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BACKGROUND: The extent of surgical management of regional lymph nodes in the treatment of cutaneous head and neck melanoma on and anterior to O'Brien's watershed line is controversial. By comparing patients' cohorts of two separate melanoma expert centers we investigate the effectiveness of comprehensive versus (super-) selective neck dissection approach.METHODS: Sixty patients with macroscopic (palpable) neck node metastases (N2b) from anterior scalp and face melanoma were retrospectively studied. Forty therapeutic modified radical neck dissections (MRND; levels I-V) combined with elective parotidectomy from The Netherlands Cancer Institute (NCI) were compared with 16 (super-) selective neck dissections [(S)SND; 3-4 levels] and 4 solely MRNDs from Erasmus Medical Center (EMC). Cohorts were analyzed for site of recurrence, overall survival (OS), melanoma-specific survival (MSS), and disease-free survival (DFS).RESULTS: Clinical characteristics of patients were equal in both groups. In the NCI cohort 62.5% (n = 25) of patients recurred versus 65% (n = 13) in the EMC cohort. None of the NCI recurrences affected the parotid gland in contrast to 3 patients in the EMC group. Survival characteristics were not different between the two groups: OS (p = 0.56), MSS (p = 0.98), DFS (p = 0.92).CONCLUSION: This study does not support to continue the practice of routine elective parotidectomy and MRND in melanoma patients undergoing a lymph node dissection for macroscopic (palpable) nodal disease and justifies (S)SND.

Background: Surgical resection is the standard of care for parotid gland tumors. Comprehensive reports on the surgical complications of parotidectomy are lacking. This study focuses on surgical wound complications of parotid gland surgery.Patients and methods: In the period 2002-2012, 390 consecutive patients (395 procedures) who underwent parotid gland surgery were selected for retrospective analysis. Based on subsequent management, the impact of surgical site complications was graded by the Clavien-Dindo Classification (CDC).Results: In 83 (21.0%) of the procedures, at least one complication was registered. In total, 118 complications were described. Rated to CDC, 61 patients (15.4%) were graded as class 2 or higher. This implies therapy was dictated. Fortyfive (11.4%) of the complications were surgical site infections (551). In 9 patients (2.3%) surgical complications required a surgical intervention under general anesthesia (CDC class 3b), and in 19 patients (4.8%) other invasive treatment (CDC class 3a) was needed.Conclusions: The Clavien-Dindo Classification proved to be very useful for retrospective registration of surgical complications. Of the 61 patients, 33 were managed by conservative therapy. No risk profile was found for patients at risk for direct surgical complications. (C) 2019 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Talimogene laherparepvec (T-VEC) is a modified herpes simplex virus, type 1 (HSV-1), which can be administered intralesionally in patients with stage IIIB/C-IVM1a unresectable melanoma (EMA label). The phase 3 OPTiM registration study showed an overall response rate (ORR) of 26%. Since December 2016, 48 eligible patients started treatment at the Netherlands Cancer Institute. We included 26 patients in this study with a follow up time ≥6 months, reporting Overall Response Rate (ORR), Disease Control Rate (DCR), Adverse Events (AE), prior treatment for melanoma and baseline characteristics, documented in a prospectively maintained database. In house developed treatment protocol consists of clinical evaluation, periodic PET-CT and histological biopsies for response evaluation. Median follow-up was 12.5 months. Of 26 patients, 16 (61.5%) had a Complete Response (CR) as their best response. Seven (26.9%) patients had a Partial Response (PR) as their best response, 1 (3.8%) patient Stable Disease (SD) and 2 (7.7%) patients Progressive Disease (PD). Best ORR was 88.5%. DCR was 92.3%. Grade 1-2 AEs occurred in all patients. Mostly, these consisted of fatigue, influenza-like symptoms and injection site erythema. All patients underwent prior treatment. Prior treatment did not influence response or toxicity of T-VEC. Best ORR for T-VEC monotherapy at our institute was 88.5% with 61.5% achieving a CR. This prospective study for T-VEC in early metastatic (stage IIIB/C-IVM1a) melanoma demonstrated superior results to the phase 3 OPTiM study and confirms the role of oncolytic immunotherapy for melanoma.

