A multidisciplinary management algorithm for brain metastases.

The incidence of brain metastases continues to present a management issue despite the advent of improved systemic control and overall survival. While the management of oligometastatic disease (ie, 1-4 brain metastases) with surgery and radiation has become fairly straightforward in the era of radiosurgery, the management of patients with multiple metastatic brain lesions can be challenging. Here we review the available evidence and provide a multidisciplinary management algorithm for brain metastases that incorporates the latest advances in surgery, radiation therapy, and systemic therapy while taking into account the latest in precision medicine-guided therapies. In particular, we argue that whole-brain radiation therapy can likely be omitted in most patients as up-front therapy.

Stereotactic radiosurgery for vestibular schwannomas in neurofibromatosis type 2 patients: a systematic review and meta-analysis.

INTRODUCTION: Neurofibromatosis type 2 (NF2) is characterized by often bilateral vestibular schwannomas (VS) that result in progressive hearing loss and compression of nearby brainstem structures causing cranial nerve palsies. Treatment of these tumors remains challenging, as both surgical removal and expectant management can result in symptom progression. Stereotactic radiosurgery (SRS) has been investigated for the management of NF2-associated VS; however, the role, promises, and pitfalls of this treatment modality remain unclear. METHODS: Ovid MEDLINE, EMBASE, Web of Science, and Cochrane Reviews were searched for studies assessing SRS outcome in NF2-associated VS only. Primary endpoints included tumor control, serviceable hearing, presence of tinnitus, and cranial nerve V and VII symptoms. RESULTS: A total of 16 studies (589 patients harboring 750 tumors) were analyzed. Clinical tumor control was achieved in 88% of cases (95% CI 80-95%); salvage surgery was needed in 8% (95% CI 4-13%) of cases. Treatment resulted in a worsening of pre-treatment serviceable hearing (OR = 0.26, p < 0.01), increased facial nerve (OR = 1.62, p < 0.01) and trigeminal nerve (OR = 1.42, p = 0.07) impairment. The incidence of vestibular symptoms and hydrocephalus were not consistently reported and thus could not be assessed. CONCLUSIONS: The treatment of NF2-associated VS continues to pose a challenge, as current SRS regimens result in impaired hearing and worse cranial nerve comorbidities, despite achieving high tumor control. It remains unclear if these findings have to be regarded as treatment complications or, rather, continued disease progression.

Benefit of adjuvant chemotherapy in node-negative T1a versus T1b and T1c triple-negative breast cancer.

PURPOSE: National comprehensive cancer network guidelines recommend delivery of adjuvant chemotherapy in node-negative triple-negative breast cancer (TNBC) if the tumor is > 1 cm and consideration of adjuvant chemotherapy for T1b but not T1a disease. These recommendations are based upon sparse data on the role of adjuvant chemotherapy in T1a and T1b node-negative TNBC. Our objective was to clarify the benefits of chemotherapy for patients with T1N0 TNBC, stratified by tumor size. METHODS: We performed a retrospective analysis of survival outcomes of TNBC patients at two academic institutions in the United States from 1999 to 2018. Primary tumor size, histology, and nodal status were based upon surgical pathology. The Kaplan-Meier plot and 5-year unadjusted survival probability were evaluated. RESULTS: Among 282 T1N0 TNBC cases, the status of adjuvant chemotherapy was known for 258. Mean follow-up was 5.3 years. Adjuvant chemotherapy was delivered to 30.5% of T1a, 64.7% T1b, and 83.9% T1c (p < 0.0001). On multivariable analysis, factors associated with delivery of adjuvant chemotherapy were tumor size and grade 3 disease. Improved overall survival was associated with use of chemotherapy in patients with T1c disease (93.2% vs. 75.2% p = 0.008) but not T1a (100% vs. 100% p = 0.3778) or T1b (100% vs. 95.8% p = 0.2362) disease. CONCLUSION: Our data support current guidelines indicating benefit from adjuvant chemotherapy in node-negative TNBC associated with T1c tumors but excellent outcomes were observed in the cases of T1a and T1b disease, regardless of whether adjuvant chemotherapy was delivered.

