Temozolomide non-responsiveness in aggressive prolactinomas and carcinomas: management and outcomes

Purpose Temozolomide is endorsed as the treatment of choice in aggressive or malignant pituitary adenomas. Herein we describe a case of an aggressive prolactinoma which was resistant to temozolomide and performed a literature review of similar non-responsive aggressive prolactinomas. Methods A 40-year-old female presented with a giant prolactinoma which required cabergoline, transsphenoidal surgery and radiotherapy to achieve near-normal prolactin and apparently no residual tumour. A year later, she presented with multiple cranial nerve involvement due to recurrent tumour extending to the infratemporal fossa. She underwent transfrontal surgery, second radiotherapy and was started on temozolomide. Despite 8 cycles of temozolomide (200mg/m 2, 5/28 day cycle), she had progressive disease and ultimately succumbed to the disease. Pubmed/MEDLINE, Google scholar and prior review articles were searched for manuscripts with aggressive prolactinomas who had been treated with temozolomide. Data on demography, duration of therapy and management outcomes were analysed in those with progressive disease. Literature review We identified 94 cases of aggressive/malignant prolactinomas in the literature who had received temozolomide. Progressive disease despite temozolomide was present in 36 cases (38%). There was a male preponderance (65%) and 40% had aggressive prolactinomas while the rest had carcinomas. Patients received a median of 8 cycles (IQR 3.5-11.5) of temozolomide. MGMT immunostaining was negative in 35%. Overall mortality at the time of publication was 40%, at a duration varying from 2 to 20 years from diagnosis. Conclusion Temozolomide resistance in aggressive/malignant prolactinomas is challenging. Progressive disease on optimal temozolomide treatment entails the use of newer agents.

Post-operative volumes following endoscopic surgery for non-functioning pituitary macroadenomas are predictive of further intervention, but not endocrine outcomes

Background Transsphenoidal surgery (TSS) remains the treatment of choice for non-functioning pituitary macroadenomas (NFPMA). The value of measuring tumour volumes before and after surgery, and its influence on endocrine outcomes and further treatment of the residual or recurrent tumour are unknown. Methods Data from patients who underwent endoscopic TSS for a NFPMA (2009–2018) in a UK tertiary centre were analysed for pre- and post-operative endocrine and surgical outcomes. Results Of 173 patients with NFPMA, 159 (61% male) were treatment naïve. At presentation, 76.2% (77/101) had ≥1 pituitary axis deficit. Older age (p = 0.002) was an independent predictor for multiple hormonal deficiencies. Preoperative tumour volume did not correlate with degree of hypopituitarism. Postoperative tumour volume and extent of tumour resection were not predictive of new onset hypopituitarism. Hormonal recovery was observed in 16 patients (20.8%) with impaired pituitary function, with the greatest recovery in the hypothalamic-pituitary-adrenal axis (21.2%, 7/33). A larger residual tumour volume was predictive of adjuvant radiotherapy (3.40 vs. 1.24 cm3, p = 0.005) and likelihood for repeat surgery (5.40 vs. 1.67cm3, p = 0.004). Conclusion Pre- and post-operative NFPMA volumes fail to predict the number of pituitary hormone deficits, however, greater post-operative residual volumes increase the likelihood of further intervention to control tumour growth.

Radiation-Associated Glioblastoma after Prophylactic Cranial Irradiation in a Patient of ALL: Review of Literature and Report of a Rare Case

<b><i>Introduction:</i></b> The cumulative incidence of radiation-induced second malignancy is 1–2% per decade after radiotherapy (RT). Radiation-induced malignant glioma (RIMG) is a rare complication of cranial RT. <b><i>Case Presentation:</i></b> We herein describe a case of left frontal glioblastoma arising 5 years after prophylactic cranial irradiation (12.6 Gy/7 fractions/1.5 weeks) as a part of INCTR-02-04 protocol in a 3-year-old boy with B-cell ALL. He underwent gross total excision (GTE) of the tumour followed by post-operative intensity modulated RT (59.4 Gy/33 fractions/6.5 weeks) and concurrent and adjuvant (3 cycles) temozolomide. Thereafter, he had rapid disease progression, which entailed re-excision of the recurrent tumour. Subsequently, there was widespread subependymal and leptomeningeal spread of tumour, leading to death 10.5 months after the initial diagnosis. <b><i>Conclusion:</i></b> RIMG is an aggressive malignancy with a dismal prognosis, and in spite of multimodality management, it exhibits relentless progression, occasionally characterized by subependymal and leptomeningeal dissemination, leading to eventual death within a year of diagnosis.