Background Parotidectomy in melanoma of the coronal scalp and face with clinically involved cervical lymph node metastasis is based on predicted cervical lymphatic drainage described by O'Brien. Methods In total, 40 parotidectomies with en bloc therapeutic neck dissection were retrospectively analyzed. Results Lymphatic spread of melanoma to the parotid lymph nodes was observed in 10 of 40 specimens (25%). Eight of the 10 parotid-positive patients developed a recurrence vs 17 of the 30 parotid-negative patients (P = 0.28). There were no differences in overall survival, melanoma-specific survival, and disease-free survival between the parotid-positive and parotid-negative patients. Conclusion Although in this series no survival differences were found, parotidectomy still merits a sustained role in therapeutic neck dissection procedures to improve regional control and to prevent facial nerve damage after surgery for a second relapse from occult metastases in the parotid.

Background TNM staging of melanoma has recently been altered by the introduction of the 8th edition of the AJCC Cancer Staging manual. The purpose of this study is to analyze the inter-observer variation of histopathology reports and its effect on recommended treatment policy. Methods We retrospectively analyzed 296 cases, diagnosed as primary cutaneous head and neck melanoma (2005–2016), referred to the Netherlands Cancer Institute (NCI) for treatment after prior diagnosis in another hospital (non-NCI). All reports were analyzed for patients demographics, tumor characteristics and histopathologic features. Results In 53% and 40% of the cases, the histopathologic parameters were discordant, according to AJCC 7th and 8th edition, respectively. This indicated a perfect inter-observer agreement for the measurement of Breslow thickness (Intraclass correlation coefficient (ICC) = 0.981) and a substantial agreement for subtype (kappa statistic (κ) = 0.648) and ulceration (κ = 0.802), while only moderate for dermal mitotic activity (κ = 0.472). After NCI review, recommended treatment policies were changed in 13% and 11% of the patients when applying TNM 7 and TNM 8, respectively. Scheduling sentinel lymph node biopsy (SLNB) changed in 14 (5%) and 10 (3%) cases when using TNM 7 and TNM 8, respectively. Conclusion Review by a NCI pathologist of histopathologic parameters of primary cutaneous head and neck melanoma led to significant changes in treatment decision. Introduction of the AJCC 8th edition led to slightly less discordances between NCI and non-NCI reports and consequently smaller impact on treatment planning. Expert review remains indicated when a SLNB is considered for additional staging in selected cases.

Author(s): Vasudevan, H; Magill, S; Seo, K; Villanueva-Meyer, J; Choudhury, A; Liu, SJ; Pekmezci, M; Findakly, S; Hilz, S; LaStella, S; Braunstein, SE; Oberheim, NA; Aghi, MK; Theodosopoulos, PV; Sneed, PK; Berger, MS; McDermott, MW; Lim, D; Ulian, E; Costello, J; Raleigh, D

To investigate whether quantitative dynamic susceptibility-weighted contrast-enhanced (DSC) perfusion magnetic resonance imaging (MRI) metrics are influenced by cellular and genomic expression patterns of glioblastoma angiogenesis.Twenty-five stereotactic neurosurgical tissue samples were prospectively obtained from enhancing and non-enhancing tumour regions from 10 patients with treatment-naïve glioblastoma. Using monoclonal antibodies, histopathological features of angiogenesis were examined: total microvascular density, vascular morphology, and hypoxia. Angiogenic expression patterns of tissue samples were investigated using RNA microarrays. DSC perfusion MRI metrics were measured from the tissue sampling sites. MRI and histopathological variables were compared using Pearson's correlations. Microarray analysis was performed using false discovery rate (FDR) statistics.Thirteen enhancing and 12 non-enhancing MR image-guided tissue specimens were prospectively obtained. Enhancing tumour regions demonstrated a significant difference in DSC perfusion and histopathological metrics of angiogenesis when compared to non-enhancing regions. Four angiogenic pathways (vascular endothelial growth factor [VEGF], hypoxia inducible factor [HIF], platelet-derived growth factor [PDGF], fibroblast growth factor [FGF]; 25 individual genes) were significantly up-regulated within enhancing regions when compared to non-enhancing regions (adjusted p0.05, FDR0.05). A statistically significant correlation was observed between VEGF-A expression, microvascular density, microvascular morphology, and DSC perfusion MRI metrics (p0.05).Pro-angiogenic genomic and cellular expression patterns of treatment-naïve primary glioblastoma significantly influences morphological and physiological DSC perfusion metrics suggesting that expression levels of therapeutically relevant genetic signatures can be quantified using MRI.

