Clinical outcomes in estrogen receptor-positive early-stage breast cancer patients with Recurrence Score 26-30: observational real-world cohort study.

Data on adjuvant chemotherapy (CT) benefit in ER + HER2‒ early-stage breast cancer (EBC) patients with Recurrence Score (RS) 26-30 are limited. This real-world study evaluated the relationships between the RS, adjuvant treatments, and outcomes in 534 RS 26-30 patients tested through Clalit Health Services (N0: n = 394, 49% CT-treated; N1mi/N1: n = 140, 62% CT-treated). The CT-treated and untreated groups were imbalanced (more high-risk clinicopathologic characteristics in CT-treated patients). With median follow-up of 8 years, Kaplan-Meier estimates for overall survival (OS), distant recurrence-free survival (DRFS), and BC-specific mortality (BCSM) were not significantly different between CT-treated and untreated N0 patients. Seven-year rates (95% CI) in CT-treated vs untreated: OS, 97.9% (94.4-99.2%) vs 97.9% (94.6-99.2%); DRFS, 91.5% (86.6-94.7%) vs 91.2% (86.0-94.6%); BCSM, 0.5% (0.1-3.7%) vs 1.6% (0.5-4.7%). For N1mi/N1 patients, OS/DRFS did not differ significantly between treatment groups; whereas BCSM did (1.3% [0.2-8.6%] vs 6.2% [2.0-17.7%] for CT-treated and untreated patients, respectively, p = 0.024).

Selective Intra-Arterial Doxorubicin Eluting Microsphere Embolization for Desmoid Fibromatosis: A Combined Prospective and Retrospective Study.

Desmoid fibromatoses (DFs) are locally aggressive tumors composed of monoclonal fibroblasts within an abundant extracellular matrix. Systemic doxorubicin treatment is effective, but toxic. We investigated arterial doxorubicin eluting embolization (DEE), an approach characterized by high drug concentrations in the tumor alongside limited systemic drug exposure. The primary and secondary endpoints were radiological response using MRI and RECIST 1.1, respectively. The study included 24 patients (median age, 24; interquartile range, 16-34 years). Data were collected prospectively for 9 patients and retrospectively for 15 patients. The most frequent tumor locations were chest/abdomen wall and neck/shoulder/axilla (29% each). Of 24 patients, 7 (24%) were treatment naïve, and 17 (71%) had received one or two prior treatments. Patients underwent a median of two treatments (range, 1-4), with a median of 49 mg (range, 8-75) doxorubicin/treatment. Efficacy outcomes were available for 23 patients. With a median follow-up of 8 months (interquartile range, 3-13), median tumor volumes decreased by 59% (interquartile range, 40-71%) and T2 signal intensity decreased by 36% (interquartile range, 19-55%). Of 23 patients, 9 (39%), 12 (52%), and 2 (9%) had a partial response, stable disease, and progressive disease, respectively. DEE was safe and well tolerated, with one reported grade 3-4 adverse event (cord injury). In conclusion, DEE was safe and achieved rapid clinical/volumetric responses in DFs.

Palbociclib in combination with sunitinib exerts a synergistic anti-cancer effect in patient-derived xenograft models of various human cancers types.

The efficacy/safety of combining palbociclib (a CDK4/6 inhibitor) and sunitinib (a multi-targeted receptor tyrosine kinase inhibitor) was evaluated, using patient-derived xenograft (PDX) models. Twenty-three PDX mice models were developed from patients with various solid tumors. The mice were randomized to 4 groups (5-6 mice in each): control/palbociclib (100 mg/kg)/sunitinib (50 mg/kg)/combination. Drugs were administered orally, 5 days/week. In 17/23 PDX models (74%), the combination demonstrated a synergistic inhibitory effect vs the monotherapies ("responder" models) with no unexpected toxicities. In 13/17 responder models, where standard-of-care (SOC) was an additional comparator, the combination was more effective than SOC in 7 models, as effective in 4, and less effective in 2. The mean ± SEM experiment duration in 15/17 responder models (2/17 were excluded due to technical issues) was 86 ± 12 and 31 ± 5 days for the combination and control groups, respectively (p = 0.0002). The effect of the combination was dose-dependent. Cell-viability experiments in A549/MDA-MB-231/HT-29 cell lines and experiments using tumor-derived primary cell spheroids supported the PDX findings. In conclusion, combination of palbociclib and sunitinib exerts a synergistic anti-tumor effect without adding unexpected toxicity. A clinical trial assessing this combination is underway.

Durvalumab after concurrent chemotherapy and high-dose radiotherapy for locally advanced non-small cell lung cancer.

