Clinical and patient-reported outcome after patient-specific 3D printer-assisted cranioplasty.

Various cranioplasty techniques exist for the reconstruction of cranial bone defects. Patient-specific implants can be produced in-house using a recently developed 3D printer-assisted cranioplasty technique. However, the resulting cosmetic outcomes from the patient's perspective are underreported. With our case series, we aim to present the clinical outcome, morbidity rate, patient-reported cosmetic results, and cost-effectiveness of patient-specific3D printer-assisted cranioplasty technique. This is a consecutive retrospective case series of adult patients undergoing cranioplasty using the patient-specific 3D printer-assisted technique. As primary endpoint, the functional outcome based on modified Rankin scale (mRS) at discharge and follow-up was assessed. A prospective telephone survey was conducted to collect and provide patient-reported outcomes. Thirty-one patients underwent patient-specific 3D printer-assisted cranioplasty, mostly to reconstruct frontotemporoparietal (61.3%) and frontotemporal defects with orbital involvement (19.4%). Good functional outcome (mRS ≤ 2) at discharge and during the last follow-up was achieved in 54.8% (n = 17) and 58.1% (n = 18) patients. Overall, the rate of clinically relevant surgery-related complications was 35.5% (n = 11). Postoperative epidural hematoma/collection (16.1%) and infections (12.9%) were the most frequent complications. Permanent morbidity occurred in one patient (3.2%) with postoperative acute ipsilateral vision loss after frontotemporal cranioplasty with orbital involvement. No surgery-related mortality occurred. The mean patient-reported cosmetic satisfaction score was 7.8 ± 1.5, with 80% of patients reporting satisfying or very satisfying cosmetic results. No significant differences were seen between the different defect localization regarding the cosmetic outcome. The mean manufacturing costs of a patient-specific 3D printer-assisted implant ranged from 748 to 1129 USD. Based on our case series, patient-specific 3D printer-assisted cranioplasty is cost-effective and leads to satisfying cosmetic results, especially in large defects and/or defects with complex geometry.

Perioperative continuation or ultra-early resumption of antithrombotics in elective neurosurgical cranial procedures.

OBJECTIVE: Discontinuation of antithrombotics (AT) prior to elective cranial procedures is common practice, despite the higher risk of thromboembolic complications in these patients. The aim of this study was to investigate the risks and benefits of a new perioperative management protocol of continuation or ultra-early AT resumption in elective cranial procedures. METHODS: This study was an analysis of a prospectively collected cohort of patients undergoing elective cranial surgery with (AT group) and without (control group) AT. For extraaxial or shunt surgeries, acetylsalicylic acid (ASA) was continued perioperatively. For intraaxial pathologies, ASA was discontinued 2 days before surgery and resumed on postoperative day 3. All other AT were discontinued according to their pharmacokinetics, and resumed on postoperative day 3 after unremarkable postoperative imaging. Additionally, the authors performed a retrospective analysis of patients with AT who underwent surgery before implementation of this new AT management protocol (historical AT group). Primary and secondary outcomes were the incidence of hemorrhagic and thromboembolic complications within 3 months after surgery. RESULTS: Outcomes of 312 patients were analyzed (83 [27%] in the AT group, 106 [34%] in the control group, and 123 [39%] in the historical AT group). For all 3 patient groups, the most common type of surgery was craniotomy for intraaxial tumors (14 [17%] in the AT group, 28 [26%] in the control group, and 60 [49%] in the historical AT group). The most commonly used AT were ASA (38 [46%] in the AT group and 78 [63%] in the historical AT group), followed by non-vitamin K oral anticoagulants (32 [39%] in the AT group and 18 [15%] in the historical AT group). The total perioperative discontinuation time in the AT group was significantly shorter than in the historical AT group (median of 4 vs 16 days; p < 0.001). The rate of hemorrhagic complications was 4% (95% CI 1-10) (n = 3/83) in the AT group, 6% (95% CI 2-12) (n = 6/106) in the control group, and 7% (95% CI 3-13) (n = 9/123) in the historical AT group (p = 0.5). The rate of thromboembolic complications was 5% (95% CI 1-12) (n = 4/82) in the AT group, 8% (95% CI 3-15) (n = 8/104) in the control group, and 7% (95% CI 3-13) (n = 8/120) in the historical AT group (p = 0.7). CONCLUSIONS: The presented perioperative management protocol of continuation or ultra-early resumption of AT in elective cranial procedures does not seem to increase the hemorrhagic risk. Moreover, it appears to potentially protect patients from thromboembolic complications.

Risks and benefits of continuation and discontinuation of aspirin in elective craniotomies: a systematic review and pooled-analysis.

