Incidence,Risk Factors,and Prognosis of Patients with Hepatocellular Carcinoma and Brain Metastases

Objective Brain metastases significantly impact the clinical course of patients with hepatocellular carcinoma(HCC).This study aimed to examine the age-related incidence,demographics,and survival of patients with HCC and brain metastases.Methods Data of HCC patients from 2010 to 2015 in the Surveillance,Epidemiology,and End Results(SEER)Registry were screened for the presence of brain metastases.They were stratified by age and ethnicity.Multivariable logistic and Cox regression analyses were used to identify factors associated with brain metastases and those with overall survival(OS)and liver cancer-specific survival(CSS),respectively.Results A total of 141 HCC patients presenting with brain metastases were identified,accounting for 0.35% of all HCC patients and 2.37% of patients with metastatic disease.Among all HCC patients,the incidence rate was the highest among patients aged 30-49 years old(0.47%).Ethnicity was not associated with the presence of brain metastases at the time of HCC diagnosis.However,African-American patients presented with a significantly lower disease-specific survival[median time:1 month;interquartile range(IQR):0-3.0 months].Initial lung or bone metastasis was independently associated with an increased risk of the presence of brain metastases[odds ratio(OR):12.62,95% confidence interval(CI):8.40-18.97]but was not associated with a worse OS or CSS among those with brain metastases.Conclusion This study identified the age-related incidence and risk factors of brain metastases in HCC patients.These results may contribute to the consideration of brain screening among patients with initial metastatic HCC with lung or bone metastases,and influence the counseling of this patient population regarding their prognosis.

Planning Target Volume Margin in Linac-Based Stereotactic Radiosurgery for Brain Metastases

Background: The treatment of brain metastases with radiotherapy has shifted to the use of Stereotactic Radio-surgery (SRS). The technical issue of expanding the treatment volume around the Gross Tumor Volume (GTV) is a current debate. Radiotherapy centers use variable GTV-PTV margins, ranging from one to 2 mm. Material and Methods: We performed a dosimetric comparison in plans of twenty patients using three margins: PTV zero, PTV1, and PTV2. We also developed imaginary Peel volumes. These volumes are described as follows: Peel1 = PTV1 − GTV, Peel2 = PTV2 − GTV. Results: Our results showed that the mean PTV volume differed significantly across the different margins (p = 0.000). The V12 of the brain significantly varied as a function of PTV margin (p = 0.000). The target coverage and plan quality indices were not significantly different. The Peel volume dosimetric analysis showed that the mean dose was significantly higher in the nearby normal brain tissue: Peel1 (p = 0.022) and Peel 2 (p = 0.013). Conclusion: According to our dosimetric analysis, expanding the GTV into a PTV by 1 mm margin is more convenient than 2 mm.

Treatment of patients with multiple brain metastases by isolated radiosurgery:Toxicity and survival

BACKGROUND Radiosurgery for multiple brain metastases has been more reported recently without using whole-brain radiotherapy.Nevertheless,the sparsity of the data still claims more information about toxicity and survival and their association with both dosimetric and geometric aspects of this treatment.AIM To assess the toxicity and survival outcome of radiosurgery in patients with multiple(four or more lesions)brain metastases.METHODS In a single institution,data were collected retrospectively from patients who underwent radiosurgery to treat brain metastases from diverse primary sites.Patients with 4-21 brain metastases were treated with a single fraction with a dose of 18 Gy or 20 Gy.The clinical variables collected were relevant to toxicity,survival,treatment response,planning,and dosimetric variables.The Spearman’s rank correlation coefficients,Mann-Whitney test,Kruskal-Wallis test,and Log-RESULTS From August 2017 to February 2020,55 patients were evaluated.Headache was the most common complaint(38.2%).The median overall survival(OS)for patients with karnofsky performance status(KPS)>70 was 8.9 mo,and this was 3.6 mo for those with KPS≤70(P=0.047).Patients with treated lesions had a median progression-free survival of 7.6 mo.There were no differences in OS(19.7 vs 9.5 mo)or progression-free survival(10.6 vs 6.3 mo)based on prior irradiation.There was no correlation found between reported toxicities and planning,dosimetric,and geometric variables,implying that no additional significant toxicity risks appear to be added to the treatment of multiple(four or more)lesions.CONCLUSION No associations were found between the evaluated toxicities and the planning dosimetric parameters,and no differences in survival rates were detected based on previous treatment status.

