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OBJECTIVE Stereotactic radiosurgery (SRS) provides a safe and effective therapeutic modality for patients with pituitary adenomas. The mechanism of delayed endocrine deficits based on targeted radiation to the hypothalamic-pituitary axis remains unclear. Radiation to normal neuroendocrine structures likely plays a role in delayed hypopituitarism after SRS. In this multicenter study by the International Radiosurgery Research Foundation (IRRF), the authors aimed to evaluate radiation tolerance of structures surrounding pituitary adenomas and identify predictors of delayed hypopituitarism after SRS for these tumors. METHODS This is a retrospective review of patients with pituitary adenomas who underwent single-fraction SRS from 1997 to 2019 at 16 institutions within the IRRF. Dosimetric point measurements of 14 predefined neuroanatomical structures along the hypothalamus, pituitary stalk, and normal pituitary gland were made. Statistical analyses were performed to determine the impact of doses to critical structures on clinical, radiographic, and endocrine outcomes. RESULTS The study cohort comprised 521 pituitary adenomas treated with SRS. Tumor control was achieved in 93.9% of patients over a median follow-up period of 60.1 months, and 22.5% of patients developed new loss of pituitary function with a median treatment volume of 3.2 cm3. Median maximal radiosurgical doses to the hypothalamus, pituitary stalk, and normal pituitary gland were 1.4, 7.2, and 11.3 Gy, respectively. Nonfunctioning adenoma status, younger age, higher margin dose, and higher doses to the pituitary stalk and normal pituitary gland were independent predictors of new or worsening hypopituitarism. Neither the dose to the hypothalamus nor the ratio between doses to the pituitary stalk and gland were significant predictors. The threshold of the median dose to the pituitary stalk for new endocrinopathy was 10.7 Gy in a single fraction (OR 1.77, 95% CI 1.17–2.68, p = 0.006). CONCLUSIONS SRS for the treatment of pituitary adenomas affords a high tumor control rate with an acceptable risk of new or worsening endocrinopathy. This evaluation of point dosimetry to adjacent neuroanatomical structures revealed that doses to the pituitary stalk, with a threshold of 10.7 Gy, and doses to the normal gland significantly increased the risk of post-SRS hypopituitarism. In patients with preserved pre-SRS neuroendocrine function, limiting the dose to the pituitary stalk and gland while still delivering an optimal dose to the tumor appears prudent.

OBJECTIVE The WHO Classification of Tumours of the Central Nervous System (2016) classifies nonmeningothelial malignant spindle cell tumors involving the extraaxial tissues of the posterior fossa as melanocytic tumors and malignant mesenchymal tumors (sarcomas). The objective of this study was to conduct a review of the literature pertaining to the management strategies of posterior fossa malignant spindle cell tumors in the pediatric population. METHODS The authors performed an institutional search of their pathology database for patients younger than 18 years of age who presented with posterior fossa malignant spindle cell tumors. A literature review was also performed using the PubMed database, with “posterior fossa” or “spindle cell tumors” or “Ewing sarcoma” or “high-grade” or “spindle cell sarcoma” or “leptomeningeal melanocytoma” as keywords. The database search was restricted to pediatric patients (age ≤ 18 years). Parameters reported from the literature review included patient age, tumor location, presenting symptoms, treatment modalities (resection, chemotherapy, and/or radiotherapy), leptomeningeal spread at or after the time of treatment, and follow-up length and resulting outcome. RESULTS The authors report 3 rare cases of posterior fossa malignant spindle cell tumors, including Ewing sarcoma in a 13-year-old male; high-grade spindle cell sarcoma, not otherwise specified in a 10-year-old male; and primary leptomeningeal melanocytoma in a 16-year-old female. All 3 patients underwent resection and radiotherapy and either chemotherapy or targeted immunotherapy. At the last follow-up, all patients were alive with either resolution or stable disease. CONCLUSIONS A review of these 3 cases and the existing literature support managing patients with intracranial malignant spindle cell tumors with multimodal therapy that can include a combination of resection, radiotherapy, and chemotherapy or immunotherapy to prolong progression-free and overall survival.

OBJECTIVE Radiation-induced meningiomas (RIMs) are associated with aggressive clinical behavior. Stereotactic radiosurgery (SRS) is sometimes considered for selected RIMs. The authors investigated the effectiveness and safety of SRS for the management of RIMs. METHODS From 12 institutions participating in the International Radiosurgery Research Foundation, the authors pooled patients who had prior cranial irradiation and were subsequently clinically diagnosed with WHO grade I meningiomas that were managed with SRS. RESULTS Fifty-two patients underwent 60 SRS procedures for histologically confirmed or radiologically suspected WHO grade I RIMs. The median ages at initial cranial radiation therapy and SRS for RIM were 5.5 years and 39 years, respectively. The most common reasons for cranial radiation therapy were leukemia (21%) and medulloblastoma (17%). There were 39 multiple RIMs (35%), the mean target volume was 8.61 ± 7.80 cm3, and the median prescription dose was 14 Gy. The median imaging follow-up duration was 48 months (range 4–195 months). RIM progressed in 9 patients (17%) at a median duration of 30 months (range 3–45 months) after SRS. Progression-free survival at 5 years post-SRS was 83%. Treatment volume ≥ 5 cm3 predicted progression (HR 8.226, 95% CI 1.028–65.857, p = 0.047). Seven patients (14%) developed new neurological symptoms or experienced SRS-related complications or T2 signal change from 1 to 72 months after SRS. CONCLUSIONS SRS is associated with durable local control of RIMs in the majority of patients and has an acceptable safety profile. SRS can be considered for patients and tumors that are deemed suboptimal, poor surgical candidates, and those whose tumor again progresses after removal.