BACKGROUND/AIM: Discontinuation of aspirin (ASA) prior to elective craniotomies is common practice. However, patients treated with ASA for secondary prevention bear a higher risk for thromboembolic complications. Aim of this systematic review is to investigate the risks and benefits of perioperative continuation and discontinuation of ASA in elective craniotomies. METHODS: PubMed and Embase databases were searched. Inclusion criteria were retro- and prospective studies, reporting hemorrhagic and thromboembolic complications in patients in whom ASA was either continued or discontinued perioperatively in elective craniotomies. We excluded shunt operations and emergency cases. The MINORS (Methodological index for non-randomized studies) score was used to quantify the methodological quality of the eligible studies. RESULTS: Out of 523 publications, 7 met the eligibility criteria (cumulative cohort of 646 patients). The mean MINORS score for the comparative studies was 18.7/24 (± SD 2.07, range: 17-22) and 9/16 for the unique non-comparative study, indicating an overall weak methodological quality of the included studies. 57.1% of the patients underwent craniotomy for intra- and extra-axial tumor removal, 39.0% for bypass surgery and 3.9% for neurovascular lesions (other than bypass). In 31.0% of the cases, ASA was prescribed for primary and in 69.0% for secondary prevention. ASA was continued perioperatively in 61.8% and discontinued in 38.2% of the cases. The hemorrhagic complication rate was 3% (95% CI [0.01-0.05]) in the ASA continuation group (Con-Group) and 3% (95% CI [0.01-0.09]) in the discontinuation group (Disc-Group) (p = 0.9). The rate of thromboembolic events in the Con-Group was 3% (95% CI [0.01-0.06]) in comparison to 6% (95% CI [0.02-0.14]) in the Disc-Group (p = 0.1). CONCLUSION: Perioperative continuation of ASA in elective craniotomies does not seem to be associated with an increased hemorrhagic risk. The potential beneficial effect of ASA continuation on thromboembolic events needs to be further investigated in patients under ASA for secondary prevention.

Rapid Versus Gradual Weaning of External Ventricular Drain: A Systematic Literature Review and Meta-analysis.

The insertion of an external ventricular drain (EVD) is one of the most common neurosurgical procedures. Whether the weaning method (gradual or rapid) influences the ventriculoperitoneal shunt (VPS) insertion rate has not been conclusively established. The aim of this study is to provide a systematic literature review and conduct a meta-analysis of studies comparing gradual with rapid EVD weaning regarding VPS insertion rate. Articles were identified by searching the Pubmed/Medline, Embase, and Web of Science databases throughout October 2022. Two independent researchers assessed the studies for inclusion and quality. We included randomized trials, prospective cohort studies, and retrospective cohort studies, which compared gradual and rapid EVD weaning. The primary outcome was VPS insertion rate, whereas secondary outcomes were EVD-associated infection (EVDAI) rate and length of stay in the hospital and intensive care unit (ICU). Four studies directly comparing rapid versus gradual EVD weaning, with 1337 patients suffering from subarachnoid hemorrhage, were identified and included in the meta-analysis. VPS insertion rate was 28.1% and 32.1% in patients with gradual and rapid EVD weaning, respectively (relative risk 0.85, 95% confidence interval 0.49-1.46, p = 0.56). Further, the EVDAI rate was comparable between the groups (gradual group 11.2%, rapid group 11.5%, relative risk 0.67, 95% confidence interval 0.24-1.89, p = 0.45), whereas length of stay in the ICU and hospital were significantly shorter in the rapid weaning group (2.7 and 3.6 days, respectively; p < 0.01). Rapid EVD weaning seems comparable to gradual EVD weaning concerning VPS insertion rates and EVDAI, whereas hospital and ICU length of stay is significantly reduced.

Gut Microbiota, Metabolome, and Body Composition Signatures of Response to Therapy in Patients with Advanced Melanoma.

Despite the recent breakthroughs in targeted and immunotherapy for melanoma, the overall survival rate remains low. In recent years, considerable attention has been paid to the gut microbiota and other modifiable patient factors (e.g., diet and body composition), though their role in influencing therapeutic responses has yet to be defined. Here, we characterized a cohort of 31 patients with unresectable IIIC-IV-stage cutaneous melanoma prior to initiation of targeted or first-line immunotherapy via the following methods: (i) fecal microbiome and metabolome via 16S rRNA amplicon sequencing and gas chromatography/mass spectrometry, respectively, and (ii) anthropometry, body composition, nutritional status, physical activity, biochemical parameters, and immunoprofiling. According to our data, patients subsequently classified as responders were obese (i.e., with high body mass index and high levels of total, visceral, subcutaneous, and intramuscular adipose tissue), non-sarcopenic, and enriched in certain fecal taxa (e.g., Phascolarctobacterium) and metabolites (e.g., anethole), which were potentially endowed with immunostimulatory and oncoprotective activities. On the other hand, non-response was associated with increased proportions of Streptococcus, Actinomyces, Veillonella, Dorea, Fusobacterium, higher neutrophil levels (and a higher neutrophil-to-lymphocyte ratio), and higher fecal levels of butyric acid and its esters, which also correlated with decreased survival. This exploratory study provides an integrated list of potential early prognostic biomarkers that could improve the clinical management of patients with advanced melanoma, in particular by guiding the design of adjuvant therapeutic strategies to improve treatment response and support long-term health improvement.