BACKGROUND Nearly 80,000 new cases of primary brain tumors are expected to be diagnosed this year in the United States: 32% of CNS tumors are malignant. Anecdotally, patients who report use of cannabis, frequently describe higher quality of life scores (QOL) in standardized instruments. However, the lack of available tools that allow systematic documentation of cannabis use results in a barrier to accurately assess efficacy and potential benefits and risks. MATERIAL AND METHODS We conducted a single center, observational study: patients with primary brain tumors answered a previously validated instrument to explore cannabis use. QOL was assessed using the instruments from the European Organisation for Research and Treatment of Cancer(EORTC): QLQ-C30 and its complementary module BN-20 as well as the EuroQol group’s instrument EQ-5D-5L. Eligible participants were identified as cannabis users or non-users, completing the instruments in a self-administered fashion. RESULTS To date, 45 patients who signed informed consent were enrolled and answered the questionnaires, mean age was 51 (SD 13.5) years, 31 were male, 25 were considered active cannabis users (624% males and 36% females). At baseline, the mean Global Health score in the QLQ-C30 instrument was 68.6 (SD: 20.6) among cannabis users and 82 (SD: 18.05) among non-users. The mean difference in Global Health QOL scores between users and non-users was 13.35 (95%CI: 1.34, 25.35; p=0.03). In contrast the difference between cannabis users and non-users in QOL index in the EQ-5D-5L instrument was 0.13 (0.77 vs 0.91; p=0.002). Among cannabis users, patients perceive their symptoms as moderate before using cannabis and mild after using cannabis (p>0.001). CONCLUSION In our analysis, patients who use cannabis have, on average, lower QOL scores signaling that sicker patients resort to cannabis to improve their symptoms and ultimately their quality of life. Patients’ perception is one of improvement in the overall quality of life when using cannabis. Our findings provide background support to perform prospective studies in the impact of cannabis in quality of life of patients with central nervous system tumors.

Background Although the EORTC 18071-trial has shown a clear survival benefit for adjuvant ipilimumab, accurately selecting patients for this toxic adjuvant therapy is important. We aimed to identify prognostic factors for death and disease recurrence in AJCC stage IIIC melanoma patients. Patients and Methods Retrospective analysis of patients who underwent lymph node dissection (LND) for stage IIIC melanoma in our institution between 2000 and 2016. Baseline characteristics, melanoma-specific survival (MSS), and disease-free survival (DFS) were assessed, and prognostic factors for recurrence and survival were analyzed using uni- and multivariable analysis. Results A total of 205 patients were included. Median follow-up was 20 months (interquartile range 11-43 months), median MSS was 28 months, and median DFS was 11 months. Five-year MSS was 33% and 5-year DFS was 23%. N3 (≥4 involved lymph nodes) and extracapsular extension (ECE) carried an increased risk of disease recurrence after LND and death by melanoma. Patients with both N3 and ECE had virtually no long-term survival. Conclusions Although survival for patients with stage IIIC is poor in general, patients with both N3 disease and ECE constitute the group with the worst prognosis and should be considered for adjuvant therapy with ipilimumab or any other future effective adjuvant therapy (study).

INTRODUCTION The aim of glioblastoma surgery is to maximize the extent of resection, while preserving functional integrity. Standards are lacking for surgical decision-making and consequently surgical strategies may differ between neurosurgical teams. In this study, we quantitated and compared surgical decision-making throughout the brain between neurosurgical teams for patients with a glioblastoma using probability maps. METHODS All adults with first-time glioblastoma surgery in 2012-2013 from 10 tertiary referral centers for neurooncological care were included in this study. For each patient, pre- and postoperative tumor were manually segmented on MRI and aligned to standard brain space. Resection probability maps and biopsy probability maps were constructed in 1 mm resolution for each team's cohort. Brain regions with differential biopsy and resection results between teams were identified. RESULTS The study cohort consisted of 931 patients of whom 293 received a biopsy and 638 a resection. Biopsy probability maps demonstrated differences between teams in biopsy rate per brain location, such as for the left precuneus and superior parietal lobule, indicating variation in biopsy decisions. Resection probability maps demonstrated differences between teams in residual tumor rate per brain location, such as for the left saggital striatum and neighboring posterior corpus callosum, indicating variation in resection decisions. CONCLUSION Biopsy and resection probability maps indicate treatment variation between teams for patients with a glioblastoma. This conveys useful objective arguments for quality of care discussions between surgical teams for these patients.

