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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Bridging the gap: Predicting brain metastasis in breast cancer

Chen et al explored clinicopathological features and prognostic factors,revealing advanced tumor stage,lung metastases,HER-2 overexpression,and triple-negative status as key contributors.Recent research connects astrocytes'role in brain metastasis with signaling pathways and the impact of Trastuzumab on HER-2 tumor survival.Factors such as positive HER2 status,lack of estrogen receptor expression,and liver metastasis are identified as additional risk factors.The routine use of magnetic resonance imaging,insights into gene mutations associated with metastasis,and the role of radiotherapy,including prophylaxis possibilities,is controversial in clinical practice.Understanding these risk factors in a multidisciplinary collaboration is precise for local treatments and targeted therapies,particularly for HER2+tumors,impacting directly on longer survival.

Weekly gemcitabine as a radiosensitiser for the treatment of brain metastases in patients with non-small cell lung cancer:phase Ⅰ trial

Background Conventional treatment for non-small cell lung cancer （NSCLC） brain metastases （BM） is whole-brain radiotherapy （WBRT）. The efficacy is limited. It might be increased by a potent radiosensitizer such as gemcitabine, which is believed to cross the disrupted blood-brain barrier. The primary objective of this study was to determine the maximum tolerated dose （MTD） of weekly gemcitabine given concurrently with WBRT. Methods Patients with BM from NSCLC were included. The dose of WBRT was 3750 cGy （total 15 times, 3 weeks）. Gemcitabine was given concurrently with WBRT on days 1, 8 and 15. The starting dose was 400 mg/m^2, escalated by 100 mg/m^2 increments. At least three patients were included per level. Dose limiting toxicity （DLT） was defined as grade 4 hematological or grade 2 neurological toxicity. When two or more patients experience DLT, the MTD was reached. Results A total of 16 patients were included; 69% had a performance status （PS） 1 （Eastern Cooperative Oncology Group, ECOG）. A total of 69% had concurrent active extra cranial diseases. All had more than 3 BM. Up to 600 mg/m^2 （level 3） no neurology toxicity was observed. At 600 mg/m^2 two out of 9 patients developed grade 4 thrombocytopenia. One of the two patients＇ thrombocytopenia was confused with disseminated intravascular coagulation （DIC）. At 700 mg/m^2 two out of 4 patients developed neurotoxicities. One developed grade 3 seizure and cognitive disorder. Another patient developed suspected grade 2 muscle weakness. Conclusions The MTD was reached at a dose of 700 mg/m^2. The dose of 600 mg/m^2 would be considered for further study.

High risk factors of brain metastases in 295 patients with advanced breast cancer

Background The incidence of brain metastases in patients with breast cancer is approximately 10%-16%, and survival after diagnosis of brain metastases is usually short. This study was designed to evaluate the risk factors associated with brain metastases in advanced breast cancer patients, with a view to help predict patient groups with high risk of brain metastases. Methods In total, 295 patients with advanced breast cancer were evaluated. All patients were pathologically confirmed and metastatic lesions were confirmed pathologically or by imaging. All patients were examined at least once every 6 months with head CT or MRI. Patients showing symptoms underwent immediate inspection, and brain metastatic lesions were confirmed by head CT and/or MRI. Results At a median follow-up of 12 months from the occurrence of metastases, brain metastases had occurred in 49 patients （16.6%）. In our univariate analysis, variables significantly related to increased risk of brain metastases were hormone receptor-negative tumors, epidermal growth factor receptor 2 （HER2）-positive tumors, and multiple distant metastases. Patients with dominant tumor sites in soft tissue, or defined as Luminal A subtype, tended to have a lower risk of brain metastases than patients with visceral metastases, Luminal B subtype, triple-negative subtype or HER2-enriched subtype tumors. Conclusions Our results strongly suggest that factors such as Luminal B, triple-negative, and HER2-enriched subtypes are high risk factors for brain metastases. These data, therefore, provide pivotal clinical evidence towards a comprehensive understanding of the risk factors of brain metastases in advanced breast cancer patients.