Outcomes following upfront radiation versus monitoring in atypical meningiomas: 16-year experience at a tertiary medical center.

BACKGROUND: The role of postoperative upfront radiotherapy (RT) in the management of gross totally resected atypical meningiomas remains unclear. This single-center retrospective review of newly diagnosed histologically confirmed cases of World Health Organization (WHO) Grade II atypical meningioma at Weill Cornell Medicine from 2004 to 2020 aims to compare overall survival (OS) and progression-free survival (PFS) of postoperative upfront RT versus observation, stratified by resection status (gross total resection [GTR] vs subtotal resection [STR]). METHODS: Ninety cases of atypical meningioma were reviewed (56% women; median age 61 years; median follow-up 41 months). RESULTS: In patients with GTR, hazard ratio (HR) of PFS was 0.09 for postoperative upfront RT versus observation alone (95% confidence interval [CI] 0.01-0.68; P = .02), though HR for OS was not significant (HR 0.46; 95% CI 0.05-4.45; P = .5). With RT, PFS was 100% at 12 and 36 months (compared to 84% and 63%, respectively, with observation); OS at 36 months (OS36) was 100% (compared to 94% with observation). In patients with STR, though PFS at 36 months was higher for RT arm versus observation (84% vs 74%), OS36 was 100% in both arms. HR was not significant (HR 0.76; 95% CI 0.16-3.5; P = .73). CONCLUSIONS: This retrospective study suggests postoperative upfront RT following GTR of atypical meningioma is associated with improved PFS compared to observation. Further studies are required to draw conclusions about OS.

Efficacy and comorbidities of hypofractionated and single-dose radiosurgery for vestibular schwannomas: a systematic review and meta-analysis.

BACKGROUND: Vestibular schwannomas (VS) are tumors of the cerebellopontine angle with significant morbidity, causing hearing loss, tinnitus, and trigeminal and facial nerve compromise. An effective alternative to microsurgical resection is stereotactic radiosurgery (SRS), which can be delivered in either single-fraction (SRS) or hypofractionated stereotactic radiotherapy (hSRT) (3-5 treatments) regimens. It remains unclear which fractionation regimen provides superior outcomes. METHODS: Ovid MEDLINE, EMBASE, CINAHL, and Cochrane Reviews were searched for studies either comparing hSRT with SRS or focusing on hSRT alone in treating VS. Primary endpoints included tumor control, serviceable hearing, tinnitus, and cranial nerve V and VII symptoms. A random-effects analysis was employed to compare pre- and post-treatment effects (hSRT alone) or SRS and hSRT outcomes (two-arm studies). RESULTS: This analysis included 21 studies focusing on hSRT alone and 13 studies comparing SRS and hSRT. Significant heterogeneity was observed. Overall, when hSRT was analyzed alone, crude tumor control was achieved in 94% (95% CI: 88%, 99%) of 1571 patients. There was no difference between pre- and post-treatment odds ratios (OR) of tinnitus, facial, or trigeminal impairment. Serviceable hearing was diminished following hSRT (OR = 0.60, 95% CI: 0.44, 0.83). Comparison with SRS showed no difference with respect to tumor control, serviceable hearing, trigeminal or facial nerve impairment. CONCLUSIONS: hSRT achieved excellent tumor control and, with the exception of serviceable hearing, did not result in worse post-treatment cranial nerve symptomatology. Analysis of comparative studies between hSRT and SRS did not reveal any significant difference in either tumor control or treatment morbidities.

Outcomes of stereotactic radiosurgery for large vestibular schwannomas: a systematic review and meta-analysis.