BACKGROUND High-grade gliomas impose substantial morbidity and mortality due to rapid cancer progression and recurrence. Factors such as surgery, chemotherapy and radiotherapy remain the cornerstones for treatment of brain cancer and brain cancer research. The role of anesthetics on glioma progression is largely unknown. METHODS This multicenter retrospective cohort study compared patients who underwent high-grade glioma resection with minimal sedation (awake craniotomy) and those who underwent craniotomy with general anesthesia (GA). Various perioperative factors, intraoperative and postoperative complications, and adjuvant treatment regimens were recorded. The primary outcome was progression-free survival (PFS); secondary outcomes were overall survival (OS), postoperative pain score, and length of hospital stay. RESULTS A total of 891 patients were included; 79% received GA, and 21% underwent awake craniotomy. There was no difference in median PFS between awake craniotomy (0.54, 95% confidence interval [CI]: 0.45-0.65 y) and GA (0.53, 95% CI: 0.48-0.60 y) groups (hazard ratio 1.05; P

OBJECTIVEMalignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas that harbor a high potential for metastasis and have a devastating prognosis. Combination chemoradiation aids in tumor control and decreases tumor recurrence but causes deleterious side effects and does not extend long-term survival. An effective treatment with limited toxicity and enhanced efficacy is critical for patients suffering from MPNSTs.METHODSThe authors recently identified that interleukin-13 receptor alpha 2 (IL-13Rα2) is overexpressed on MPNSTs and could serve as a precision-based target for delivery of chemotherapeutic agents. In the work reported here, a recombinant fusion molecule consisting of a mutant human IL-13 targeting moiety and a point mutant variant of Pseudomonas exotoxin A (IL-13.E13 K-PE4E) was utilized to treat MPNST in vitro in cell culture and in an in vivo murine model.RESULTSIL-13.E13 K-PE4E had a potent cytotoxic effect on MPNST cells in vitro. Furthermore, intratumoral administration of IL-13.E13 K-PE4E to orthotopically implanted MPNSTs decreased tumor burden 6-fold and 11-fold in late-stage and early-stage MPNST models, respectively. IL-13.E13 K-PE4E treatment also increased survival by 23 days in the early-stage MPNST model.CONCLUSIONSThe current MPNST treatment paradigm consists of 3 prongs: surgery, chemotherapy, and radiation, none of which, either singly or in combination, are curative or extend survival to a clinically meaningful degree. The results presented here provide the possibility of intratumoral therapy with a potent and highly tumor-specific cytotoxin as a fourth treatment prong with the potential to yield improved outcomes in patients with MPNSTs.

The sellar and parasellar regions are a rare site of brain metastasis, most commonly from breast and lung cancer. Pituitary metastasis (PM) often presents as the first sign of metastatic disease but may herald early disseminated cancer. The diagnosis of PM requires differentiation from a benign pituitary adenoma. Although this may be proven definitively via surgical biopsy, a constellation of clinical findings including oculomotor palsy, visual disturbances, retroorbital pain, and diabetes insipidus is more suggestive of PM. Imaging is neither sensitive nor specific for differentiation but may inform the broader clinical picture. Due to its rarity, treatment guidelines for PM lack consensus, often including a mixture of radiation and surgery. Gross resection is challenging because of the vascular, invasive nature of these lesions. Stereotactic radiosurgery may be used to good effect either alone or in addition to resection. Even with treatment, the prognosis is poor. In this article, we present the third reported case of urothelial carcinoma metastasis to the pituitary. In addition, we review the clinical presentation, diagnosis, and treatment options including surgical resection and radiosurgery.

Arachnoiditis ossificans (AO) is a rare spinal pathology that develops because of bony metaplasia secondary to chronic inflammation. AO may present with debilitating myelopathy secondary to nerve root compression, making it distinct from spinal calcification commonly seen with aging. AO is extremely rare, having been reported less than 100 times, most commonly in the thoracic spine. Even rarer still, AO has been associated with syringomyelia and arachnoid cyst because of associated cerebrospinal fluid (CSF) flow disruption. In this report, we describe a case of AO that presented with right shoulder pain, right-hand numbness, and bilateral lower extremity fatigue who had syringomyelia and arachnoid cyst discovered on MRI imaging. When brought to the operating room for syrinx shunting and cyst fenestration the dural opening was complicated by severe calcification and a diagnosis of AO was made. The patient was treated with partial resection of the calcified plaques. Syringomyelia shunting was abandoned due to low volume. Post-operatively, the patient had improvement in their myelopathy though syrinx was still visualized on follow-up imaging. This report reviews the pathology, clinical and radiographic diagnosis, and treatment strategies for arachnoiditis ossificans.