Occurrence of breast-cancer-related lymphedema after reverse lymphatic mapping and selective axillary dissection versus standard surgical treatment of axilla: A two-arm randomized clinical trial.

BACKGROUND: The need for axillary dissection (AD) is declining, but it is still essential for many patients with nodal involvement who risk developing breast-cancer-related lymphedema (BCRL) with lifelong consequences. Previous nonrandomized studies found axillary reverse mapping and selective axillary dissection (ARM-SAD) a safe and feasible way to preserve the arm's lymphatic drainage. METHODS: The present two-arm prospective randomized clinical trial was held at a single comprehensive cancer center to ascertain whether ARM-SAD can reduce the risk of BCRL, compared with standard AD, in patients with node-positive breast cancer. Whatever the type of breast surgery or adjuvant treatments planned, 130 patients with nodal involvement met our inclusion criteria: 65 were randomized for AD and 65 for ARM-SAD. Twelve months after surgery, a physiatrist assessed patients for BCRL and calculated the excess volume of the operated arm. Lymphoscintigraphy was used to assess drainage impairment. Self-reports of any impairment were also recorded. RESULTS: The difference in the incidence of BCRL between the two groups was 21% (95% CI, 3-37; p = .03). A significantly lower rate of BCRL after ARM-SAD was confirmed by a multimodal analysis that included the physiatrist's findings, excess arm volume, and lymphoscintigraphic findings, but this was not matched by a significant difference in patients' self-reports. CONCLUSIONS: Our findings encourage a change of surgical approach when AD is still warranted. ARM-SAD may be an alternative to standard AD to reduce the treatment-related morbidity.

Weekly cisplatin with or without imatinib in advanced chordoma: A retrospective case-series analysis from the Italian Rare Cancers Network.

BACKGROUND: To report on a retrospective case-series analysis of weekly cisplatin (wCDDP) as a single agent or combined with imatinib (wCDDP/I) in patients with advanced chordoma treated within the Italian Rare Cancer Network. METHODS: Adult patients with a diagnosis of advanced, brachyury-positive chordoma, treated from April 2007 to October 2020 with wCDDP or wCDDP/I were retrospectively identified. Imatinib was withheld at the same time as wCDDP. Response according to Response Evaluation Criteria in Solid Tumors, overall survival (OS), and progression-free survival (PFS) were analyzed. RESULTS: Thirty-three consecutive patients were identified (wCDDP as front-line n = 8 [24.2%]; wCDDP as a further line n = 25 [75.8%]; prior imatinib n = 25 [75.8%]; evidence of progression before starting wCDDP n = 33). Of 32 patients evaluable for response (wCDDP, n = 22 [68.8%]; wCDDP/I, n = 10 [31.3%]), best response was stable disease (SD) in 27 patients (84.3%) and progression in 5 patients (15.6%). At a median follow-up of 54 months, the median OS (m-OS) was 30.3 months (interquartile range [IQR], 18.1-56.6), the m-PFS was 8.0 months (IQR, 5.1-17.0), the 6-month PFS rate was 65.2%, and the 12-month PFS rate was 30.3%. Of 22 patients who received wCDDP, the best response was SD in 18 patients (81.8%) and progression in 4 patients (18.2%), and the m-PFS was 8.0 months (IQR, 5.1-17.0 months). Of 10 patients who received treatment with wCDDP/I, the best response was SD in 9 patients (90%) and progression in 1 patient (10%), and the m-PFS was 9.3 months (IQR, 4.9-26.5 months). CONCLUSIONS: This series suggests that wCDDP, both as a single agent and combined with imatinib, has antitumor activity in chordoma. Although no dimensional responses were observed, 65% and 30% of previously progressive patients were progression-free at 6 and 12 months, respectively. A prospective study is warranted.

Preclinical and clinical role of interleukin-6 in the development of delayed cerebral vasospasm and neuronal cell death after subarachnoid hemorrhage: towards a potential target therapy?

Delayed cerebral vasospasm (DCVS), early brain injury (EBI), and delayed cerebral ischemia (DCI) are devastating complications after aneurysmal subarachnoid hemorrhage (SAH). Interleukin (IL)-6 seems to be an important interleukin in the inflammatory response after SAH, and many studies describe a strong correlation between IL-6 and worse outcome. The aim of this study was to systematically review preclinical and clinical studies that evaluated systemic and cerebral IL-6 levels after SAH and their relation to DCVS, neuronal cell death, and DCI. We conducted two systematic literature searches using PubMed to identify preclinical and clinical studies evaluating the role of IL-6 after SAH. Suitable articles were selected based on predefined eligibility criteria following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A total of 61 and 30 preclinical and clinical articles, respectively, were included in the systematic reviews. Of the preclinical studies in which IL-6 was measured in cerebrospinal fluid (CSF), parenchyma, and systemically, 100%, 94.4%, and 81.3%, respectively, showed increased expression of IL-6 after SAH. Preclinical results were mirrored by clinical findings in which elevated levels of IL-6 in CSF and plasma were found after SAH, correlating with DCVS, DCI, and worse outcome. Only two preclinical studies analyzed the direct inhibition of IL-6, which resulted in reduced DCVS and neuronal cell death. IL-6 is a marker of intracranial inflammation and plays a role in the pathophysiology of DCVS and DCI after SAH in preclinical animal models and clinical studies. Its inhibition might have therapeutic potential to improve the outcome of SAH patients.