Value of serial magnetic resonance imaging in the assessment of brain metastases volume control during stereotactic radiosurgery

AIM To evaluate brain metastases volume control capabilities of stereotactic radiosurgery(SRS) through serial magnetic resonance(MR) imaging follow-up. METHODS MR examinations of 54 brain metastases in 31 patients before and after SRS were reviewed. Patients were included in this study if they had a pre-treatment MR examination and serial follow-up MR examinations at 6 wk, 9 wk, 12 wk, and 12 mo after SRS. The metastasis volume change was categorized at each follow-up as increased(> 20% of the initial volume), stable(± 20% of the initial volume) or decreased(< 20% of the initial volume). RESULTS A local tumor control with a significant(P < 0.05) volume decrease was observed in 25 metastases at 6-wk follow-up. Not significant volume change was observed in 23 metastases and a significant volume increase was observed in 6 metastases. At 9-wk followup, 15 out of 25 metastases that decreased in size at 6 wk had a transient tumor volume increase, followed by tumor regression at 12 wk. At 12-wk follow-up there was a significant reduction in volume in 45 metastases, and a significant volume increase in 4 metastases. At 12-mo follow-up, 19 metastases increased significantly in size(up to 41% of the initial volume). Volume tumor reduction was correlated to histopathologic subtype.CONCLUSION SRS provided an effective local brain metastases volume control that was demonstrated at follow-up MR imaging.

Brain metastases from hepatocellular carcinoma after hepatectomy

Hepatocellular carcinoma is a highly malignant neoplasm and frequently involves extrahepatic organs but decidedly rarely occurs in brain. We describe 3 cases of brain metastases in patients suffering from post-HBV hepatocarcinoma. The ＂stroke-like＂ presentation of the cerebral localization of the disease can be explained by both the important vascularization of the tumor and the frequent hemocoagulative alterations caused by the cirrhosis. The importance of diagnostic neuroradiology is briefly addressed, with reference to the fundamental role played by MRI. Surgery of these lesions does not present any particular technical problems as long as they are located in accessible areas and the patient＇s general and neurological conditions allow it. Postoperative radiotherapy seems to improve the quality and quantity of residual life, although the number of patients described in the literature was too small to draw any definite conclusion in this regard.

Integration of stereotactic radiosurgery or whole brain radiation therapy with immunotherapy for treatment of brain metastases

The prognosis of brain metastases(BM)is traditionally poor.BM are mainly treated by local radiotherapy,including stereotactic radiosurgery(SRS)or whole brain radiation therapy(WBRT).Recently,immunotherapy(i.e.,immune checkpoint inhibitors,ICI)has demonstrated a survival advantage in multiple malignancies commonly associated with BM.Individually,radiotherapy and ICI both treat BM efficiently;hence,their combination seems logical.In this review,we summarize the existing preclinical and clinical evidence that supports the applicability of radiotherapy as a sensitizer of ICI for BM.Further,we discuss the optimal timing at which radiotherapy and ICI should be administered and review the safety of the combination therapy.Data from a few clinical studies suggest that combining SRS or WBRT with ICI simultaneously rather than consecutively potentially enhances brain abscopal-like responses and survival.However,there is a lack of conclusion about the definition of"simultaneous";the cumulative toxic effect of the combined therapies also requires further study.Thus,ongoing and planned prospective trials are needed to further explore and validate the effect,safety,and optimal timing of the combination of immunotherapy with radiotherapy for patients with BM.