Acellular dermal matrices (ADM) were used to cover the implant to reduce implant rotations and to improve esthetic results. Current retrospective data on complication rates are heterogeneous. Prospective data are rare. Primary objective was to evaluate the explantation rate. 11 German sites, with experience in breast reconstruction using ADM, have been selected for participation in this study. Patients were enrolled according to predefined in- and exclusion criteria into two cohorts: group A - primary reconstruction and group B - secondary reconstruction after capsular contracture. After documentation of baseline characteristics and surgical parameters, endpoints such as rate of seroma, red breast syndrome, infection and explantation were assed at 1 day, 7 days, 1 month, 3, 6 and 12 months after surgery. In addition, patient- and surgeon-satisfaction were recorded. Data of 83 patients were analyzed (A: 50, B: 33). In 29 patients Epiflex was used bilaterally, so that it was used 112-times in total. The average age of the patient was 45.1 years (A: 41.5; B: 50.3), the average BMI was 22.2 (A: 22.3; B: 22.1). In total, 17.0 % seromas (A: 19.4 %; B: 12.5 %), 10.7 % red breast syndrome (A: 9.7 %; B: 12.5 %), 4.5 % infections (A: 6.9 %; B: 0 %) and 5.4 % explantations (A: 6.9 %; B: 2.5 %) were observed. During the average observation period of 8 month, the satisfaction of the patients and surgeons was high at all measured time points. On a scale from (1 - very satisfied to 6 - not satisfied) the satisfaction of patients and surgeons was 2.3 (A: 2.3; B:1.9) and 2.0 (A: 2.2; B: 1.8) respectively. Our data show, that both patients and surgeons are generally satisfied with the outcome of breast reconstruction using ADM. Complication rates were adequate and commonly lower in secondary reconstructions. Citation Format: Blohmer J-U, Ankel C, Faridi A, Krause-Bergmann B, Neumann C, Schnuppe K, Beier L, Mau C, Strittmatter H-J, Gerber-Schäfer C, Bauer L, Paepke S. First results of the NOGGO-AWOGyn observational study: Skin and nipple sparing mastectomy and breast reconstruction with an implant and Epiflex® [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-16-13.

Radiation is utilized in the therapy of more than 50% of cancer patients. Unfortunately, many malignancies become resistant to radiation over time. We investigated the hypothesis that one method of a cancer cell's ability to survive radiation occurs through cellular communication via exosomes. Exosomes are cell-derived vesicles containing DNA, RNA, and protein. Three properties were analyzed: 1) exosome function, 2) exosome profile and 3) exosome uptake/blockade. To analyze exosome function, we show radiation-derived exosomes increased proliferation and enabled recipient cancer cells to survive radiation in vitro. Furthermore, radiation-derived exosomes increased tumor burden and decreased survival in an in vivo model. To address the mechanism underlying the alterations by exosomes in recipient cells, we obtained a profile of radiation-derived exosomes that showed expression changes favoring a resistant/proliferative profile. Radiation-derived exosomes contain elevated oncogenic miR-889, oncogenic mRNAs, and proteins of the proteasome pathway, Notch, Jak-STAT, and cell cycle pathways. Radiation-derived exosomes contain decreased levels of tumor-suppressive miR-516, miR-365, and multiple tumor-suppressive mRNAs. Ingenuity pathway analysis revealed the most represented networks included cell cycle, growth/survival. Upregulation of DNM2 correlated with increased exosome uptake. To analyze the property of exosome blockade, heparin and simvastatin were used to inhibit uptake of exosomes in recipient cells resulting in inhibited induction of proliferation and cellular survival. Because these agents have shown some success as cancer therapies, our data suggest their mechanism of action could be limiting exosome communication between cells. The results of our study identify a novel exosome-based mechanism that may underlie a cancer cell's ability to survive radiation.

Background External ventricular drains (EVD) are used for emergent management of acute hydrocephalus and for monitoring of intracranial pressure. Common complications of EVDs include malposition, infection, and hemorrhage. Here, the authors present a novel case of EVD migration causing Parinaud's syndrome. Case description A thirty-three-year-old female presented with witnessed seizure secondary to a left supraclinoid internal carotid artery aneurysm and trace subarachnoid hemorrhage. Two days after radiographic confirmation of an accurately placed EVD, she was found to have vertical gaze palsy (Parinaud's syndrome). Repeat CT head demonstrated inward migration of the EVD with left midbrain compression. After readjustment of the EVD, her Parinaud's syndrome improved each day until discharge home. Conclusions This is a novel clinical presentation of an EVD causing Parinaud's syndrome. There is only one other case report in the literature of this phenomenon. Although a practical solution to prevent this incident from occurring is unclear, vigilance for changes in neurological exam allowed for quick assessment and revision of the EVD and subsequent recovery in this patient.

Admiral Lord Horatio Nelson is perhaps the most renowned naval commander, who allowed Britain to have dominion over the sea for 100 years after his victory at the Battle of Trafalgar. He was able to do so despite suffering from a multitude of communicable diseases and traumatic injuries, including the functional loss of his right eye, amputation of his right arm, scalp laceration, head injury, and finally a spinal injury. These injuries had permanent consequences but did not stop him from leading the charge and allowing the British to defeat the French and Spanish fleets in the decisive Battle of Trafalgar.