Radiotherapy of brain metastases from non-small cell lung cancer

Brain metastases risk at the time of diagnosis or during the course of disease is high in non-small cell lung cancer (NSCLC). Even the incidence of brain metastases has increased in recent years, due to detection of smaller asymptomatic lesions with MRI screening as well as improved survival as a consequence of developments in systemic therapies. In the last decade, there have been many trials in the management of NSCLC patients with brain metastases, questioning the role of adjuvant whole brain radiotherapy (WBRT) after surgery or stereotactic radiosurgery (SRS), WBRT, compared to best supportive care in patients not amenable to surgery, aggressive local therapies in solitary brain metastases, postsurgical cavity SRS, SRS in non-oligometastatic patients, cranial radiotherapy in patients with driver mutations, thyrosine kinase inhibitors, immune check point inhibitors and the impact of therapies on neurocognitive functions and quality of life. The main objective of this review is to provide an update on current trends in radiotherapy in the management of newly diagnosed brain metastases from NSCLC.

SIMULTANEOUS THORACO－CRANIAL OPERATION FOR THE TREATMENT OF LUNG CANCER WITH BRAIN METASTASES

We performed simultaneous one-stage thoraciccranial surgery on ten cases of lung cancer with brain metastases during the period of 1990 to 1994. Surgical mortality was 0% with low morbidity. By the end of the follow-up in February 1995, 4 patients died, with a mean survival of 8.25 months, and 6 patients survived, with a mean survival of 16 months and the longest one being approximately 36 months. Our results showed that, if patient's general condition permits, simultaneous onestage thoraco-cranial operation is feasible for the treatment of lung cancer involved the Periphery with solitary intracranial metastasis. Postoperative adjuvant chemotherapy is indicated to achieve better results.

Training and evaluation of a knowledge-based model for automated treatment planning of multiple brain metastases

Aim: Volumetric modulated arc therapy (VMAT) has been utilized to plan and treat multiple cranial metastases using a single isocenter due to its ability to provide steep dose gradients around targets as well as low doses to critical structures. VMAT treatment is delivered in a much shorter time compared to using a single isocenter for the treatment of each lesion. However, there is a need to develop methods to reduce the treatment planning time for these cases while also standardizing the plan quality. In this work we demonstrate the use of RapidPlan, which is knowledge-based treatment (KBP) planning software to plan multiple cranial SRS cases. Methods: The 66 patient plans with 125 lesions (range 1-4, median 1) were used to train a model. In addition, the model was validated using 10 cases that were previously treated and chosen randomly. The clinical plans were compared to plans generated by RapidPlan for target coverage and critical organ dose. Results: Coverage to the target volume, gradient index, conformity index and minimum dose to the target showed no significant difference between the original clinical plan vs. the plan generated by KBP. A comparison of doses to the critical organs namely the brainstem, brain, chiasm, eyes, optic nerves and lenses showed no significant difference. Target dose homogeneity was slightly better with the clinical plan, however this difference was also statistically insignificant. ;Conclusion: This work demonstrates that KBP can be trained and efficiently utilized to help not only speed up the planning process but also help standardize the treatment plan quality.

Radiotherapy of brain metastases from small-cell lung cancer: standards and controversies

Small-cell lung cancer (SCLC) has a high propensity to metastasize into the brain. Radiotherapy plays a major role in the treatment of brain metastases (BM) from SCLC. Whole-brain radiotherapy (WBRT) is the standard treatment of BM from SCLC. However, the neurocognitive toxicity and modest efficacy of this approach have led to the increased use of stereotactic radiosurgery. We have no strong evidence for the use of different forms of radiation (WBRT vs. radiosurgery) in SCLC, because BM from this primary tumor were excluded from clinical trials. In this review, the use of radiation in form of WBRT or radiosurgery is discussed in distinct clinical indications: as a primary treatment and at relapse;without prior use of prophylactic cranial irradiation (PCI);and after PCI. Combinations of radiotherapy with chemotherapy are discussed as BM in SCLC occur rarely as a sole event.