Whole brain radiotherapy concomitant or sequential Vm26/DDP in treating small cell lung cancer patients with brain metastases

Objective： The aim of the study was to compare efficacies and safeties of 2 different treatments of whole brain radiotherapy （WBRT） sequential or concomitant Vm26/DDP for small cell lung cancer （SCLC） patients with brain metastases. Methods： A total of 39 patients were randomly divided into sequential chemoradiotherapy regime （A group, 20 patients） and concomitant chemoradiotherapy regime （B group, 19 patients）. The close of WBRT was 36 Gy in 18-20 fractions, chemotherapy of Vm26/DDP regimen with teniposide 60 mg/m^2 on dl to d3 and cisplatin 20 mg/m^2 on dl to d5, repeating every 3 weeks. The response was evaluated after WBRT and 2 cycles of chemotherapy. Results： Total response rates of A and B groups were 70.0% and 78.9% respectively （P = 0.520）. The median survival was 11 months in A group and 10 months in B group. Six, twelve and eighteen months cumulative survival rates of A and B groups were 75.0%, 42.5%, 26.2%, and 81.6%, 26.4%, 10.5%, respectively （χ^2 = 0.383, P 〉 0.05）. Response rate and the number of brain metastases were independent prognostic factors. Conclusion： Both sequential and concomitant chemoradiotherapy groups are effective, and the main toxicity with myelosuppression is tolerable after therapy. It can be applied firstly and effectively to the SCLC patients with brain metastases in clinic.

BRAIN METASTASES FROM CARCINOMA OF UTERINE CERVIX

Objective: To study the mechanism, clinical characteristics, therapy regimens, and survival of cervical carcinoma metastases to the brain. Methods: We retrospectively analyzed 11 patients with brain metastases from cervical carcinoma. Results: Two cases were at stage lb, two at IIa, and seven at IIIb, respectively. Histologically, they were squamous cell carcinoma (6 cases), adenosquamous carcinoma (2 cases), small cell carcinoma (2 cases), or adenocarcinoma (1 cases), poorly differentiated. Eight were accompanied with lung, liver, and bone metastases disease and three had no any other systemic metastases at the time of the brain metastases diagnosis. Two had controlled, and other nine were uncontrolled or progressive primary disease. The median interval from the diagnosis of the primary carcinoma to the detection of brain lesion was 14.6 months. Headache was the most common symptom of brain metastases. Eight of 11 patients developed multiple lesions and other 3 cases had a solitary lesion in brain. The patients were treated by combination of surgery and whole brain radiation therapy (WBRT) (3 cases), stereotactic radiosurgery (SRS) (3 cases), or WBRT (5 cases). The patients had a median survival of 6.6 months. Conclusion: Brain metastases are not always a late complication of cervical carcinoma. The development of the metastases is related to pathological type, poorly differentiation, and advanced stage. Surgery and SRS are the appropriate therapy regimen for these patients.

Science Letters:Brain metastases of melanoma-mechanisms of attack on their defence system by engineered stem cells in the microenvironment

This report gives a better emphasis on the role of targeted effectors (e.g. a combination of 5-FC with CD-NSPCs as compared to the application of NSPCs alone) and how such delivery of pro-drug activating enzymes and other tumor-killing substances may overcome melanocytic defence system, interact with and promote the host defence and immune response modulations not only in melanoma but, potentially, in other highly-metastatic cancers.

Long-term control of melanoma brain metastases with co-occurring intracranial infection and involuntary drug reduction during COVID- 19 pandemic: A case report

BACKGROUND Melanoma brain metastasis is a common cause of death in melanoma patients andis associated with a poor prognosis. There are relatively few reports onintracranial infections after brain metastasis resection.CASE SUMMARY Here we report a case of melanoma brain metastases in a patient harboring aBRAF V600E mutation, who experienced intracranial tumor progression despiteprevious combined treatment with a programmed death (PD)-1 inhibitor, axitinib,and vemurafenib. She repeatedly underwent local therapy, including stereotacticradiosurgery and intracranial surgery, and developed central nervous systeminfection. Treatment with vemurafenib combined with cobimetinib resulted in anintracranial progression-free survival of 10 mo. During the coronavirus disease2019 (COVID-19) pandemic, the patient did not visit the hospital for regularvemurafenib treatment, and experienced intracranial progression afterinvoluntary drug reduction for 1 mo. The patient subsequently received varioussystemic treatments including vemurafenib, PD-1 inhibitor, and chemotherapy,with an overall survival of 29 mo as of September 2020.CONCLUSION We report the first case of melanoma brain metastases with co-occurringintracranial infection and unintended drug reduction during the COVID-19outbreak. Long-term control of the intracranial lesions was achieved withsystemic and local therapies.