Background: Atypical teratoid rhabdoid tumors (ATRTs) are highly malignant tumors that usually present as a posterior fossa mass in children less than 3 years old. Only 38 cases have been reported in adults. They are also typically located in the supratentorial region. In none of the reported cases of suprasellar ATRT in the adult, intrathecal chemotherapy (via ommaya) has been used. Clinical case: A 70-year-old woman presented with a severe headache and magnetic resonance imaging (MRI) revealed a suprasellar mass measuring 2.9 x 2.1 x 3.0 cm. Shortly after her presentation, she developed an acute 3rd nerve palsy, and repeat MRI found dramatic interval growth. A transsphenoidal approach for biopsy/resection was attempted, but the lesion was not accessible via this corridor. She then underwent a right frontotemporal craniotomy and subsequently developed panhypopituitarism, including diabetes insipidus. Pathology revealed poorly differentiated malignant cells. Immunohistochemistry was positive for synaptophysin, Epithelial Membrane Antigen (EMA), Tumor protein p53, and negative for integrase interactor 1 (INI-1 antibody) with loss of expression in tumor nuclei with positive internal control in endothelial cells. These findings confirmed the diagnosis of ATRT. The Ki-67 index was 60% consistent with a highly proliferative tumor. One month later, she developed acute mental status change. Repeat computed tomography, and MRI showed recurrence of the tumor at the same location with new leptomeningeal enhancement involving the left facial nerve. Multimodal treatment was instituted, consisting of intraventricular/intrathecal chemotherapy with etoposide and topotecan plus fractionated external beam cranial irradiation (30 Gy in 10 fractions). She continued to deteriorate, and following consultation with her family, she was transferred to hospice care and died six months following her initial surgery. Conclusion: This is the first case of adult suprasellar ATRT that has been treated with intrathecal chemotherapy. There is no consensus on the best combination of chemotherapy, and often the St. Jude’s protocol used in the treatment of pediatric ATRT is used. In line with the biological behavior reported for this tumor in children and adults in different locations, the tumor was very aggressive, resulting in the patient’s death only after 6 months from the diagnosis despite aggressive surgical and medical treatment. Reference: 1. Athale, U. H., J. Duckworth, I. Odame, and R. Barr. 2009. Childhood atypical teratoid rhabdoid tumor of the central nervous system: a meta-analysis of observational studies. J. Pediatr. Hematol. Oncol. 31:651-663. 2. Shonka N, Armstrong T (2011) Atypical teratoid/rhabdoid tumors in adults: A case report and treatment-focused review. J Clin Med Res 3: 85-92.

Implant-based or expander-supported breast reconstruction is an established surgical method after mastectomies due to cancer or to prophylactic reasons. Patient reported outcome (PRO) and cosmetic outcome after breast reconstruction with a synthetic surgical mesh was investigated in a prospective, single-arm, multi-center study.Primary or secondary implant-based breast reconstruction with support of TiLOOP® Bra was performed in 269 patients during the PRO-BRA study. PRO 12 months after breast reconstruction was evaluated using Breast-Q questionnaire. Cosmetic outcome was evaluated by two independent experts by means of pictures taken preoperatively and at the follow-up visits.Breast-Q and 12 months FU were completed by 210 women. Patients without adverse event had a significantly higher Breast-Q score for "sexual well-being" (p = 0.001); "psychosocial well-being" was negatively influenced by prior therapies (p 0.01), and older patients had significantly lower scores at 12 months FU compared to pre-OP for "satisfaction with breasts" (p 0.01) while the opposite was true for younger patients. Unilateral surgery resulted in reduced "satisfaction with breast" at 12 months FU (p 0.01). Radiotherapy negatively influenced "satisfaction with breast", "sexual well-being" and "physical well-being chest". The cosmetic evaluation showed a significant difference (p 0.001) in the evaluation by the patients and experts with the patients' assessment being worse compared to experts' assessment.Our study showed that two years after implant-based breast reconstruction with support of TiLOOP® Bra PRO is influenced by different factors. This information can be used to improve the decision-making process for women who chose implant-based breast reconstruction.

Background: Over the last decades, the number of acellular dermal matrix (ADM)-assisted implant-based breast reconstructions (IBBR) has substantially increased. However, there is still a lack of prospective data on complication rates. Methods: We performed a non-interventional, multicenter, prospective cohort study to evaluate complication rates of a human ADM in patients undergoing an IBBR after skin- and nipple-sparing mastectomies. Patients with primary reconstruction (cohort A) and patients undergoing a secondary reconstruction after capsular fibrosis (cohort B) using the human ADM Epiflex® (DIZG gGmbH, Berlin, Germany) were enrolled in this study. Patients were followed-up for 12 months after surgery. Results: Eighty-four eligible patients were included in this study of whom 28 women underwent a bilateral breast reconstruction, leading to 112 human ADM-assisted reconstructions in total (cohort A: 73, cohort B: 39). In 33.0% of the reconstructed breasts at least one of the complications of primary interest occurred, including implant loss 7.1%, seroma 15.2%; infection 5.4%, rash 8.0%, and Baker grade III/IV capsular fibrosis 2.7%, with no statistically significant differences between the cohorts. Previous radiation therapy was significantly associated with occurrence of any postoperative complication (OR 20.41; p value 0.027). Conclusion: The rates of most complications were comparable to the rates reported for other ADMs with relatively low rates of capsular fibrosis and infections. The rate of seroma was increased in our study. Prior radiation therapy increased the risk of any postoperative complications. Therefore, the use of ADM in these patients should be considered carefully.