The Role of Endonasal Endoscopic Skull Base Repair in Posttraumatic Tension Pneumocephalus.

OBJECTIVES: Information about the endonasal endoscopic approach (EEA) for the management of posttraumatic tension pneumocephalus (PTTP) remains scarce. Concomitant rhinoliquorrhea and posttraumatic hydrocephalus (PTH) can complicate the clinical course. METHODS: The authors systematically reviewed pertinent articles published between 1961 and December 2020 and identified 6 patients with PTTP treated by EEA in 5 reports. Additionally, the authors share their institutional experience including a seventh patient, where an EEA resolved a recurrent PTTP without rhinoliquorrhea. RESULTS: Seven PTTP cases in which EEA was used as part of the treatment regime were included in this review. All cases presented with a defect in the anterior skull base, and 3 of them had concomitant rhinoliquorrhea. A transcranial approach was performed in 6/7 cases before EEA was considered to treat PTTP. In 4/7 cases, the PTTP resolved after the first intent; in 2/ 7 cases a second repair was necessary because of recurrent PTTP, 1 with and 1 without rhinoliquorrhea, and 1/7 case because of recurrent rhinoliquorrhea only. Overall, PTTP treated by EEA resolved with a mean radiological resolution time of 69 days (range 23-150 days), with no late recurrences. Only 1 patient developed a cerebrospinal fluid diversion infection probably related to a first incomplete EEA skull base defects repair. A permanent cerebrospinal fluid diversion was necessary in 3/7 cases. CONCLUSIONS: Endonasal endoscopic approach repair of air conduits is a safe and efficacious second-line approach after failed transcranial approaches for symptomatic PTTP. However, the strength of recommendation for EEA remains low until further evidence is presented.

Activity of sirolimus in patients with progressive epithelioid hemangioendothelioma: A case-series analysis within the Italian Rare Cancer Network.

BACKGROUND: The objective of this study was to report on a retrospective series of patients with epithelioid hemangioendothelioma (EHE) who received treatment with sirolimus within the Italian Rare Cancer Network. METHODS: From January 2005, 38 adult patients with advanced EHE received continuous-dosing sirolimus, 5 mg daily, until they developed either toxicity or disease progression. Disease progression in the 6 months before the start of treatment was required. Each pathologic diagnosis was reviewed. The daily dose of sirolimus was adjusted based on plasma levels. Response was retrospectively assessed by local investigators using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST). Survival was estimated using the Kaplan-Meier method. RESULTS: All 38 patients (WW Domain Containing Transcription Regulator 1 [WWTR1]-positive, n = 37; transcription factor E3 [TFE3]-positive, n = 1) had disease progression before starting sirolimus (at baseline, 13 of 38 patients had the presence of serosal effusions and systemic symptoms). Thirty-seven patients were evaluable for response (there was 1 early interruption). The best RECIST responses were a partial response in 4 patients (10.8%), stable disease in 28 patients (75.7%), and disease progression in 5 patients (13.5%). At a 41.5-month median follow-up (interquartile range [IQR], 23.9-56.8 months), the median PFS was 13 months (95% CI, 3.7 months to not estimated [NE]), and the median OS was 18.8 months (95% CI, 10.6 months to NE). In patients who had serosal effusions at baseline, the median PFS was 4.8 months (IQR, 3.5-11.7 months), and the median OS was 10.6 months (IQR, 5.1-13.0 months), compared with 47.8 months (IQR, 11.4 months to NE) and 47.8 months (IQR, 15.7 months to NE), respectively, in patients without serosal effusions. Overall, sirolimus was fairly well tolerated, with 10 patients reporting irregular menstruation/ovary disfunction. CONCLUSIONS: The current results confirm that sirolimus is active in EHE, leading to prolonged stabilization in most patients who present without serosal effusions. Serosal effusions are confirmed as an unfavorable prognostic sign associated with short survival, and sirolimus displays limited activity in this subgroup.

Selective resection of cushing microadenoma guided by preoperative hybrid 18-fluoroethyl-L-tyrosine and 11-C-methionine PET/MRI.