Efficacy and nursing of stereotactic radiotherapy in lung cancer patients with brain metastases

Objective: To observe the efficacy of stereotactic radiotherapy (SRT) in lung cancer patients with brain metas-tases and explore the nursing for those patients. Methods: From June 2002 to December 2006, 43 patients of lung cancer with brain metastases were treated with SRT, 8 of them were treated with the association of whole-brain radiotherapy (WBRT) and 6 of them were treated with combination of chemotherapy. During the period of SRT, the patients were applied with active psychological nursing and diet nursing. We also tried to prevent patients from epicranium injury, and meanwhile, patients were asked to took active convalesce exercise. Results: All patients finished SRT without serious reaction and complication. Local control rate was 81.4%, nervous system symptoms relief rate was 76.7% and KPS score was raised significantly. Survival time ranged from 2 to 34 months, median survival time was 8.5 months, and 6-month, 1-and 2-year survival rates were 58.9%, 26.2%, and 6.0% respectively. Conclusion: SRT was one of the effective palliation treatments for the lung cancer patients with brain metastases, and with the assistance of effective nursing, which would prolong their survival time and improved quality of life.

Icotinib, an EGFR-TKI, for the treatment of brain metastases in non-small cell lung cancer:a retrospective study

Objective Treatment of brain metastases from non-small cell lung cancer(NSCLC) is a challenge because of the poor prognosis. Icotinib is a new type of oral epidermal growth factor receptor(EGFR) tyrosine kinase inhibitor(TKI) used in the treatment of advanced NSCLC. The aim of this study was to evaluate the efficacy of icotinib in NSCLC patients with brain metastasis.Methods This study reviewed records of 51 NSCLC patients with brain metastases who took icotinib 125 mg, 3 times a day. Response rate, progression free survival, and overall survival were analyzed. SPSS software version 17.0 was used for univariate analysis, and Cox regression analysis to analyze factors affecting survival. Results Thirty-six cases had partial response, 6 cases had stable disease, and 10 cases had progressive disease. In 31 cases, EGFR gene mutation test were performed. EGFR was mutated in 26 cases and was with wild-type in 5 cases. In patients with EGFR mutations, 23 patients responded to icotinib [the disease control rate(DCR) was 88.5%], significantly higher than in patients with wild-type EGFR(1 patient, DCR 20%)(P = 0.005). The overall median progression-free survival(PFS) was 7.6 months. PFS was longer in the patients with EGFR mutations than in those with wild type EGFR(7.8 months vs 1.2 months, P = 0.03). The overall median overall survival(OS) time was 10.7 months. OS was longer in patients with EGFR mutations than in those with wild type EGFR(15.1 months vs 6.7 months, P = 0.003). The main side effects of the treatment were skin rash and diarrhea; no stage 3 or 4 toxic effects occurred. Univariate analysis demonstrated that OS was related to sex, Eastern Cooperative Oncology Group performance status(ECOG PS), smoking history, and EGFR mutation. Multivariate analysis showed that OS was independently related to sex, ECOG PS, and EGFR mutations.Conclusion Icotinib has a favorable effect on NSCLC patients with brain metastases harboring EGFR mutations. Icotinib can be a new choice of treatment for brain metastases in patients with NSCLC harboring EGFR mutations.

Research of radiosurgery for brain metastases

Objective To explore the efficacy of gamma knife radiosurgery for brain metastases. Methods 112 cases with brain metastases were treated by gamma knife. Among them,most cases were performed with surgery combined with whole brain radiation therapy and chemotherapy. Results 85 cases were followed-up

Suppressing Wnt signaling of the blood-tumor barrier to intensify drug delivery and inhibit lipogenesis of brain metastases

