high grade tumour, diffuse large cell being the most common type. Unlike nodal Diffuse Large B-Cell Lymphoma (DLBCL), testicular DLBCL has a less aggressive course and better prognosis. Metastasis is uncommon in testicular DLBCL. Commonly involved sites are contralateral testes, Waldeyer's ring, skin, lung, Central Nervous System (CNS) and prostate, however the kidneys, liver, bone marrow, pleura and bones are more rarely involved. We report a case of testicular DLBCL which has metastasized to skin and bone marrow with an aggressive clinical course in a year, in-spite of combined modality of therapy given to the patient. Bone marrow infiltration is common and well documented with nodal DLBCL, however there is no published literature for simultaneous bone marrow and skin infiltration in testicular DLBCL till date. Other large studies done in the west have shown that distinct metastasis is usually common but the median progression-free survival is usually in years. This case stresses on shorter period of progression after standard treatment protocol in this part of the world, thus highlighting the need for other extensive studies to define specific treatment protocol for testicular DLBCL.