PURPOSE: 11-C-methionine (MET)-positron emission tomography (PET) as an adjunct to magnetic resonance imaging (MRI) has been proposed as a suitable molecular imaging modality for localizing pituitary adenomas in Cushing's disease. 18-F-Fluoroethyl-L-tyrosine (FET)-PET, which is more widely available has not yet been reported in this context. METHODS: Retrospective double-center cohort study on 15 patients who underwent transsphenoidal surgery for biochemically proven Cushing's disease between 2011 and 2019. Preoperative MET-PET/MRI and/or FET-PET/MRI were compared with intraoperative and histopathological examinations using the Mann Whitney U test and the Fisher's Exact test, along with positive predictive value calculations. RESULTS: Fifteen patients were included, with a mean age of 47.2 (18-69) years. Six patients received either a MET-PET/MRI or a FET-PET/MRI and 3 patients both exams, respectively. 67% of the tumors were detected by MRI (MET-PET-group [56%]; FET-PET-group [78%]). All tumors were microadenomas with a mean adenoma volume of 0.19 cm3 (0.02-0.78), all of which displayed a circumscribed pathological FET- and/or MET-uptake. FET-PET/MRI results positively correlated with the localization of the tumor confirmed intraoperatively and histopathologically in all cases, resulting in a sensitivity and specificity of FET-PET/MRI for tumor localization of 100% (95% CI 66.37-100%). One MET-PET/MRI suggested a localization contralateral to the expected spot. The sensitivity and specificity of MET-PET for tumor localization hence was 89% (95% CI 51.75-99.72%). CONCLUSIONS: Preoperative hybrid FET-PET/MRI and MET-PET/MRI have a high predictive value in localizing corticotroph adenoma for selective adenomectomy in Cushing's disease.

Prevalence and outcome of comorbidities associated with acromegaly.

BACKGROUND: Acromegaly is associated with various comorbidities, such as arterial hypertension (aHT), type 2 diabetes mellitus (DM2), obstructive sleep apnoea syndrome (OSAS), carpal tunnel syndrome (CTS) and polyposis coli. For therapeutic decisions, it is essential to know if, and to what extent, these associated morbidities are reversible or preventable. The aim of this study is to assess the prevalence and course of aHT, obesity, OSAS, CTS, DM2 and polyposis coli in acromegalic patients. METHODS: The following criteria for inclusion in this database study were used: treatment for acromegaly at the authors' institutions; full endocrinological and radiological work- and follow-up; screening for aHT, DM2, CTS, OSAS, obesity and polyposis coli. All patients were followed-up for > 3 months, and treatments were indicated with the intent of biochemical remission (normal IGF-1 and random growth hormone level). RESULTS: Sixty-three patients were included. Twelve (19%), 45 (71%) and 6 (10%) patients harboured micro-, macro- and giant adenomas, respectively. Nineteen tumours (30%) invaded the cavernous sinus. Mean tumour volume was 5.4 cm3. Mean follow-up time was 42 months. Sixty-one (97%) patients had transsphenoidal surgery; two patients only had drug therapy. Surgery led to remission in 31 (51%) patients. Intracavernous growth and larger tumour volume were negative predictors for cure. Drug therapy lead to remission in 22 (73%) patients within a mean follow-up of 54 months. The pretherapeutic prevalence of associated morbidities was as follows: aHT, 56%; DM2, 25%; OSAS, 29%; CTS, 29%; polyposis coli, 5%. There were neither age nor gender preferences for the respective prevalences. Surgery leads to remission of aHT and DM2 in 6% and 25%, respectively. Additional drug therapy resulted in remission of aHT, DM2 and CTS in 17%, 14% and 14%, respectively. Other associated morbidities persisted regardless of therapeutic efforts. Even if criteria for remission were not met, no new comorbidities of acromegaly developed during follow-up. CONCLUSIONS: Treating acromegaly may relieve threatening associated morbidities such as aHT and DM2; nevertheless, only few comorbidities are reversible, which highlights the importance of treating acromegaly as early as possible.

Lateral one-third gland resection in Cushing patients with failed adenoma identification leads to low remission rates: long-term observations from a small, single-center cohort.

BACKGROUND: Currently, there are no guidelines for neurosurgeons treating patients with Cushing's disease (CD) when intraoperative adenoma identification is negative. Under these circumstances, a total hypophysectomy or hemi-hypophysectomy on the side indicated by inferior petrosal sinus sampling (IPSS) is the approach being used, although there is a subsequent risk of hypopituitarism. Data on whether one-third lateral pituitary gland resection results in cure of hypercortisolism and low rates of hypopituitarism remain inconclusive. METHODS: Retrospective single-center study of CD patients with failed intraoperative adenoma identification and subsequent resection of the lateral one-third of the pituitary gland as predicted by IPSS. We assessed (i) histopathological findings, (ii) early and long-term remission rates, and (iii) rates of additional pituitary hormone insufficiency. RESULTS: Ten women and three men met the inclusion criteria. At 3 months, remission was noted in six (46%) patients: three (23%) had histologically confirmed adenomas, two (15%) had ACTH hyperplasia, and one patient (8%) was positive for Crooke's hyaline degeneration. New pituitary hormone deficits were noted in two patients (15%). After a median (±SD) follow-up of 14±4 years, recurrence was noted in two (15%) patients. Long-term control of hypercortisolism was attained by 10 patients (77%), with additional therapies required in nine (69%) of them. CONCLUSIONS: In CD patients with failed intraoperative adenoma visualization, lateral one-third gland resection resulted in low morbidity and long-term remission in 31% of patients without the need for additional therapies. Bearing in mind the sample size of this audit, the indication for lateral one-third-gland resection has to be critically appraised and discussed with the patients before surgery.