Lipogenesis is often highly upregulated in breast cancer brain metastases to adapt to intracranial low lipid microenvironments.Lipase inhibitors hold therapeutic potential but their intra-tumoral distribution is often blocked by the blood-tumor barrier(BTB).BTB activates its Wnt signaling to maintain barrier properties,e.g.,Mfsd2a-mediated BTB low transcytosis.Here,we reported VCAM-1-targeting nano-wogonin(W@V-NPs)as an adjuvant of nano-orlistat(O@V-NPs)to intensify drug delivery and inhibit lipogenesis of brain metastases.W@V-NPs were proven to be able to inactivate BTB Wnt signaling,downregulate BTB Mfsd2a,accelerate BTB vesicular transport,and enhance tumor accumulation of O@V-NPs.With the ability to specifically kill cancer cells in a lipid-deprived environment with IC_(50) at 48 ng/mL,W@V-NPs plus O@V-NPs inhibited the progression of brain metastases with prolonged survival of model mice.The combination did not induce brain edema,cognitive impairment,and systemic toxicity in healthy mice.Targeting Wnt signaling could safely modulate the BTB to improve drug delivery and metabolic therapy against brain metastases.

HyperArc performance in radiotherapy and its correlations with number and volume of multiple brain metastases

Objective:To assess the performance and advantages of HyperArc for radiotherapy of multiple brain metastases with dosimetric parameters with respect to coplanar volumetric modulated arc radiotherapy(c-VMAT),and characterize implicit correlations between tumor features and dosimetric parameters.Methods:This retrospective study involved 40 patients with multiple brain metastases(4–16 tumors,12.8–240.8 cm3)who received simultaneous radiotherapy at the Department of Radiation Oncology,Shenzhen People's Hospital from January 2019 to December 2022.Both HyperArc and c-VMAT plans were designed by the same and qualified physicist using the Eclipse system with Truebeam.A single isocenter and a 6 MV flattening filter-free(6FFF)photon beam were used for radiotherapy of multiple brain metastases in each plan.Dosimetric parameters of tumors and organs at risk(OARs)were compared between HyperArc and c-VMAT plans.Corre-lations between tumor features(number and volume)and dosimetric parameters were revealed and analyzed.Furthermore,monitor units(MUs)of both plan types were recorded to assess rays utilization and delivery efficiency.Results:Compared to c-VMAT plans,HyperArc plans achieved higher maximum dose(D_(max))(5.23%,t=7.87,P<0.01),but lower minimum dose(Dmin)(3.94%,t=-2.12,P=0.04)and mean dose(D_(mean))(1.05%,t=-3.29,P<0.01)for planning gross tumor volumes(PGTVs).The conformity index(CI),homogeneity index(HI),gradient index(GI)and R50%of PGTVs with HyperArc were better than those with c-VMAT,with the improve-ments of 20.78%,1.68%,19.83%and 36.20%,respectively(P<0.01).The dosimetric parameters of OARs were significantly improved in HyperArc plans compared to c-VMAT plans.Specifically,the D_(max)and the D_(mean)to the brainstem decreased by 16.14%and 11.37%,respectively.The D_(max)for eye_L decreased by 16.88%,for eye_R decreased by 11.67%,for optical nerve_L decreased by 12.56%,and for chiasm decreased by 18.12%.Few correlations were observed between the differences of CI/HI/GI/R50%and the number of PGTVs between the two plan types.Whereas,regression analysis indicated that the differences of CI/GI/R50%were negatively correlated with the volume of PGTVs,respectively.Moreover,although HyperArc plans reduced the MUs by 4.74%compared to c-VMAT,no significant difference was observed(P>0.05).Conclusions:This study demonstrates the promising performance of HyperArc for radiotherapy of multiple brain metastases,including better dose conformity for the tumors,more rapid dose drop and less dose spillage outside the tumors area,effective reduction of dose bridges among close tumors,and sparing OARs.It also reveals the correlations between the number or volume of tumors and dose parameters,which can help optimize the use of HyperArc and predict clinical benefits.

Random forests to predict survival of octogenarians with brain metastases from nonsmall-cell lung cancer

Background:To create and validate nomograms for the personalized prediction of survival in octogenarians with newly diagnosed nonsmall-cell lung cancer(NSCLC)with sole brain metastases(BMs).Methods:Random forests(RF)were applied to identify independent prognostic factors for building nomogram models.The predictive accuracy of the model was evaluated based on the receiver operating characteristic(ROC)curve,C-index,and calibration plots.Results:The area under the curve(AUC)values for overall survival at 6,12,and 18 months in the validation cohort were 0.837,0.867,and 0.849,respectively;the AUC values for cancer-specific survival prediction were 0.819,0.835,and 0.818,respectively.The calibration curves visualized the accuracy of the model.Conclusion:The new nomograms have good predictive power for survival among octogenarians with sole BMs related to NSCLC.