BACKGROUND: Large vestibular schwannomas (VS) pose a treatment challenge for both microsurgery (MS) and stereotactic radiosurgery (SRS). Technical developments have allowed for safer irradiation of large tumors. It remains unclear if SRS can achieve appropriate tumor control and acceptable cranial nerve toxicities. In this study, we assess outcomes of irradiation for large VS. METHODS: PubMed MEDLINE, EMBASE, Web of Science, and Cochrane were searched for all the studies assessing SRS outcome in large VS. Primary endpoints included clinical and radiographic tumor control, need for salvage surgery, serviceable hearing, cranial nerve V and VII impairment, presence of hydrocephalus requiring shunting, and presence of vertigo/dizziness. RESULTS: Twenty-two studies were identified that met selection criteria for analysis from an initial pool of 1272 reports. They were evaluated according to treatment protocol: 1) single-dose SRS (13 studies, 483 patients), 2) combination of MS and SRS (7 studies, 182 patients), and 3) fractionated SRS (3 studies, 82 patients). Tumor control was achieved in 89%, 94%, and 91% of patients, respectively. Odds ratios (ORs) of post- over pretreatment serviceable hearing were 0.42 (P < .01), 0.47 (P = .05), and 0.60 (P = .22); for facial nerve impairment, these ORs were 1.08 (P = .69), 3.45 (P = .28), and 0.87 (P = .71), respectively. CONCLUSIONS: The management of large VS remains challenging. All treatment modalities resulted in high tumor control rates and worsening of pretreatment hearing. None, however, caused significant facial nerve impairment, suggesting that management strategies incorporating focal irradiation can be successful.

[68Ga]-DOTATATE PET/MRI as an adjunct imaging modality for radiation treatment planning of meningiomas.

BACKGROUND: Meningiomas express high levels of somatostatin receptor 2 (SSTR2). SSTR2-targeted PET imaging with [68Ga]-DOTATATE can aid with distinguishing residual meningioma from reactive changes in the postoperative setting. We present initial dosimetric analyses, acute events, and local control data utilizing [68Ga]-DOTATATE PET/MRI-assisted target delineation for prospectively-treated intermediate-risk meningiomas. METHODS: Twenty-nine patients underwent DOTATATE PET/MRI meningioma evaluation in 2019. Eight patients with 9 postoperative meningiomas met RTOG 0539 intermediate-risk criteria (recurrent WHO grade I, 1/9; WHO grade II, 8/9). Target volumes were created using DOTATATE PET/MRI to determine residual disease and received a nominal dose of 35.0 Gy over 5 fractions. For comparison, cases were recontoured and planned with MRI alone per RTOG 0539 guidelines. Mean and maximum equivalent 2 Gy doses were generated for target volumes and organs at risk (OAR) within 1 cm of the PTV and compared using Wilcoxon matched pairs signed rank test. RESULTS: DOTATATE PET/MRI-guided planning significantly reduced mean PTV (11.12 cm3 compared to 71.39 cm3 based on MRI alone, P < .05) and mean and max dose to the whole brain, optic nerves, and scalp. PET/MRI plans resulted in at least 50% reduction of mean and max doses to the lens, eyes, chiasm, cochlea, brainstem, and hippocampi. One patient experienced focal alopecia. There were no local recurrences at 6 months. CONCLUSION: Incorporating DOTATATE-PET/MRI for postoperative target delineation in patients with intermediate-risk intracranial meningiomas results in PTV reduction and decreased OAR dose. Our findings warrant larger studies evaluating DOTATATE-PET/MRI in the radiotherapeutic planning of postoperative meningiomas.

Clinical Considerations in Neurosurgical Radiosurgery in the Time of COVID-19.

The COVID-19 pandemic is affecting all aspects of the healthcare ecosystem, including administration of stereotactic radiosurgery (SRS). The clinical and logistical challenges created by the COVID-19 public health crisis are clear, but the solutions to these issues are less readily apparent. The goal of this work is to use our experience at a large, academic medical center as a lens for interpreting the many looming issues specific to radiosurgery and its role in the treatment of brain and spine disorders. While the full impact of the pandemic remains to be seen, the aim of this paper is to provide a structural framework to optimize delivery of neurosurgically oriented radiosurgery with proposed clinical workflow strategies. Innovative solutions to the current pandemic crisis affecting the healthcare ecosystem will be driven by increased interdisciplinary and global dialogue.

The Impact of Radiation Therapy on Innate and Adaptive Tumor Immunity.