The standard of care for stage III non-small cell lung cancer (NSCLC) is chemoradiotherapy (CRT) followed by durvalumab. Although doses higher than 66 Gy are standard in our center, they were used in only 6.9% of patients in the PACIFIC trial. We report our experience with durvalumab after high-dose radiotherapy. The database of a tertiary hospital for patients with stage III NSCLC who were treated with CRT and adjuvant durvalumab was evaluated. Progression-free survival (PFS), overall survival (OS), and local-regional failure (LRF) were measured from the administration of durvalumab. Thirty-nine patients were included. All were treated with intensity-modulated radiation (mean dose 69.9 Gy); Median follow-up time was 20.4 months (range 1-35.4). At 12 months, PFS was 49%, OS 79%, and LRF 14%. Intrathoracic failure at first progression was demonstrated in 8 (21%) patients. Adverse events requiring corticosteroids occurred in 10(25.6%) patients: pneumonitis - 6 (15.4%), hepatitis - 2 (5.1%), and arthralgia and pericarditis - 1 (2.6%). One patient (2.6%) died of pneumonitis. The occurrence of pneumonitis was significantly associated with lung V5 (55% vs. 42%, p = .04) and V20 (28% vs. 19%, p = .01) and mean lung dose (14.8 Gy vs.11.6 Gy, p = .05). The similar 12-month PFS and OS rates of our cohort and the PACIFIC trial support the use of high-dose radiotherapy in patients with stage III NSCLC. Treatment-related mortality was similar to the PACIFIC results. The intrathoracic failure rate in our cohort was lower than that reported from the PACIFIC trial, suggesting that radiation dose escalation may improve local control.

Neutrophil-to-Lymphocyte Ratio Predicts Recurrence Pattern in Patients with Resectable Colorectal Liver Metastases.

BACKGROUND: Studies have suggested that neutrophil-to-lymphocyte ratio (NLR) has value as a predictor of long-term outcomes in various cancer types. Its prognostic potential in patients with CRLM has not been thoroughly investigated. This original, retrospective study assessed the relationship between the preoperative NLR, survival outcomes, and recurrence patterns in patients after colorectal liver metastasis resection (CRLM). METHODS: The prospectively maintained database of a tertiary medical center was queried for all patients who underwent CRLM resection between 2005 and 2017. Patients were divided into two groups: NLR <3 (normal) or >3 (high). Recurrence risk was analysed using Fine and Gray correction for competing risk method and cause specific analyses. RESULTS: The cohort included 231 patients of whom 53 (23%) had a high neutrophil-to-lymphocyte ratio. At presentation, 35% had synchronous disease and 48% had a solitary metastasis; median tumor size was 2 cm. Patients with a high NLR had a significantly higher rate of simultaneous colorectal resection (P = 0.01). A high NLR was independently associated with worse OS (P = 0.02), worse DFS (P = 0.03), and higher risk of recurrence (P = 0.048), specifically recurrence with an extrahepatic pattern (P = 0.03). CONCLUSIONS: A high preoperative NLR was independently associated with poorer survival outcomes and extrahepatic recurrence pattern. The NLR appears to have prognostic importance in CRLM and may serve as a surrogate marker of aggressive systemic disease after resection. These findings warrant external validation, preferably in a prospective design.

Tyrosine Kinase Inhibitors as a Treatment of Symptomatic CNS Metastases in Oncogene-Driven NSCLC.

Central nervous system (CNS) metastases occur frequently in oncogene-driven non-small cell lung cancer (NSCLC). Standard treatment approaches can potentially delay systemic treatment (surgical intervention) or result in neurocognitive impairment (radiotherapy). Recently, next-generation tyrosine kinase inhibitors (TKIs) have demonstrated remarkable intracranial activity. However, most clinical trials did not enroll patients suffering neurological symptoms. Our study aimed to assess the CNS activity of targeted therapies in this patient population. We present a case series of nine NSCLC patients with either EGFR mutation or ALK rearrangement and symptomatic CNS metastases that were treated with TKIs. Clinicopathological characteristics, treatment, and outcomes were analyzed. Most patients presented with symptomatic CNS metastases at time of metastatic disease presentation (6/9). Additionally, the majority of patients had leptomeningeal disease (6/9) and multiple parenchymal metastases. Patients presented with a variety of CNS symptoms with the most common being nausea, vomiting, headache, and confusion. Most patients (6/9) responded rapidly both clinically and radiographically to the targeted treatment, with a marked correlation between systemic and intracranial radiographic response. In conclusion, upfront use of next-generation TKIs in patients with oncogene-driven NSCLC with symptomatic CNS metastases is associated with reasonable intracranial activity and represents a valuable treatment option.

Potential Association between Kaposi Sarcoma and Gout: An Exploratory Observational Study.