The application of focal radiation therapies in the management of malignant gliomas has gone through a number of stages. Earlier efforts to improve local control of malignant gliomas involved the use of brachytherapy. Despite some early encouraging results, Phase 3 studies did not prove a significant survival benefit for the addition of brachytherapy for newly diagnosed glioblastoma. Most recently radiosurgery has been employed using the same rationale in that improved local control may improve survival. Results of the RTOG Phase 3 study are pending final publication, but early abstracted reports are negative. While radiosurgery and brachytherapy continue to be used as a form of therapy for selected patients with recurrent gliomas, new information from metabolic imaging studies suggests our problem with these techniques in part may be related to targeting. This paper reviews the recent literature and results of the use of brachytherapy and radiosurgery in the management of newly diagnosed and recurrent malignant gliomas.

Summary We investigated the expression of c-erbB-2 protein in two matched groups of breast cancer patients, one with and one without relapse. 37 patients with relapse were compared with 42 patients without recurrence for time of observation, adjuvant treatment, age, menopausal status and estrogen receptor content. Paraffin-embedded sections were stained with the polyclonal antibody 21N, raised against a synthetic peptide from the predicted sequence of the c-erbB-2 protein. The staining of c-erbB-2 was measured on a scale of 0 to 3+. C-erbB-2 staining was negative in 16 (38%) patients in the relapse-free group, and in 8 (22%) of the patients with metastases. Neither disease-free survival (DFS) nor overall survival (OS) were dependent upon the extent of c-erbB-2 expression. An analysis by estrogen receptor (ER) status (i.e. positive or negative) and by c-erbB-2 expression (i.e. positive or negative) revealed that patients with ER-positive primaries and negative c-erbB-2 have the longest disease-free survival (DFS) and overall survival (OS). We conclude that c-erbB-2 expression might be clinically useful only if other prognostic variables (e.g. estrogen receptor content in the tumor) are also considered.

Purpose/Objective(s): Pituitary tumors are relatively uncommon. Primary goals of treatment include normalization of hormonal level and improving visual or neurological symptoms. Surgery, medical treatment, irradiation, or combination of these modalities is used to achieve these goals. The purpose of this analysis is to determine the clinical outcome of pituitary adenoma treated with fractionated external beam radiation therapy. Materials/Methods: This is a retrospective analysis of pituitary adenoma treated at our center between 2006 and 2014. A total of 88 patients with biopsy-proven adenomas were identified. Median age at diagnosis was 38 years (18e79 years) and 49 patients (56%) were males. Majority of tumors were marcoadenoma (87%). Presenting symptoms were mainly hormonal disturbance in 43 patients (49%), visual defects in 29 patients (33%) and headache in 21 patients (23%). Prolactinomas were the most common secretory adenoma in 22 patients (51%), followed by growth hormone secreting adenomas in 15 patients (35%) and ACTH-secreting tumors in 5 patients (12%), while one patient had TSH-secreting adenoma. The cohort follow up time reached 87 months (mean; 32 months). The primary endpoints are clinical and biochemical control. Results: Thirteen patients lost to follow up, therefore 75 patients were included in the final analysis. Surgery was the primary treatment modality in 70 patients (93%).While medical treatment was used for inoperable or hormonal secreting adenoma in 30 patients (40%). Fractionated radiation therapy was delivered to 28 patients (37%), indications for radiation were symptomatic, incompletely resected tumors (16 patients) or persistent hypersecretion (12 patients). For secretory tumors the median radiation dose was 52Gy (50-54Gy), and lower dose was delivered for non-secretory adenoma; mean 50Gy (45-52Gy). For patients received radiation therapy, the tumor control rate is 75% for non-functioning adenomas, and 69% for functioning adenomas. Conclusion: Pituitary adenoma is a slow growing benign tumor; however devastating effect can result from neurological deficits or hormonal imbalance. Our results reveal that functioning adenomas carry worse prognosis. Fractionated radiation therapy, as an adjunct to surgery and medical treatment, offers good clinical and biochemical control for pituitary adenoma. More aggressive multimodal approach and incorporation of new radiation technique may help to achieve better clinical outcome. Author Disclosure: R.A. Abu-Hijlih: None. Y. Ismael: None. H. Ghatasheh: None. A. Fawzi: None. A. Alsharbaji: None. M. Elyan: None. B. Al-Haj: None. A. Almousa: None.