Background Cystic vestibular schwannomas (VS) are associated with unpredictable growth behavior and potentially worse surgical outcomes compared with their solid counterparts. Growth control and potential adverse effects of radiosurgery for cystic VS have created concerns surrounding this modality. We sought to compare the treatment efficacy and safety profile of radiosurgery between cystic and solid VS through a systematic review. Methods PubMed, EMBASE, Web of Science, and Cochrane were searched for related terms and studies reporting radiosurgical outcomes of cystic and solid VS. A meta-analysis was performed to compare the rates of tumor control. Random-effect models with generic inverse variance method was used to calculate overall pooled estimates. Study quality was assessed with the Newcastle Ottawa Criteria. Results In total, 2989 studies were retrieved, and 6 including 1358 VS (79.89% solid; 20.11% cystic, median follow-up range 31.8–150 months) were selected. The median maximal dose was 25 Gy (range, 13–36 Gy) and the median marginal tumor dose was 12 Gy (10–18 Gy). There was no difference between cystic and solid VS (risk ratio, 1.02; 95% confidence interval 0.94–1.10; P = 0.69; I2 = 78%). Transient enlargement of cystic tumors may be associated with trigeminal or facial neuropathy. Conclusions The evidence collected by this study suggests that radiosurgery for cystic VS exhibits effective tumor control probabilities similar to solid VS. Consensus definitions and standard criteria are needed in the future to better understand the patterns of tumor growth and response to treatment following radiosurgery for cystic VS, as well as long-term neurological and functional outcomes.

OBJECTIVE The utility of routine repeat head CT (HCT) scans in the management of minimal head injury (MHI) patients with an intracranial hemorrhage (ICH) has been questioned in multiple studies. All these studies analyzed this by obtaining a repeat HCT study, and none examined the effects of eliminating these routine HCT studies in neurologically intact patients. The authors' institution implemented a new “Neurologic Observation without Repeat HCT” (NORH) protocol with no repeat HCT scanning for patients admitted for MHI and ICH whose neurological status was maintained or improved to a Glasgow Coma Scale score of 15 at 24 hours after admission. This purpose of this study was to assess the outcomes and safety of this novel protocol. METHODS Records of patients who sustained blunt trauma MHI and an ICH and/or skull fracture on initial HCT between January 1, 2009, and December 31, 2012, were retrieved from the trauma registry of a Level I trauma center. The authors analyzed 95 patients in whom the NORH protocol was followed. Outcome measures included death, emergency department readmission, neurosurgical intervention, delayed repeat HCT, and length of stay. RESULTS The NORH protocol was followed for 95 patients; 83% of the patients were male, the average age was 38 ± 16.0 years old, and the most common cause of trauma was assault (35%). Of the 95 patients in whom the NORH protocol was followed, 8 (8%) had a delayed repeat HCT study (> 24 hours) after admission, but none resulted in neurosurgical intervention because of progression of ICH. The average length of stay was 4 ± 7.2 days. None of the patients were readmitted to the hospital. CONCLUSIONS Implementation of the NORH protocol (eliminating routine follow-up HCT) resulted in very low rates of delayed neurological deterioration, no late neurosurgical interventions resulting from ICH progression, very few emergency department revisits, and no readmissions. For a select group of MHI patients with ICH, the NORH protocol is safe and effective, and can reduce radiation exposure and costs.

An exceedingly rare manifestation of leukemia, termed neuroleukemiosis, involves peripheral nerve infiltration by leukemic cells. Patients with neuroleukemiosis typically present with a peripheral neuropathy and/or chloromatous masses. The diagnosis is supported by, and established with, electrophysiologic testing, imaging, histopathology, and immunophenotyping. We present the case of 21 year old male with multiply relapsed M4 type of acute myelogenous leukemia (AML) who presented with extremity pain and was subsequently found to have multiple cervical, thoracic, and lumbosacral nerve root masses. A diagnosis of neuroleukemiosis was established via CT-guided biopsy and immunophenotyping. The patient's neuroleukemiosis responded well to chemotherapy, donor lymphocyte infusions, and spinal irradiation. The literature is reviewed regarding this interesting and rare clinical condition.

Peripheral nerve sheath tumors (PNSTs) may arise sporadically or in the presence of genetic disorders, including neurofibromatosis (NF) types 1 and 2, schwannomatosis, and in patients with large genetic deletions involving the CDKN2A gene. Surgical resection is the treatment of choice for symptomatic PNSTs and offers patients a potential cure; however, pre-existing conditions or tumor location may limit a patient's surgical options. Radiofrequency ablation (RFA) may provide an alternative therapeutic strategy for the treatment of selected PNSTs that are not amenable to surgical resection. Here, we present a case report of a 49-year-old patient with multiple neurofibromas who underwent RFA treatment of two symptomatic retroperitoneal neurofibromas and review previously reported cases of percutaneous treatment of PNSTs.

Studies assessing the effect of bevacizumab (BEV) on breast cancer (BC) outcome have shown different effects on progression-free and overall survival, suggesting that a subgroup of patients may benefit from this treatment. Unfortunately, no biomarkers exist to identify these patients. Here, we investigate whether single nucleotide polymorphisms (SNPs) in VEGF pathway genes correlate with pathological complete response (pCR) in the neoadjuvant GeparQuinto trial. HER2-negative patients were randomized into treatment arms receiving either BEV combined with standard chemotherapy or chemotherapy alone. In a pre-planned biomarker study, DNA was collected from 729 and 724 patients, respectively from both treatment arms, and genotyped for 125 SNPs. Logistic regression assessed interaction between individual SNPs and both treatment arms to predict pCR. Five SNPs may be associated with a better response to BEV, but none of them remained significant after correction for multiple testing. The two SNPs most strongly associated, rs833058 and rs699947, were located upstream of the VEGF-A promoter. Odds ratios for the homozygous common, heterozygous and homozygous rare rs833058 genotypes were 2.36 (95% CI, 1.49-3.75), 1.20 (95% CI, 0.88-1.64) and 0.61 (95% CI, 0.34-1.12). Notably, some SNPs in VEGF-A exhibited a more pronounced effect in the triple-negative subgroup. Several SNPs in VEGF-A may be associated with improved pCR when receiving BEV in the neoadjuvant setting. Although none of the observed effects survived correction for multiple testing, our observations are consistent with previous studies on BEV efficacy in BC. Further research is warranted to clarify the predictive value of these markers.