BACKGROUND: Kaposi sarcoma is a rare vascular mesenchymal neoplasm, associated with Human Herpes Virus 8 (HHV8). Gout is a condition clinically characterized by recurrent flares of arthritis and hyperuricemia. Following our clinical impression that patients with classical Kaposi sarcoma (CKS) have a high rate of gout, we explored this in a retrospective manner. METHODS: All consecutive patients diagnosed with sarcoma or carcinosarcoma within a single tertiary center between 1/2012-12/2017 were identified through the pathology department database. A cohort of CKS patients was compared with the non-Kaposi sarcoma and carcinosarcoma cohort. Data were extracted from patients' electronic medical records. Patients younger than 18 and patients without clinical data available were excluded. Association between diagnosis of gout and CKS was assessed and adjusted for risk factors. RESULTS: Three hundred and sixty-one patients were eligible for this analysis, 61 were diagnosed with CKS and 300 with other types of sarcoma. We found a higher incidence of gout in CKS patients, 11/61 (18%) patients, compared with 8/300 (2.6%) with other types of sarcoma, odds ratio (OR) 8.0 (P < 0.00001). This association persisted when adjusted for age >39 years (OR = 6.7, P < 0.00001), age and male sex (OR = 4.97, P < 0.0001), and when adjusting for multiple confounding factors and medical comorbidities. CONCLUSIONS: We have demonstrated a statistically significant association between gout and CKS. As risk factors for gout were accounted for, this association may be explained by HHV8 immune-related effects. This should be further explored in vitro and in population-based studies.

Safety and efficacy of VB-111, an anticancer gene therapy, in patients with recurrent glioblastoma: results of a phase I/II study.

BACKGROUND: VB-111 is a non-replicating adenovirus carrying a Fas-chimera transgene, leading to targeted apoptosis of tumor vascular endothelium and induction of a tumor-specific immune response. This phase I/II study evaluated the safety, tolerability, and efficacy of VB-111 with and without bevacizumab in recurrent glioblastoma (rGBM). METHODS: Patients with rGBM (n = 72) received VB-111 in 4 treatment groups: subtherapeutic (VB-111 dose escalation), limited exposure (LE; VB-111 monotherapy until progression), primed combination (VB-111 monotherapy continued upon progression with combination of bevacizumab), and unprimed combination (upfront combination of VB-111 and bevacizumab). The primary endpoint was median overall survival (OS). Secondary endpoints were safety, overall response rate, and progression-free survival (PFS). RESULTS: VB-111 was well tolerated. The most common adverse event was transient mild-moderate fever. Median OS time was significantly longer in the primed combination group compared with both LE (414 vs 223 days; hazard ratio [HR], 0.48; P = 0.043) and unprimed combination (414 vs 141.5 days; HR, 0.24; P = 0.0056). Patients in the combination phase of the primed combination group had a median PFS time of 90 days compared with 60 in the LE group (HR, 0.36; P = 0.032), and 63 in the unprimed combination group (P = 0.72). Radiographic responders to VB-111 exhibited characteristic, expansive areas of necrosis in the areas of initial enhancing disease. CONCLUSIONS: Patients with rGBM who were primed with VB-111 monotherapy that continued after progression with the addition of bevacizumab showed significant survival and PFS advantage, as well as specific imaging characteristics related to VB-111 mechanism of action. These results warrant further assessment in a randomized controlled study.

Prognostic Value of the Detection of Lymphovascular Invasion in Hormone Receptor-Positive Early Breast Cancer in the Era of Molecular Profiling.

BACKGROUND: Lymphovascular invasion (LVI) is considered a negative prognostic factor in early breast cancer, but its role in decision-making regarding adjuvant chemotherapy is unclear in the current era of molecular profiling. This study sought to evaluate the association of LVI status with the recurrence score (RS) on the multigene Oncotype DX (ODX) assay and its impact on outcome. METHODS: Patients with early estrogen receptor-positive breast cancer who underwent ODX analysis in 2005-2012 were retrospectively identified. Clinical data were collected from the medical records. The Cox proportional-hazards ratio was used to determine recurrence rates. The prognostic significance of LVI was evaluated by competing risks analysis. RESULTS: LVI was detected in 38 of 657 patients (6%). LVI was not associated with ODX RS (p = 0.225). However, it was significantly associated with other known prognostic factors and with worse 5-year disease-free survival (HR 2.93; 95% CI 1.02-8.39; p = 0.04). Overall survival (OS) analysis according to the ODX subgroups showed that the presence of LVI was associated with worse 5-year OS (p = 0.04) only in the intermediate-risk group, while LVI had no effect on the low- or high-risk groups. CONCLUSIONS: Although LVI was not significantly associated with a higher ODX RS, it may infer a worse outcome, especially in ODX intermediate-risk patients.