Nanomaterials with dual immunomodulatory functions for synergistic therapy of breast cancer brain metastases

A long-standing paucity of effective therapies results in the poor outcomes of triple-negative breast cancer brain metastases.Immunotherapy has made progress in the treatment of tumors,but limited by the non-immunogenicity of tumors and strong immunosuppressive environment,patients with TNBC brain metastases have not yet benefited from immunotherapy.Dual immunoregulatory strategies with enhanced immune activation and reversal of the immunosuppressive microenvironment provide new therapeutic options for patients.Here,we propose a cocktail-like therapeutic strategy of microenvironment regulation-chemotherapy-immune synergistic sensitization and construct reduction-sensitive immune microenvironment regulation nanomaterials(SIL@T).SIL@T modified with targeting peptide penetrates the BBB and is subsequently internalized into metastatic breast cancer cells,releasing silybin and oxaliplatin responsively in the cells.SIL@T preferentially accumulates at the metastatic site and can significantly prolong the survival period of model animals.Mechanistic studies have shown that SIL@T can effectively induce immunogenic cell death of metastatic cells,activate immune responses and increase infiltration of CD8+T cells.Meanwhile,the activation of STAT3 in the metastatic foci is attenuated and the immunosuppressive microenvironment is reversed.This study demonstrates that SIL@T with dual immunomodulatory functions provides a promising immune synergistic therapy strategy for breast cancer brain metastases.

Immune checkpoint inhibitors for the treatment of non-small cell lung cancer brain metastases

Lung cancer has the highest risk of brain metastasis(BM)among all solid carcinomas.The emergence of BM has a significant impact on the selection of oncologic treatment for patients.Immune checkpoint inhibitors(ICIs)are the most promising treatment option for patients without druggable mutations and have been shown to improve survival in patients with non-small cell lung cancer(NSCLC)BM in clinical trials with good safety.Moreover,ICI has shown certain effects in NSCLC BM,and the overall intracranial efficacy is comparable to extracranial efficacy.However,a proportion of patients showed discordant responses in primary and metastatic lesions,suggesting that multiple mechanisms may exist underlying ICI activity in BM.According to studies pertaining to tumor immune microenvironments,ICIs may be capable of provoking immunity in situ.Meanwhile,systematic immune cells activated by ICIs can migrate into the central nervous system and exert antitumor effects.This review summarizes the present evidence for ICI treatment efficacy in NSCLC BM and proposes the possible mechanisms of ICI treatment for NSCLC BMs based on existing evidence.

Current landscape and challenges ahead of immuno-molecular mechanism and immunotherapy strategy of brain metastases

Brain metastases are the most common central nervous system malignancies in adults.The popular view is that due to the existence of the blood–brain barrier,whether there are immune cells in the central nervous system has always been controversial.Current research shows that immune cells do exist in the central nervous system and play a vital role in the occurrence and development of brain metastasis.The central nervous system has a unique immune microenvironment,and the study of its mechanism is of great significance for the prediction and treatment of brain metastases.This article aims to discuss the components of the brain tumor microenvironment(TME)and immune mechanism of tumor brain metastasis,in the hopes of making better treatment through combination therapy.

Stage Ⅳ non-small cell lung cancer with multiple metastases to the small intestine leading to intussusception: A case report

BACKGROUND Gastrointestinal tract metastasis from lung cancer is rare and compared to small cell lung cancer(SCLC),non-SCLC(NSCLC)is even less likely to metastasize in this manner.Additionally,small intestinal tumors can also present with diverse complications,some of which require urgent intervention.CASE SUMMARY In this report,we detail a unique case of stage IV lung cancer,where the presence of small intestine tumors led to intussusception.Subsequent to a small intestine resection,pathology confirmed that all three tumors within the small intestine were metastases from adenocarcinoma of the lung.The postoperative follow-up period extended beyond 14 mo.CONCLUSION In patients with stage IV NSCLC,local tumor control can be achieved with various treatments.However,if small intestinal metastasis occurs,surgical intervention remains necessary,as it may improve survival.