IMG-18. ASSESSMENT OF SUSPECTED DISEASE PROGRESSION USING MULTIPARAMETRIC 18F-CHOLINE PET/MRI IN CHILDHOOD AND TEENAGE-YOUNG ADULT GLIOMAS

OBJECTIVES Evaluation of post-treatment glioma burden remains a significant challenge in children, teenagers and young adults (TYA). The aim of this study was to evaluate the utility of ChoPET/MRI for evaluation of suspected disease progression in childhood and TYA gliomas. METHODS 27 patients (mean age 14 years, range 6–21 years) with suspected glioma disease progression were evaluated with ChoPET/MRI (n=59). Relative cerebral blood volume (rCBV), apparent diffusion coefficient (ADC) and maximum standardised uptake values (SUVmax) in enhancing (enh) and non-enhancing (ne) tumour and normal-appearing white matter (wm) were calculated (rCBVenh, rCBVne, rCBVwm, ADCenh, ADCne, ADCwm, SUVenh, SUVne, SUVwm). 2 blinded radiologists scored tumour probability (1 = unlikely; 5 = definitely). Sensitivity and specificity calculated with gold standard histopathology or clinical follow-up. RESULTS Accuracy for the detection of residual/recurrent tumour on conventional MRI was 96.3% (91.7% ≤14 years, 100% ≥15 years) and ChoPET was 73.1% (66.7% ≤14 years, 80.0% ≥15 years). Lack of agreement was observed in 9/27 patients, with ChoPET superior to MRI in 1 case of a posterior fossa tumour. Tumour component analysis demonstrated significantly higher SUVenh and SUVne than SUVwm (SUVenh: p&lt;0.001; SUVne: p=0.004, equivalent to results were observed for ADV and rCBV (ADCenh, ADCne: p&lt;0.001 vs ADCwm; rCBVenh, rCBVne: p&lt;0.001 vs rCBVwm). CONCLUSIONS MRI is more sensitive than ChoPET in the evaluation of suspected disease progression in TYA gliomas. However, quanititative ChoPET is able to detect enhancing and non-enhancing tumour and may be helpful in evaluating posterior fossa disease where MRI is equivocal.

Permutation entropy in intraoperative ECoG of brain tumour patients in awake tumour surgery– a robust parameter to separate consciousness from unconsciousness

Awake craniotomies represent an essential opportunity in the case of lesions in eloquent areas. Thus, optimal surveillance of the patient during different stages of sedation, as well as the detection of seizure activity during brain surgery, remains difficult, as skin electrodes for electroencephalographic (EEG) analysis are not applicable in most cases. We assessed the applicability of ECoG to monitor different stages of sedation, as well as the influence of different patient characteristics, such as tumour volume, size, entity, and age or gender on permutation entropy (PeEn). We conducted retrospective analysis of the ECoG data of 16 patients, who underwent awake craniotomies because of left-sided brain tumours at our centre between 2014 and 2016. PeEn could be easily calculated and compared using frontal and parietal cortical electrodes. A comparison of PeEn scores showed significantly higher values in awake patients than in patients under anaesthesia (p ≤ 0.004) and significantly higher ones in the state of transition than under general anaesthesia (p = 0.023). PeEn scores in frontal and parietal leads did not differ significantly, making them both applicable for continuous surveillance during brain surgery. None of the following clinical characteristics showed significant correlation with PeEn scores: tumour volume, WHO grade, first or recurrent tumour, gender, and sex. Being 50 years or older led to significantly lower values in parietal leads but not in frontal leads. ECoG and a consecutive analysis of PeEn are feasible and suitable for the continuous surveillance of patients during awake craniotomies. Hence, the analysis is not influenced by patients’ clinical characteristics.

IMMU-51. PROFILING THE IMMUNE SYSTEM IN PRIMARY AND RECURRENT GLIOBLASTOMA

Immunotherapy has been shown to have benefit in some solid tumours including melanoma where immune infiltration can be pronounced. Until recently the central nervous system was thought to be immune privileged. Whilst research has shown that immune cells are capable of infiltrating tumours from glioblastoma patients, to date immunotherapy trials have not consistently shown a benefit in these patients. The aim of this study was to profile the immune system in primary and recurrent tumours from glioblastoma patients. Formalin-fixed paraffin-embedded sections of primary and matched recurrent tumours from 13 patients with glioblastoma were processed for immunohistochemical labelling of a range of immune cell markers. Immune infiltration was scored on digitally scanned immunolabelled sections using a categorical system of 0 (absent), 1 (present), 2 (moderate) and 3 (marked). CD3+ cells were observed in three topographical locations within primary and recurrent glioblastoma tumours namely the tumour proper, perivascular spaces and associated with haemorrhages within the tumour. CD3+ cell infiltration into the tumour proper was present (Score = 1) in 7 of 13 primary and recurrent tumours. Only one case (case #9) had CD3+ infiltration scores > 1 for both primary (score = 3) and recurrent tumour (score = 2). CD3+ cells were observed in perivascular spaces in 10 of the 13 cases of primary and recurrent glioblastoma. Only case #9 had CD3+ cells in perivascular spaces that was scored >1 for both primary and recurrent tumours. In conclusion, whilst CD3+ infiltration was observed in the tumour proper and perivascular spaces within both primary and recurrent glioblastomas, the level of infiltration was quite low in this small cohort and as such requires further investigation in a larger cohort.