The role of radiation therapy for cancer is evolving as its biologic effects on tumors becomes more clearly defined. Traditionally, radiobiology models dose-response curves based on direct cytocidal effects of radiation on tumor cells. However, a more dynamic picture is emerging of the impact of radiation on the tumor microenvironment and the patient's innate and adaptive immune system. Radiation produces damage associated molecular patterns that activate innate immune receptors leading to a cascade of downstream signals. These signals alter the tumor infiltrating immune population, modulate immune cell activation status, and enhance antigen presentation. The changes are conducive to an adaptive immune response with the generation of antitumor T cells. Early findings from clinical trials incorporating radiation and immune checkpoint inhibitors show promising synergy between the 2 modalities. As more data matures from ongoing trials, clinicians can refine new strategies for using radiation together with immunotherapy to achieve improved clinical outcomes.

PTEN in the maintenance of genome integrity: From DNA replication to chromosome segregation.

Faithful DNA replication and accurate chromosome segregation are the key machineries of genetic transmission. Disruption of these processes represents a hallmark of cancer and often results from loss of tumor suppressors. PTEN is an important tumor suppressor that is frequently mutated or deleted in human cancer. Loss of PTEN has been associated with aneuploidy and poor prognosis in cancer patients. In mice, Pten deletion or mutation drives genomic instability and tumor development. PTEN deficiency induces DNA replication stress, confers stress tolerance, and disrupts mitotic spindle architecture, leading to accumulation of structural and numerical chromosome instability. Therefore, PTEN guards the genome by controlling multiple processes of chromosome inheritance. Here, we summarize current understanding of the PTEN function in promoting high-fidelity transmission of genetic information. We also discuss the PTEN pathways of genome maintenance and highlight potential targets for cancer treatment.

Cell Cycle Control by PTEN.

Continuous and error-free chromosome inheritance through the cell cycle is essential for genomic stability and tumor suppression. However, accumulation of aberrant genetic materials often causes the cell cycle to go awry, leading to malignant transformation. In response to genotoxic stress, cells employ diverse adaptive mechanisms to halt or exit the cell cycle temporarily or permanently. The intrinsic machinery of cycling, resting, and exiting shapes the cellular response to extrinsic stimuli, whereas prevalent disruption of the cell cycle machinery in tumor cells often confers resistance to anticancer therapy. Phosphatase and tensin homolog (PTEN) is a tumor suppressor and a guardian of the genome that is frequently mutated or deleted in human cancer. Moreover, it is increasingly evident that PTEN deficiency disrupts the fundamental processes of genetic transmission. Cells lacking PTEN exhibit cell cycle deregulation and cell fate reprogramming. Here, we review the role of PTEN in regulating the key processes in and out of cell cycle to optimize genomic integrity.

PTEN at the interface of immune tolerance and tumor suppression.

BACKGROUND: PTEN is well known to function as a tumor suppressor that antagonizes oncogenic signaling and maintains genomic stability. The PTEN gene is frequently deleted or mutated in human cancers and the wide cancer spectrum associated with PTEN deficiency has been recapitulated in a variety of mouse models of Pten deletion or mutation. Pten mutations are highly penetrant in causing various types of spontaneous tumors that often exhibit resistance to anticancer therapies including immunotherapy. Recent studies demonstrate that PTEN also regulates immune functionality. OBJECTIVE: To understand the multifaceted functions of PTEN as both a tumor suppressor and an immune regulator. METHODS: This review will summarize the emerging knowledge of PTEN function in cancer immunoediting. In addition, the mechanisms underlying functional integration of various PTEN pathways in regulating cancer evolution and tumor immunity will be highlighted. RESULTS: Recent preclinical and clinical studies revealed the essential role of PTEN in maintaining immune homeostasis, which significantly expands the repertoire of PTEN functions. Mechanistically, aberrant PTEN signaling alters the interplay between the immune system and tumors, leading to immunosuppression and tumor escape. CONCLUSION: Rational design of personalized anti-cancer treatment requires mechanistic understanding of diverse PTEN signaling pathways in modulation of the crosstalk between tumor and immune cells.

Excellent Long-term Breast Preservation Rate After Accelerated Partial Breast Irradiation Using a Balloon Device.