The effect of anti-thrombotics on the postoperative bleeding rate in patients undergoing craniotomy for brain tumor.

OBJECTIVE: The peak prevalence of many brain tumors is in elderly patients. These patients are often treated with platelet inhibitors (PIs) or anticoagulants (ACs), creating a challenge for neurosurgeons concerning the perioperative management. The aim of this study is to analyze the effect of PI/AC treatment on the postoperative bleeding rates in patients undergoing craniotomy due to a brain tumor. METHODS: Retrospective analysis of 415 consecutive patients undergoing craniotomy/craniectomy due to a brain tumor. Ninety-nine patients with PI/AC treatment (PI/AC group consisting of 64 PI, 29 AC, and six multiple) and 316 patients without PI/AC (control group) were primarily compared for hemorrhage rate. Secondary outcome measures were clinical outcome and mortality. The association between short preoperative discontinuation (≤5 days), early postoperative resumption time (≤5 days), as well as short total discontinuation time (≤5 days) of PI/AC and postoperative bleeding rates was analyzed. RESULTS: Postoperative bleeding rates were comparable between the groups (12.2% and 13.5% in the PI/AC and control group, respectively; p=.74). The majority of bleeds were asymptomatic (85.2%). No significant difference in the postoperative mortality rate was observed (1.0% and 1.6% in the PI/AC and the control group, respectively; p=.67). Shorter discontinuation time of PI/AC was not significantly associated with higher postoperative bleeding rates (preoperative: 12.1% vs. 12.3%; p=.94, postoperative: 11.1% vs. 12.5%, respectively; p=.87, total: 16.7% vs. 12%, respectively; p=.73). CONCLUSIONS: Patients treated with PI/AC undergoing craniotomy for the resection of brain tumor do not seem to have increased rates of postoperative bleeding or mortality. We did not find a significant correlation between short discontinuation time of PI/AC in the perioperative period and postoperative bleeding.

Influence of inferior petrosal sinus drainage symmetry on detection of adenomas in Cushing's syndrome.

BACKGROUND: Asymmetric inferior petrosal sinuses (IPS) are not infrequently encountered during bilateral IPS sampling. There is little data on whether IPS symmetry influences success in predicting the adenoma side in patients with ACTH-dependent Cushing's syndrome (CS). OBJECTIVE: To assess the influence of IPS drainage patterns on detection of an adenoma in CS. METHODS: Retrospective single-center cohort analysis reviewing records of patients with CS and negative MRI findings who subsequently underwent BIPSS. RESULTS: BIPSS was performed in 38 patients with a mean age of 45±15 years. The overall technical success rate was 97% for bilateral cannulation. Asymmetric IPS were observed in 11 (39%) patients with Cushing's disease (CD). A side-to-side ACTH ratio was not significantly different between patients with symmetric outflow and those with asymmetric outflow at baseline (8.6±2.7 versus 16.4±6.0; P=0.45), but ratios were significantly different after ovine corticotropin-releasing hormone (oCRH) stimulation (6.0±2.5 versus 35.7±22.5; P=0.03). BIPSS correctly predicted the side of the adenoma in 25 (96%) patients with CD. Prediction was better when the venous outflow was symmetric (100%) rather than asymmetric (93%), although the difference was not significant (P=0.42). Remission from CS was achieved in 32 patients (87%), independent of the symmetry of IPS. CONCLUSIONS: Bearing in mind the sample size of this audit, asymmetric IPS at least do not seem to diminish the accuracy of diagnosis of ACTH-dependent CS, nor do they influence the clinical outcome.

Liver transplantation in hepatocellular carcinoma after tumour downstaging (XXL): a randomised, controlled, phase 2b/3 trial.