Positive predictive value (PPV) of computed tomography in diagnosing wilms’ tumor using histopathology as gold standard.

CT can also accurately identify vascular invasion that will impact surgical approach along with identification of the preoperative parameters associated with increased risk of intraoperative Wilms’ tumor spill. Objectives: To determine positive predictive value of CT scan in diagnosing wilm’s tumour, taking histopathology as gold standard. Study Design: Descriptive, cross sectional study. Setting: Department of Urology & Renal Transplantation Centre, Bahawal Vitoria Hospital, Bahawalpur. Period: From July 2017 to June 2018. Materials & Methods: A total of 81 patients with suspected wilm’s tumour on ultrasonography of age 1-12 years of either gender were included. Patients with recurrent tumour and undergoing pre-op chemotherapy were excluded. All the patients were then underwent CT scan and looked for presence or absence of wilm’s tumour. The results were compared with histopathology. Results: Mean age was 5.23 ± 3.28 years. Majority of the patients 56 (69.14%) were between 1 to 6 years of age. Out of these 81 patients, 61 (75.31%) were female and 20 (24.69%) were males with female to male ratio of 2.9:1. CT scan supported the diagnosis of wilm’s tumour in all 46 patients. Histopathology confirmed wilm’s tumour in 41 (true positive) cases where as 05 (False Positive) had no wilm’s tumour on histopathology. Positive predictive value of CT scan in diagnosing wilm’s tumour, taking histopathology as gold standard was 89.13%. Conclusion: This study concluded that positive predictive value of CT scan in diagnosing wilm’s tumour is quite high.

Minimálisan invazív, endoszkóppal asszisztált, transcribriform reszekció a koponyaalap rosszindulatú daganatainak sebészetében

Introduction: Malignant tumours of the sinonasal region – including those with invasion of the skull base – necessitate surgical resection. The majority of the cases give an opportunity to perform the procedure via minimally invasive, endoscopic approach, without external, craniofacial surgery. Aim: To assess our clinical experience in treating anterior skull base malignancies, performing minimally invasive endoscopic transcribriform resection. Method: Between February 2015 and July 2017, four male and one female patient underwent minimally invasive, endoscopic skull base procedure. The mean age was 64.6 years (59–70, median: 66). Every surgery was performed via transnasal, endoscopic transcribriform approach. In two cases Kadish C esthesioneuroblastomas, while in one case a T3N0 sinonasal non-differentiated carcinoma, a T1N0 intestinal type adenocarcinoma and a T4N0 squamous cell carcinoma was the indication of surgery, respectively. Results: The mean follow-up time was 22.8 months, between 14 and 46 months. Intraoperative complications did not occur during the procedures. Regarding the postoperative period, liquorrhoea and pneumocephalus occurred in one case. Complications were solved with lumbar drainage. During follow-up, neither residual nor recurrent tumour was observed in our patients. Conclusion: Endoscopic transcribriform resection of the skull base malignancies is a safe and viable alternative to the traditional open approach. Orv Hetil. 2019; 160(40): 1584–1590.

The Transplant Surgeon: An Unlikely, Yet Suitably Qualified, Member of The Complex Neuro Endocrine Multi-Disciplinary Team

Curative surgery for retro-peritoneal tumours involving vascular structures is challenging and multi-visceral resection is often required to obtain clear resection margins. Abdominal transplant surgeons have considerable experience in all aspects of visceral, vascular and retro-peritoneal surgery. Application of these skills to resect tumours involving vascular structures, and re-implant organs to preserve function is unique. We present the case of a 15- year old girl with a complex retro-peritoneal tumour which was resected en-bloc with the kidneys and vena-cava followed by auto-transplantation of the left kidney. Seven years later, the patient represented with a recurrent tumour which was successfully excised in its entirety. We discuss how innovative surgical strategies can be performed safely on an individualized basis. We highlight the importance of balancing the benefits of the ‘technically possible procedure’ with its risks, along with consideration of the outcomes of treatment and non-treatment alike.