BACKGROUND: Accelerated partial breast irradiation (APBI) using a balloon device has been well tolerated. A recent retrospective population-based study showed an increase in the rate of subsequent mastectomy for patients who undergo APBI compared with whole breast radiation therapy. Our aim was to analyze the long-term results of patients treated with APBI at our institution to determine the salvage mastectomy and locoregional recurrence rates and cosmesis outcomes. MATERIALS AND METHODS: After institutional review board approval, we conducted a retrospective review of 111 patients treated from June 2003 to October 2014 at our institution for early-stage breast cancer using a balloon device. After lumpectomy and nodal staging, the patients underwent APBI with high-dose rate iridium-192 brachytherapy. A computed tomography-based 3-dimensional plan was created, and a dose of 34 Gy in 10 fractions was given twice daily, 6 hours apart, over 5 days. Follow-up examinations were performed 2 to 3 times annually by either a surgeon and/or a radiation oncologist. Annual mammograms were obtained. The patients included postmenopausal women with node-negative early-stage invasive ductal carcinoma with a tumor size < 3 cm (n = 93) or ductal carcinoma in situ (n = 18). Cosmesis was evaluated using the Harvard criteria, as excellent, good, fair, or poor. RESULTS: At a median follow-up period of 66 months (range, 1-139 months) after completing treatment, with a minimum of 5 years of follow-up data for 62 patients (55.9%), the incidence of ipsilateral breast tumor recurrence (IBTR) was 2.7% (n = 3) and the incidence of ipsilateral axilla nodal recurrence was 1.8% (n = 2). The ipsilateral breast preservation rate was 97.3%. The salvage mastectomy rate was 2.7% (n = 3), and the 5-year salvage mastectomy-free rate was 98.7% (95% confidence interval, 91.0%-99.8%). No distant failure developed, and no breast cancer-related deaths occurred. The 5-year overall survival rate was 91.7% (95% confidence interval, 83.2%-96.0%), and the 10-year breast cancer-specific survival rate was 100%. Of the 3 cases of IBTR, 2 were estrogen receptor negative (P = .076). The mean interval to IBTR was 78.7 ± 27.5 months from treatment completion. A significant association was noted between African-American ethnicity and IBTR (P = .0398). Excellent to good cosmesis was observed in 98.1% of the patients. The maximum skin dose (mean value) for patients with excellent, good, and fair cosmesis was 302.2 Gy, 315.4 Gy, and 372.5 Gy (88.9%, 92.7%, and 109.5% of the prescription dose), respectively. The maximum skin dose was < 340 Gy (100% of the prescribed dose) in 69.9% of patients with excellent to good cosmesis. CONCLUSION: The long-term follow-up data of patients receiving APBI with a balloon device showed a low salvage mastectomy rate with durable long-term breast preservation. Excellent local control with good cosmesis was noted in these postmenopausal patients treated with APBI.

Transplantation of mouse HSCs genetically modified to express a CD4-restricted TCR results in long-term immunity that destroys tumors and initiates spontaneous autoimmunity.

The development of effective cancer immunotherapies has been consistently hampered by several factors, including an inability to instigate long-term effective functional antitumor immunity. This is particularly true for immunotherapies that focus on the adoptive transfer of activated or genetically modified mature CD8+ T cells. In this study, we sought to alter and enhance long-term host immunity by genetically modifying, then transplanting, mouse HSCs. We first cloned a previously identified tumor-reactive HLA-DR4-restricted CD4+ TCR specific for the melanocyte differentiation antigen tyrosinase-related protein 1 (Tyrp1), then constructed both a high-expression lentivirus vector and a TCR-transgenic mouse expressing the genes encoding this TCR. Using these tools, we demonstrated that both mouse and human HSCs established durable, high-efficiency TCR gene transfer following long-term transplantation into lethally irradiated mice transgenic for HLA-DR4. Recipients of genetically modified mouse HSCs developed spontaneous autoimmune vitiligo that was associated with the presence of a Th1-polarized memory effector CD4+ T cell population that expressed the Tyrp1-specific TCR. Most importantly, large numbers of CD4+ T cells expressing the Tyrp1-specific TCR were detected in secondary HLA-DR4-transgenic transplant recipients, and these mice were able to destroy subcutaneously administered melanoma cells without the aid of vaccination, immune modulation, or cytokine administration. These results demonstrate the creation of what we believe to be a novel translational model of durable lentiviral gene transfer that results in long-term effective immunity.