BACKGROUND: Indications for liver transplantation for hepatocellular carcinoma are evolving and so-called expanded criteria remain debated. Locoregional therapies are able to downstage hepatocellular carcinoma from beyond to within the Milan criteria. We aimed to investigate the efficacy of liver transplantation after successful hepatocellular carcinoma downstaging. METHODS: We did an open-label, multicentre, randomised, controlled trial designed in two phases, 2b and 3, at nine Italian tertiary care and transplantation centres. Patients aged 18-65 years with hepatocellular carcinoma beyond the Milan criteria, absence of macrovascular invasion or extrahepatic spread, 5-year estimated post-transplantation survival of at least 50%, and good liver function (Child-Pugh A-B7) were recruited and underwent tumour downstaging with locoregional, surgical, or systemic therapies according to multidisciplinary decision. After an observation period of 3 months, during which sorafenib was allowed, patients with partial or complete responses according to modified Response Evaluation Criteria in Solid Tumors were randomly assigned (1:1) by an interactive web-response system to liver transplantation or non-transplantation therapies (control group). A block randomisation (block size of 2), stratified by centre and compliance to sorafenib treatment, was applied. Liver transplantation was done with whole or split organs procured from brain-dead donors. The control group received sequences of locoregional and systemic treatment at the time of demonstrated tumour progression. The primary outcomes were 5-year tumour event-free survival for phase 2b and overall survival for phase 3. Analyses were by intention to treat. Organ allocation policy changed during the course of the study and restricted patient accrual to 4 years. This trial is registered with ClinicalTrials.gov, NCT01387503. FINDINGS: Between March 1, 2011, and March 31, 2015, 74 patients were enrolled. Median duration of downstaging was 6 months (IQR 4-11). 29 patients dropped out before randomisation and 45 were randomly assigned: 23 to the transplantation group versus 22 to the control group. At data cutoff on July 31, 2019, median follow-up was 71 months (IQR 60-85). 5-year tumour event-free survival was 76·8% (95% CI 60·8-96·9) in the transplantation group versus 18·3% (7·1-47·0) in the control group (hazard ratio [HR] 0·20, 95% CI 0·07-0·57; p=0·003). 5-year overall survival was 77·5% (95% CI 61·9-97·1) in the transplantation group versus 31·2% (16·6-58·5) in the control group (HR 0·32, 95% CI 0·11-0·92; p=0·035). The most common registered grade 3-4 serious adverse events were hepatitis C virus recurrence (three [13%] of 23 patients) and acute transplant rejection (two [9%]) in the transplantation group, and post-embolisation syndrome (two [9%] of 22 patients) in the control group. Treatment-related deaths occurred in four patients: two (8%) of 23 patients in the transplantation group (myocardial infarction and multi-organ failure) versus two (9%) of 22 patients in the control group (liver decompensation). INTERPRETATION: Although results must be interpreted with caution owing to the early closing of the trial, after effective and sustained downstaging of eligible hepatocellular carcinomas beyond the Milan criteria, liver transplantation improved tumour event-free survival and overall survival compared with non-transplantation therapies Post-downstaging tumour response could contribute to the expansion of hepatocellular carcinoma transplantation criteria. FUNDING: Italian Ministry of Health.

Patients with adenoid cystic carcinomas of the salivary glands treated with lenvatinib: Activity and quality of life.

BACKGROUND: The treatment of patients with recurrent and/or metastatic (R/M) salivary gland adenoid cystic carcinoma (ACC) remains an unmet need. METHODS: Patients with R/M disease with a history of clinical or symptomatic disease progression within 6 months and a maximum of 1 previous line of chemotherapy or a multiple kinase inhibitor received oral lenvatinib at a dose of 24 mg/day. The primary endpoint was the objective response rate; secondary endpoints included quality of life (QOL) (according to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Items [EORTC QLQ-C30] and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Module Head and Neck Module [EORTC QLQ-H&N35]), progression-free survival and overall survival, duration of response, and toxicities. RESULTS: Twenty-eight patients with R/M ACC were enrolled. Among 26 evaluable patients, 3 partial responses (11.5%) were reported. Target lesion reductions between 23% to 28% were observed in 4 of 20 patients with stable disease. Treatment-related adverse events were frequent (all grades, 96%; grade≥3 in 50% of cases according to version 4.03 of the National Cancer Institute Common Terminology Criteria for Adverse Events). The dose of lenvatinib was reduced in 24 patients, whereas in 21 patients the dose was reduced within the first 12 weeks and 4 patients maintained the full dose throughout treatment. The QOL deteriorated between baseline and 6 months with regard to Fatigue and Dry Mouth. There was no evidence of changes in Swallowing and Physical Functioning. At a median follow-up of 29 months, 2 patients remained on treatment, 10 patients were off protocol for disease progression and were alive with disease, and 14 patients had died of disease progression. The median overall survival, progression-free survival, and duration of response were 27 months, 9.1 months, and 3.1 months, respectively. CONCLUSIONS: Lenvatinib appears to have modest activity in ACC. Toxicities are common but manageable and QOL was found to deteriorate in some domains.

Systemic treatments in MDM2 positive intimal sarcoma: A multicentre experience with anthracycline, gemcitabine, and pazopanib within the World Sarcoma Network.

BACKGROUND: Intimal sarcoma (InS) is an exceedingly rare neoplasm with an unfavorable prognosis, for which new potentially active treatments are under development. We report on the activity of anthracycline-based regimens, gemcitabine-based regimens, and pazopanib in patients with InS. METHODS: Seventeen sarcoma reference centers in Europe, the United States, and Japan contributed data to this retrospective analysis. Patients with MDM2-positive InS who were treated with anthracycline-based regimens, gemcitabine-based regimens, or pazopanib between October 2001 and January 2018 were selected. Local pathological review was performed to confirm diagnosis. Response was assessed by RECIST1.1. Recurrence-free survival (RFS), progression-free survival (PFS) and overall survival were computed by Kaplan-Meier method. RESULTS: Seventy-two patients were included (66 anthracycline-based regimens; 26 gemcitabine-based regimens; 12 pazopanib). In the anthracycline-based group, 24 (36%) patients were treated for localized disease, and 42 (64%) patients were treated for advanced disease. The real-world overall response rate (rwORR) was 38%. For patients with localized disease, the median RFS was 14.6 months. For patients with advanced disease, the median PFS was 7.7 months. No anthracycline-related cardiac toxicity was reported in patients with cardiac InS (n = 26). For gemcitabine and pazopanib, the rwORR was 8%, and the median PFS was 3.2 and 3.7 months, respectively. CONCLUSION: This retrospective series shows the activity of anthracycline-based regimens in InS. Of note, anthracyclines were used in patients with cardiac InS with no significant cardiac toxicity. The prognosis in patients with InS remains poor, and new active drugs and treatment strategies are needed.