OBJECTIVEMalignant peripheral nerve sheath tumors (MPNSTs) are soft-tissue sarcomas arising from peripheral nerves. MPNSTs have increased expression of the oncogene aurora kinase A, leading to enhanced cellular proliferation. This makes them extremely aggressive with high potential for metastasis and a devastating prognosis; 5-year survival estimates range from a dismal 15% to 60%. MPNSTs are currently treated with resection (sometimes requiring limb amputation) in combination with chemoradiation, both of which demonstrate limited effectiveness. The authors present the results of immunohistochemical, in vitro, and in vivo analyses of MLN8237 for the treatment of MPNSTs in an orthoxenograft murine model.METHODSImmunohistochemistry was performed on tumor sections to confirm the increased expression of aurora kinase A. Cytotoxicity analysis was then performed on an MPNST cell line (STS26T) to assess the efficacy of MLN8237 in vitro. A murine orthoxenograft MPNST model transfected to express luciferase was then developed to assess the efficacy of aurora kinase A inhibition in the treatment of MPNSTs in vivo. Mice with confirmed tumor on in vivo imaging were divided into 3 groups: 1) controls, 2) mice treated with MLN8237, and 3) mice treated with doxorubicin/ifosfamide. Treatment was carried out for 32 days, with imaging performed at weekly intervals until postinjection day 42. Average bioluminescence among groups was compared at weekly intervals using 1-way ANOVA. A survival analysis was performed using Kaplan-Meier curves.RESULTSImmunohistochemical analysis showed robust expression of aurora kinase A in tumor cells. Cytotoxicity analysis revealed STS26T susceptibility to MLN8237 in vitro. The group receiving treatment with MLN8237 showed a statistically significant difference in tumor size compared with the control group starting at postinjection day 21 and persisting until the end of the study. The MLN8237 group also showed decreased tumor size compared with the doxorubicin/ifosfamide group at the conclusion of the study (p = 0.036). Survival analysis revealed a significantly increased median survival in the MLN8237 group (83 days) compared with both the control (64 days) and doxorubicin/ifosfamide (67 days) groups. A hazard ratio comparing the 2 treatment groups showed a decreased hazard rate in the MLN8237 group compared with the doxorubicin/ifosfamide group (HR 2.945; p = 0.0134).CONCLUSIONSThe results of this study demonstrate that MLN8237 is superior to combination treatment with doxorubicin/ifosfamide in a preclinical orthoxenograft murine model. These data have major implications for the future of MPNST research by providing a robust murine model as well as providing evidence that MLN8237 may be an effective treatment for MPNSTs.

Summary Background: Breast cancer is the most common cancer diagnosed during pregnancy. Case Report: We report on a case of a 26-year-old woman who was diagnosed with right-sided breast cancer in her 15th week of gestation. We discussed possible treatment scenarios and the patient opted for neoadjuvant therapy with taxanes and anthracyclines during pregnancy, followed by delivery and then followed by surgery, antibody therapy, and radiotherapy. The patient received neoadjuvant chemotherapy with paclitaxel 80 mg/m2 weekly for 12 cycles, followed by 4 cycles of epirubicin and cyclophosphamide (90/600 mg/m 2 ) every 3 weeks. Complete clinical response was seen after preoperative chemotherapy. After delivery of a healthy child at 40 weeks of gestation, she received breast-conserving surgery and axillary dissection. Anti-HER2 antibody treatment with trastuzumab was started concomitantly with adjuvant radiotherapy. Endocrine treatment with a gonadotropin-releasing hormone (GnRH) analog and tamoxifen for 5 years was planned to be started after radiotherapy. Conclusion: Treatment of breast cancer during pregnancy requires an interdisciplinary approach and careful consideration of the patient’s stage of disease, the gestational age, and the preferences of the patient and her family.