High-avidity autoreactive CD4+ T cells induce host CTL, overcome T(regs) and mediate tumor destruction.

Despite progress made over the past 25 years, existing immunotherapies have limited clinical effectiveness in patients with cancer. Immune tolerance consistently blunts the generated immune response, and the largely solitary focus on CD8+ T cell immunity has proven ineffective in the absence of CD4+ T cell help. To address these twin-tier deficiencies, we developed a translational model of melanoma immunotherapy focused on the exploitation of high-avidity CD4+ T cells that become generated in germline antigen-deficient mice. We had previously identified a tyrosinase-related protein-1 specific HLA-DRB1*0401-restricted epitope. Using this epitope in conjunction with a newly described tyrosinase-related protein-1 germline-knockout, we demonstrate that endogenous tyrosinase-related protein-1 expression alters the functionality of the autoreactive T cell repertoire. More importantly, we show, by using major histocompatibility complex-mismatched combinations, that CD4+ T cells derived from the self-antigen deficient host indirectly triggers the eradication of established B16 lung metastases. We demonstrate that the treatment effect is mediated entirely by endogenous CD8+ T cells and is not affected by the depletion of host regulatory T cells. These findings suggest that high-avidity CD4+ T cells can overcome endogenous conditions and mediate their antitumor effects exclusively through the elicitation of CD8+ T cell immunity.

Cofactors, redox state, and directional preferences of hydroxysteroid dehydrogenases.

The hydroxysteroid dehydrogenases (HSDs) interconvert pairs of weak and potent steroids, thus serving as key enzymes in the regulation of intracellular hormone potency. These enzymes may appear to drive unidirectional steroid flux in intact cells but actually catalyze bi-directional metabolism that achieve pseudo-equilibria with strong directional preferences. Even small shifts in the magnitude of these pseudo-equilibria can profoundly change steroid potency and thus contribute to disease. Consequently, we are studying the structural and biochemical principles that govern these directional preferences and the resilience of these pseudo-equilibria in intact cells. HSD directional preferences in intact cells are governed largely by relative affinities for nicotinamide cofactors [NAD(P)(H)] and existing cofactor gradients. We can attenuate the directional preferences for human 17betaHSD type 1 and rat AKR1C9 in intact cells by either diminishing the NADPH/NADP(+) gradient or by mutating the arginine residues that form salt bridges with the 2'-phosphate of NADP(H) (R38 and R276, respectively).

Arginine 276 controls the directional preference of AKR1C9 (rat liver 3alpha-hydroxysteroid dehydrogenase) in human embryonic kidney 293 cells.

Rat liver AKR1C9 is the best-studied 3alpha-hydroxysteroid dehydrogenase (3alphaHSD) of the aldo-keto reductase superfamily. The physiologic function of AKR1C9 is to catalyze the reduction of 5alpha-androstane-17beta-ol-3-one (dihydrotestosterone) to 5alpha-androstane-3alpha,17beta-diol (androstanediol) rather than the reverse reaction, and all of the known AKR1C enzymes with 3alphaHSD activity also preferentially catalyze dihydrotestosterone reduction in intact cells. Because the utilization of pyridine-nucleotide cofactors NAD(P)(H) primarily governs the directional preference of HSD enzymes in intact cells, and because R276 participates in NADP(H) binding, we hypothesized that mutation of R276 would alter directional preference in intact cells. To test this model, we constructed stable lines of human embryonic kidney 293 cells expressing wild-type AKR1C9 and mutations R276M, R276G, and R276E. Mutations R276M and R276G retained reductive preference with slightly reduced magnitude compared with wild-type AKR1C9. NADPH depletion by glucose deprivation minimally altered the equilibrium steroid distribution for wild-type AKR1C9 but further reduced the reductive preference of mutations R276M and R276G. Mutation R276E, in contrast, showed an oxidative preference under all conditions. The intrinsic rates of the reductive and oxidative reactions for all four enzymes were similar at the functional equilibrium states. We conclude the R276 maximizes the reductive preference of AKR1C9 in intact cells and maintains this strong preference despite NADPH depletion; mutation R276E reverses the directional preference.