previously reported improvement in PFS (10.4 vs. 4.0 years, p Z 0.002; HR Z 0.50). Treatment arm was identified as a prognostic variable in favor of RT + PCV for both OS (p Z 0.003; HR Z 0.59) and PFS (p < 0.001; HR Z 0.49). Histology was prognostic for OS (p < 0.001; HR Z 2.16) and PFS (p < 0.001; HR Z 1.85) in favor of O compared to A. Male gender was prognostic for inferior OS (p Z 0.02; HR Z 1.51). Molecular markers were not pre-specified; post-hoc analysis of these is ongoing. Conclusions: For “high-risk” LGG, defined as age < 40 years with subtotal resection/biopsy or 40 years with any degree of resection, RT followed by 6 cycles of PCV prolongs both OS and PFS, and RT plus chemotherapy should therefore be considered a new standard of care for such patients. Astrocytic histology and male gender predict for poorer survival. Acknowledgment: This project was supported by RTOG grant U10 CA21661, and CCOP grant U10 CA37422 from the National Cancer Institute (NCI). Author Disclosure: M.P. Mehta: E. Research Grant; Novocure. F. Honoraria; Research to Excellence, Soreno Foundation. G. Consultant; Abbvie, BMS, Elekta, Merck, Novocure, Novelos, Phillips. I. Travel Expenses; Abbvie, Celldex, Elekta, Phillips, Roche. K. Advisory Board; Celldex, Roche. N. Stock Options; Pharmacyclics, Accuray. P. Royalty; Demos. S. Leadership; RTOG. M. Won: None. E.G. Shaw: None. J. Buckner: None. M. Gilbert: E. Research Grant; Merck, Genentech, GSK. F. Honoraria; Genentech, Merck. K. Advisory Board; Merck, Genentech, BMS, Abbvie, EMD Serono. G. Barger: None. S. Coons: None. P. Ricci: None. D. Bullard: None. P.D. Brown: None. K. Stelzer: None. D.G. Brachman: None. J.H. Suh: G. Consultant; Varian. C. Schultz: None. J. Bahary: None. B.J. Fisher: None. H. Kim: None. A.D. Murtha: None. W.J. Curran: S. Leadership; RTOG.

This paper discusses some special features of VLSI semiconductor devices due to the nonlinearity of the partial differential equations defining the electric potential and the density of holes and electrons flowing within the device. Currently, solutions for these nonlinear partial differential equations are computed with great speed on very large modern computers. However, a theoretical analytical treatment of these systems has not been systematically carried through. It is hoped that this analytical study may shed some light on some aspects of VLSI device operation that, until now, have required ingenious physical intuition and arguments for their understanding. In particular, the analytic approach has the potential to consider the following problems of importance in VLSI semiconductor devices: 1) arbitrarily shaped devices, 2) high space dimensional effects (especially those with curved boundaries), 3) nonuniqueness of solutions, 4) bifurcation phenomena, 5) instabilities and parameter dependence, and 6) latch up phenomena and high bias effects. I personally, believe there is much to be gained from an interplay between the impressive numerical simulation already attained and an analytic consideration of the equations themselves. Typical questions are (for example) (i) Electronic Instabilities. How do these arise from the boundary value problems themselves? What are the mathematical mechanisms involved? (ii) Structural Problems. Do the equations themselves have special structures that may aid the numerical simulation of their solutions? Another key point here is that the partial differential equation systems for semiconductors are another nonlinear generalization of Maxwell's equations of electromagnetism. As semiconductor devices become smaller, there is, of course, a greater need to rely on theoretical analysis. The immense success of Maxwell's mathematical electromagnetic theory and his own statistical mechanics ideas (here fused together) gives one confidence of the ultimate validity of the partial differential equation approach. In this article we shall limit ourselves to a discussion of the standard Van Roosbroeck equations (assuming the validity of the Einstein relations and Boltzmann statistics) and to questions of steady-state processes (i.e., time-independent problems). We hope to address other aspects in latter publications.