Background: The oral signal transduction inhibitor everolimus (RAD001 = R), binds selectively to mTOR (mammalian target of rapamycin), an intracellular protein kinase implicated in the control of cellular proliferation of activated T-lymphocytes and neoplastic cells. Phase II data suggested that R can enhance the clinical efficacy of endocrine treatment in the metastatic and neoadjuvant setting. The GeparQuinto phase III study had 3 settings (HER2−positive: trastuzumab vs lapatinib; HER2−negative: +/− bevacizumab (Bev); HER2−negative non-responder: +/− R). Primary aim of the last setting was to improve pathological complete response (pCR) for patients with HER2−negative breast cancer not responding to 4x epirubicin/cyclophosphamide (EC) +/− Bev by adding R to weekly paclitaxel as neoadjuvant chemotherapy. Patients and Methods: Patients with untreated HER2−negative breast cancer were eligible if their tumors were stage cT3/4a-d; or estrogen (ER) and progesterone (PgR) receptor-negative; or ER/PgR-positive tumors with clinically N+ (for cT2) or pNSLN+ (for cT1). Only patients without response ( Results: Between 11/07 and 15/06/11 402 P were randomized to Pac (N=201) and Pac+R (N=201). Median age was 51.0 and 50.0 [-R/+R] years. Median clinical tumor size was 40/40 mm; 62%/55% had cT2, 18% / 20% cT3, and 16.7% / 16.7% cT4a-d tumors; 88% / 89% had non-lobular; 35% / 33% grade 3; 55% / 57% node-positive; and 29% / 27% ER and PgR-negative (triple-negative) disease. The futility interim analysis was performed in 02/10, futility boundary was not reached and the trial was continued. After the other 2 settings completed accrual in 06/10, recruitment to the 3rd setting dropped such that it appeared not possible to recruit the full number of patients.. The trial will therefore close recruitment on June, 30th 2011 with an estimated statistical power of 65%. Results on histological response and surgical outcome will be reported. Conclusion: This will be the first report on efficacy data of neoadjuvant R + Pac for patients with early breast cancer. The results of the GeparQuinto study will have to be set into context with the results from the Bolero studies in metastatic disease. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S3-6.

Background: Bevacizumab has been reported to increase the risk of surgical complications, especially in pts treated with neoadjuvant chemotherapy. Methods: In January 2010 it was decided to collect surgical complications prospectively on a specifically developed from. All patients received chemotherapy with epirubicin/cyclophosphamide (EC) followed by docetaxel (T) with or w/o bevacizumab. Patients not responding to the first 4 cycles of EC+/−B were enrolled in another setting. All patients receiving bevacizumab were supposed to be operated at 5 weeks after the last infusion of bevacizumab. Results: Data from 699 patients have been prospectively collected, 329 received EC-T and 370 ECB-TB. Median age was 48 years in both arms. Median tumor size was 30mm in the ET-C arm vs 35mm in the ECB-TB arm (p=0.13). Multifocal or multicentric disease was present in 21% in the EC-T arm vs 22.4% (p=0.74). 36% of the patients received a sentinel node biopsy prior to start of neoadjuvant chemotherapy in both groups. 68.7% of patients received breast conserving therapy in the EC-T arm compared to 71.1% in the ECB-TB arm (p=0.54). The rate of pathological complete response was 19.5% with EC-T compared to 23.2% with ECB-TB (p=0.26). The median time from last CHT+/− bevacizumab to surgery was 29 days in EC-T and 34 days in ECB-TB. Bleeding or hematoma were reported in 6.7% of the patients treated by EC-T and 7.1% with ECB-TB (p=0.88). Wound infections or abscess were reported in 2.5% with EC-T and 3.9% with ECB-TB (p=0.39). Delayed wound healing was reported in 3.4% with EC-T and 6.3% with ECB-TB (p=0.11). Necrosis was reported in 1.9% with EC-T and 2.5% with ECB-TB (p=0.80). Any complication was reported in 11% with EC-T compared to 15.3% with ECB-TB (p=0.12). Conclusion: In general the rate of surgical complications was low. Patients treated with bevacizumab had a numerical increase of surgical complications. However, none of the differences were statistically significant. The intervals from last infusion to surgery as defined by the study protocol appear to be safe. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-14-05.

Glioblastoma Multiforme (GBM) is the most common CNS malignancy in adults, and even with multimodal therapies, carries a poor prognosis. These tumors are heterogeneous and modify their environment, promoting tumor growth, invasion, and therapeutic resistance. The intratumoral heterogeneity of GBM is accentuated during treatment. Even in the face of surgical resection and adjuvant chemoradiation, the unfortunate but inevitable recurrence and progression of GBM is nearly universal. This mechanism of acquired radiation resistance is not understood. We believe that acquired resistance of GBM is due to exosomes secreted from radiated GBM cells conferring resistance to the local cell population. Exosomes are nanometer cell-derived vesicles containing RNAs and proteins. Growing evidence demonstrates exosomes are instrumental to a cell’s interaction with its microenvironment, and have the ability to transfer information to recipient cells contributing to tumorigenicity. We utilized nanoparticle tracking analysis to analyze characteristics of exosome secretion after exposure to radiation. We used cell proliferation assays and cell survival assays to interrogate radiation derived exosome effects on the local cancer cell population. We assessed the potential of exosome blocking agents as a possible avenue for therapeutic manipulation to abrogate this oncogenic effect. We demonstrate that resistance and proliferative factors in GBM derived exosomes change after radiation exposure. Moreover, radiation derived exosomes have functional impact on tumor cell proliferation and radiation resistance. We also demonstrate the therapeutic potential of exosome blocking agents to inhibit acquired resistance, which develops in nearly all GBM patients. Radiation-derived exosomes cause increases in cellular proliferation and survival in the local cancer cell population and may be the hidden mediators of an ultimately radiation resistant tumor recurrence and the dire prognosis that follows. Adjuvant therapy with exosome blocking agents may be used to inhibit these oncogenic effects, leading to optimal patient outcomes.