The Activity of Chemotherapy in Inflammatory Myofibroblastic Tumors: A Multicenter, European Retrospective Case Series Analysis.

BACKGROUND: This study aimed to review the activity of cytotoxic chemotherapy in patients with inflammatory myofibroblastic tumors (IMTs) treated at nine European sarcoma reference centers. MATERIALS AND METHODS: Patients of any age, with histologically proven IMT, treated with anthracycline-based methotrexate plus/minus vinorelbine/vinblastine (MTX-V) or other chemotherapeutic regimens between 1996 and 2018 were retrospectively reviewed. Diagnosis was confirmed at the local level by an expert pathologist. Response was retrospectively assessed by local investigators by RECIST v1.1. Progression-free survival (PFS), relapse-free survival (RFS), and overall survival (OS) were computed by Kaplan-Meier method. RESULTS: Thirty-eight patients were included. Twenty-five patients (8 localized, 17 advanced disease) received an anthracycline-based regimen; 21 were evaluable for response. Overall response rate (ORR) was 10/21 (47.6%). At a 70.8-month median follow-up (FU), median RFS and median OS were not reached (NR) in patients with localized disease; median PFS and median OS were 6.3 (interquartile range [IQR]: 1.9-13.4) and 21.2 (IQR: 7.7-40.7) months in patients with advanced disease. Thirteen patients received MTX-V (4 localized, 9 advanced disease), all evaluable for response. ORR was 7/13 (53.8%). At a 56.6-month median FU, median RFS and median OS were 42.5 (IQR: 12.9-61.2) months and NR (no death events) in patients with localized disease, and NR (IQR: 24.9 to NR) and 83.4 months (IQR: 83.4 to NR) in patients with advanced disease. In the "other-regimens group," responses were seen in 3/4 patients treated with oral cyclophosphamide and 1/2 with docetaxel/gemcitabine. CONCLUSION: Anthracycline-based and MTX-V regimens are very effective in IMT, with a similar ORR in both groups. MTX-V achieved a prolonged disease control. Responses were also seen with oral cyclophosphamide and docetaxel/gemcitabine, but few patients were treated with these schedules. IMPLICATIONS FOR PRACTICE: Inflammatory myofibroblastic tumor (IMT) is an ultrarare sarcoma with known sensitivity to anaplastic lymphoma kinase (ALK) inhibitors in ALK-fused cases, although ALK inhibitors are not licensed in the disease. The current knowledge on the activity of cytotoxic chemotherapy is limited. This multi-institutional retrospective study on pediatric and adult patients with IMT shows that cytotoxic chemotherapy, and in particular anthracycline-based and methotrexate plus/minus vinorelbine/vinblastine regimens, represents a treatment option and can be considered in IMT patients irrespectively from ALK status. This study provides a benchmark for future studies on new medical therapies.

Red clover and lifestyle changes to contrast menopausal symptoms in premenopausal patients with hormone-sensitive breast cancer receiving tamoxifen.

PURPOSE: To determine whether a red clover preparation plus dietary intervention administered to premenopausal women with breast cancer (BC), improves menopausal symptoms due to anti-oestrogen treatment, and hence promotes compliance with tamoxifen, prevents weight gain and is safe. METHODS: Surgically-treated premenopausal women with oestrogen receptor (ER) positive disease taking tamoxifen were recruited to a prospective double-blind randomized trial (NCT03844685). The red clover group (N = 42) received one oral tablet/day (Promensil® Forte) containing 80 mg red clover extract for 24 months. The placebo group (N = 39) received one oral tablet/day without active ingredient. All women were encouraged to follow a Mediterranean-type diet and keep active. Outcomes were Menopausal Rating Score (MRS), body mass index (BMI), waist and hip girth, insulin resistance, and levels of cholesterol, triglycerides, and sex hormones. As safety indicators, endometrial thickness, breast density, and effects of patient serum on ER-positive BC cell lines were investigated. RESULTS: MRS reduced significantly (p < 0.0001) with no between-group difference (p = 0.69). The red clover group had significantly greater reductions in BMI and waist circumference (p < 0.0001 both cases). HDL cholesterol increased significantly in both groups (p = 0.01). Hormone levels and insulin resistance changed little. Endometrial thickness remained constant (p = 0.93). Breast density decreased significantly in both groups (p < 0.0001). Proliferation and oestrogen-regulated gene expression didn't differ in cell lines treated with serum from each group. CONCLUSIONS: This is the first trial to assess red clover in BC patients on tamoxifen. The preparation proved safe clinically and in vitro, and was associated with reduced BMI and waist circumference, but the diet-lifestyle intervention probably improved the menopausal symptoms.