The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction–based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.

In the authors' experience with both primary and secondary resection of malignant brain astrocytomas, increasing extent of resection was associated with improved survival independent of age, degree of disability, WHO grade, or subsequent treatment modalities used. The maximum extent of resection should be safely attempted while minimizing the risk of surgically induced neurological injury.

Cell-free DNA shed by cancer cells has been shown to be a rich source of putative tumor-specific biomarkers. Because cell-free DNA from brain and spinal cord tumors cannot usually be detected in the blood, we studied whether the cerebrospinal fluid (CSF) that bathes the CNS is enriched for tumor DNA, here termed CSF-tDNA. We analyzed 35 primary CNS malignancies and found at least one mutation in each tumor using targeted or genome-wide sequencing. Using these patient-specific mutations as biomarkers, we identified detectable levels of CSF-tDNA in 74% [95% confidence interval (95% CI) = 57-88%] of cases. All medulloblastomas, ependymomas, and high-grade gliomas that abutted a CSF space were detectable (100% of 21 cases; 95% CI = 88-100%), whereas no CSF-tDNA was detected in patients whose tumors were not directly adjacent to a CSF reservoir (P < 0.0001, Fisher's exact test). These results suggest that CSF-tDNA could be useful for the management of patients with primary tumors of the brain or spinal cord.CSF-tDNA | CNS tumors | biomarker

GTR was associated with a delay in tumor progression and malignant degeneration as well as improved OS independent of age, degree of disability, histological subtype, or revision versus primary resection. GTR should be safely attempted when not limited by eloquent cortex.

Introduction. Surgery is first-line therapy for glioblastoma, and there is evidence that gross total resection is associated with improved survival. Gross total resection, however, is not always possible, and relationships among extent (percent) of resection (EOR), residual volume (RV), and survival are unknown. The goals were to evaluate whether there is an association between EOR and RV with survival and recurrence and to establish minimum EOR and maximum RV thresholds. Methods. Adult patients who underwent primary glioblastoma surgery from 2007 to 2011 were retrospectively reviewed. Three-dimensional volumetric tumor measurements were made. Multivariate proportional hazards regression analysis was used to evaluate the relationship between EOR and RV with survival and recurrence. Results. Of 259 patients, 203 (78%) died and 156 (60%) had tumor recurrence. The median survival and progression-free survival were 13.4 and 8.9 months, respectively. The median (interquartile range) pre-and postoperative tumor volumes were 32.2 (14.0-56.3) and 2.1 (0.0-7.9) cm 3 , respectively. EOR was independently associated with survival (hazard ratio [HR], 0.995; 95% confidence interval [CI]: 0.990-0.998; P ¼ .008) and recurrence (HR [95% CI], 0.992 [0.983-0.998], P ¼ .005). The minimum EOR threshold for survival (P ¼ .0006) and recurrence (P ¼ .005) was 70%. RV was also associated with survival (HR [95% CI], 1.019 [1.006-1.030], P ¼ .004) and recurrence (HR [95% CI], 1.024 [1.001-1.044], P ¼ .03). The maximum RV threshold for survival (P ¼ .01) and recurrence (P ¼ .01) was 5 cm 3. Conclusion. This study shows for the first time that both EOR and RV are significantly associated with survival and recurrence, where the thresholds are 70% and 5 cm 3 , respectively. These findings may help guide surgical and adjuvant therapies aimed at optimizing outcomes for glioblastoma patients.

In our experience, the development of new perioperative motor or language deficits was associated with decreased overall survival despite similar extent of resection and adjuvant therapy. Although it is well known that surgically induced neurological deficits affect quality of life, our results suggest that these surgical morbidities may also affect survival. Care should be taken to avoid surgically induced deficits in the management of GBM.

Basal ganglia lesions, thalamic lesions, and patients with diabetes were independent risk factors for biopsy-associated morbidity. Hyperglycemia on the day of biopsy predicted morbidity in the diabetic population. Epilepsy did not predispose to biopsy-associated seizure. For deep-seated lesions, increasing the number of biopsy samples along an established track rather than performing a second trajectory may minimize the incidence of morbidity. Close perioperative observation of glucose levels may be warranted.

Object Gliadel (BCNU) wafer and concomitant temozolomide (TMZ) therapy, when used individually as adjuvant therapies, extend survival from that achieved by resection and radiation therapy (XRT) for glioblastoma multiforme (GBM). It remains unstudied whether combining Gliadel and TMZ therapy is safe or further improves survival in patients with newly diagnosed GBM. The authors reviewed their initial experience utilizing combined Gliadel, TMZ, and radiation therapy for the treatment of GBM. Methods All cases involving patients undergoing primary resection of GBM with or without Gliadel wafer (3.85% BCNU) implantation and adjuvant XRT over a 10-year period (1997–2006) were retrospectively reviewed. Beginning in 2004, concomitant TMZ became the standard of care at the authors’ institution and all patients with Gliadel implantation also received concomitant TMZ (Stupp protocol). Overall survival and treatment-related morbidity were assessed for all patients treated with Gliadel plus concomitant TMZ (XRT + Gliadel + TMZ). Age-matched (≤ 70 years) comparison of survival and morbidity was performed between the XRT + Gliadel + TMZ (post-2003) and XRT + Gliadel (pre-2004) cohorts. Results Thirty-three patients were treated with XRT + Gliadel + TMZ. The median survival in this group was 20.7 months, with a 2-year survival rate of 36%. Six-month morbidity included surgical site infection in 1 case (3%), perioperative seizures in 2 cases (6%), deep-vein thrombus in 1 (3%), pulmonary embolism in 3 (9%), and cerebral edema requiring admission for intravenous dexamethasone in 1 case (3%). Myelosuppression required premature termination of TMZ in 7 patients (21%) (thrombocytopenia in 5, neutropenia in 2 cases). In patients ≤ 70 years of age, XRT + Gliadel + TMZ (30 patients, post-2003) was independently associated with improved median survival (21.3 vs 12.4 months, p = 0.005) versus XRT + Gliadel (78 patients, pre-2004), with 2-year survival of 39 versus 18%, respectively. In these patients, XRT + Gliadel + TMZ was not associated with an increase in perioperative morbidity in comparison with XRT + Gliadel. Conclusions In this experience, concomitant TMZ therapy in addition to Gliadel wafer implantation was associated with a median survival of nearly 21 months without increased perioperative morbidity. Temozolomide can be safely administered to patients receiving Gliadel wafers after resection of GBM.