Trastuzumab and lapatinib are established treatments for patients with HER2 (human epidermal growth factor receptor 2)-positive breast cancer with different mechanisms of action. The focus of this study is to investigate, whether altered expression levels of potentially relevant microRNAs (miRs) in serum are associated with response to trastuzumab or lapatinib. Circulating miR-21, miR-210, and miR-373 were quantified with TaqMan MicroRNA assays in serum of 127 HER2-postive breast cancer patients before and after neoadjuvant therapy and in 19 healthy controls. Patients received chemotherapy combined with either trastuzumab or lapatinib within the prospectively randomized Geparquinto trial. The association between miR levels and pathological response (pCR) to therapy and type of therapy was examined. Serum levels of miR-21 (p = 5.04e-08, p = 1.43e-10), miR-210 (p = 0.00151, p = 1.6e-05), and miR-373 (p = 7.87e-06, p = 1.75e-07) were significantly higher in patients before and after chemotherapy than in healthy women. Concentrations of miR-21 (p = 5.73e-08), miR-210 (p = 0.000724), and miR-373 (p = 0.00209) increased further after chemotherapy. A significant association of higher serum levels of miR-373 with advanced clinical tumor stage could be detected (p

Invasive lobular carcinomas (ILC) show better clinical behaviour compared with other histological types, but significantly lower pathological complete response (pCR) rates after neoadjuvant chemotherapy (NACT). We investigated whether factors influencing pCR rate in ILC after NACT can be identified and whether clinical outcome is different. 9,020 breast cancer patients from nine German neoadjuvant trials with known histological type were pooled. 11.7 % of tumours were ILC. Endpoints were: pCR rate, surgery type and survival. ILC was associated with older age, larger tumour size, lymph node negativity, lower grade and positive hormone-receptor-status (HR). Patients with ILC achieved a significantly lower pCR rate compared with non-ILC patients (6.2 vs. 17.4 %, P < 0.001). The pCR rate was 4.2 % in ILC/HR+/G1-2, 7.0 % in ILC with either HR- or G3, and 17.8 % in ILC/HR-/G3. Mastectomy rate was higher in ILC compared with non-ILC patients irrespective of response to NACT (pCR: 27.4 vs. 16.6 %, P = 0.037 and non-pCR: 41.8 % vs. 31.5 %, P < 0.0001). Age and HR independently predicted pCR in ILC. In ILC patients, pCR did not predict distant disease free (DDFS) and loco-regional disease free survival (LRFS), but overall survival (OS). Non-pCR patients with ILC had significantly better DDFS (P = 0.018), LRFS (P < 0.0001) and OS (P = 0.044) compared with non-ILC patients. Patients with ILC had a low chance of obtaining a pCR and this is not well correlated with further outcome. The mastectomy rate was considerably high in ILC patients even after obtaining a pCR. We, therefore, suggest to offer NACT mainly to ILC patients with HR-negative tumours. © 2014 Springer Science+Business Media New York.

Background We tested the oral mammalian target of rapamycin (mTOR) inhibitor everolimus in addition to paclitaxel in patients with HER2-negative tumours not responding to initial neoadjuvant cytotoxic and anti-angiogenic treatment. Methods Patients with primary HER2-negative tumours received four neoadjuvant cycles of epirubicin/cyclophosphamide (EC) with or without bevacizumab. Patients without clinical response were randomised to receive weekly paclitaxel (80 mg/m 2 ) with or without everolimus (5 mg p.o. daily, after a step-wise dose–escalation starting from 2.5 mg bid) for 12 weeks before surgery. To detect an increase in pathological complete response (pCR; ypT0 ypN0) from 5% to 12.1% (odds ratio 2.62) 566 patients had to be recruited. The trial was stopped prematurely due to completion of accrual in the main study. Findings Of 1948 patients initially starting neoadjuvant treatment 403 were randomised. A total of 18 (4.6%) patients, 7 (3.6%) treated with paclitaxel and everolimus and 11 (5.6%) treated with paclitaxel alone had a pCR (odds ratio 0.36 (OR) (95% confidence interval (CI), 0.24–1.6) p = 0.34). Overall response rate in breast and lymph nodes at surgery was 52.2% after paclitaxel plus everolimus and 61.7% after paclitaxel alone ( p = 0.063). Breast conserving treatment was performed in 54.4% of patients with the combination treatment and 61.9% with paclitaxel alone ( p = 0.20). Mucosal inflammation, thrombocytopenia, neutropenia, infection, and skin rash were more frequent when everolimus was added to paclitaxel. Interpretation Neoadjuvant therapy with everolimus and paclitaxel for patients with HER2-negative disease unresponsive to EC with or without bevacizumab did not improve the pCR rate. Long-term outcome is awaited. Funding Novartis, Roche, and Sanofi-Aventis.

541 Background: Patients (pts) with infiltrating lobular carcinoma (ILC) have a different response to neoadjuvant chemotherapy compared to patients with non-lobular carcinoma (NLC). The aim of our analysis was to characterize correlates of the outcome impact of neoadjuvant chemotherapy in ILC and to compare those with NLC. Methods: Between 1998 and 2006; 6377 breast cancer patients were enrolled to 7 randomized neoadjuvant chemotherapy trials in Germany. For 6205 (98.3%) pts the histological type was available. 844 (13.6%) were classified as ILC, 5361 (86.4%) were classified as NLC. Endpoints of the analyses were: pathological complete response (pCR) defined as no invasive and no in-situ residuals in the breast and the lymph nodes, type of surgery, disease-free (DFS), local recurrence (LRFS) and overall survival (OS). Results: ILC was associated with older age, larger tumor size, negative nodes, lower grading, and hormone receptor (HR) positivity (all p