Management of external ventricular drain: to wean or not to wean?

PURPOSE: External ventricular drain (EVD) is one of the most frequent procedures in neurosurgery and around 15 to 30% of these patients require a permanent cerebrospinal fluid (CSF) diversion. The optimal EVD weaning strategy is still unclear. Whether gradual weaning compared to rapid closure, reduces the rate of permanent CSF diversion remains controversial. The aim of this trial is to compare the rates of permanent CSF diversion between gradual weaning and rapid closure of an EVD. METHODS: This was a single-center, retrospective cohort study including patients between 2010 to 2020. Patients were divided into a weaning (WG) and non-weaning (NWG) group. The primary outcome was permanent CSF diversion rates, secondary outcomes included hospitalization time, EVD-related morbidity, and clinical outcome. RESULTS: Out of 412 patients, 123 (29.9%) patients were excluded due to early death or palliative treatment. We registered 178 (61.6%) patients in the WG and 111 (38.4%) in the NWG. Baseline characteristics were comparable between groups. The VPS rate was comparable in both groups (NWG 37.8%; WG 39.9%, p = 0.728). EVD related infection (13.5% vs 1.8%, p < 0.001), as well as non-EVD related infection rates (2.8% vs 0%, p < 0.001), were significantly higher in the WG. Hospitalization time was significantly shorter in the NWG (WG 24.93 ± 9.50 days; NWG 23.66 ± 14.51 days, p = 0.039). CONCLUSION: Gradual EVD weaning does not seem to reduce the need for permanent CSF diversion, while infection rates and hospitalization time were significantly higher/longer. Therefore, direct closure should be considered in the clinical setting.

Characteristics and outcomes of men with erectile dysfunction as the presenting symptom due to a lactotroph adenoma.

PURPOSE: Erectile dysfunction (ED) is frequently underreported in men suffering from prolactinomas and can be challenging to manage. Both dopamine agonists (DAs) and transsphenoidal surgery (TSS) correct hyperprolactinemia and restore gonadal function. However, there is scarce data regarding their effectiveness in correcting ED over the long term. METHODS: This study is a retrospective single-center comparative cohort study analyzing men diagnosed with prolactinomas, both with and without confirmed erectile dysfunction (ED) at diagnosis. Independent risk factors for persistent ED over the long term were examined using multivariate logistic regression. RESULTS: Among the 39 men with lactotroph adenomas, ED was one of the presenting symptoms in 22 (56%). The mean age at diagnosis was 45 ± 12 years. Surgery was the primary treatment in 6 (27%) ED patients and 8 (47%) non-ED patients. After a mean follow-up of 74 ± 48 months, remission from hyperprolactinemia was achieved in the majority (76%) of men: 71% in the non-ED cohort and 81% in the ED group (p = 0.70), regardless of the primary treatment strategy (surgical 84% versus medical 72%, p = 0.46). Long-term remission of ED was noted in 16 (73%) patients. Interestingly, high baseline BMI levels emerged as potential risk factors for persistent ED over the long term (OR 1.4, 95%CI 1.0-1.9; p = 0.04), while neither the initial adenoma size nor the primary treatment strategy (i.e., TSS vs. DAs) reached statistical significance. CONCLUSIONS: Correcting hyperprolactinemia and its associated hypogonadism significantly improves ED in the majority of men with prolactinomas over the long term, regardless of the primary treatment strategy employed. In addition to addressing endocrine deficiencies, the early initiation of weight control programs may be considered for men with lactotroph adenomas and ED. Although our study suggests an association between BMI and the risk of persistent ED, further research is needed to establish any causal relationships.

Fulminant hemorrhagic course of a thalamic H3 K27-altered diffuse midline glioma in an adult patient: illustrative case.

BACKGROUND: H3 K27-altered diffuse midline gliomas (DMGs) are rare tumors, which are, regardless of their histological appearance, classified as World Health Organization grade 4 tumors. They are characterized by a diffuse growth pattern, midline anatomical location, and poor prognosis. Although DMGs occur predominantly in childhood, these tumors can also be found in young adults. OBSERVATIONS: The authors present a case of a 29-year-old patient who was found unconscious with a Glasgow Coma Scale score of 4, along with abnormal extensor movements and bilateral middilated nonreactive pupils. Computed tomography revealed obstructive hydrocephalus due to an acute hemorrhage in a right thalamic lesion. To drain the hydrocephalus and relieve the ongoing central herniation, emergent placement of a right-sided, and later a left-sided, extraventricular drain was performed. Despite the postoperative resolution of hydrocephalus, the patient died shortly after because of the central brain herniation that had occurred. Brain autopsy revealed a H3 K27-altered DMG in the right thalamus. LESSONS: Although typically described in the pediatric population and located in the pons, H3 K27-altered DMG should also be considered in young adult patients with midline lesions, particularly if they are located in the thalamus or brainstem. In rare cases, H3 K27-altered DMG may present with an acute tumor-related hemorrhage, leading to a fulminant clinical course.

Management of Recurrent Cerebrospinal Fluid Rhinorrhea Caused by Sequential, Anatomically Separated Skull Base Defects-A Case-Based Systematic Review.

OBJECTIVE: Recurrent cerebrospinal fluid (CSF) rhinorrhea caused by sequential, anatomically separated skull base defects is rarely reported in the literature. Neither management nor etiology has been sufficiently investigated. We present an illustrative case and a systematic review of the literature regarding etiology, diagnostics, and management of this rare phenomenon. METHODS: A systematic literature search looking for articles reporting sequential CSF leaks with multiple skull base defects was performed. Data from included articles were descriptively reported, and the quality of the included studies was assessed with Grading of Recommendations Assessment, Development and Evaluation. RESULTS: A 71-year-old woman with posttraumatic CSF rhinorrhea and left-sided CSF otorrhea due to a left-sided horizontal fracture of the petrous bone presented at our institution. After initial surgical repair and a 10-week symptom-free interval, CSF rhinorrhea recurred. Imaging revealed a preexisting contralateral meningoencephalocele of the lateral sphenoid recess causing recurrent CSF rhinorrhea most likely after initial traumatic laceration. The defect was successfully treated. A literature search identified 366 reports, 6 of which were included in the systematic review with a total of 10 cases. Quality was deemed good in 8 of 10 cases. The most common location for primary and sequential CSF leaks was along the sphenoid bone (4/10 and 5/10 patients, respectively). All publications except one reported the presence of a meningo (encephalo)cele as cause of the sequential CSF leak. CONCLUSIONS: Occurrence of recurrent CSF rhinorrhea due to an anatomically separated sequential skull base lesion remains a rare phenomenon. Reassessment of imaging studies and a structured diagnostic workup to detect sequential CSF leaks independent of the primary lesion should is recommended.

Gender-specific prolactin thresholds to determine prolactinoma size: a novel Bayesian approach and its clinical utility.

Background: In clinical practice, the size of adenomas is crucial for guiding prolactinoma patients towards the most suitable initial treatment. Consequently, establishing guidelines for serum prolactin level thresholds to assess prolactinoma size is essential. However, the potential impact of gender differences in prolactin levels on estimating adenoma size (micro- vs. macroadenoma) is not yet fully comprehended. Objective: To introduce a novel statistical method for deriving gender-specific prolactin thresholds to discriminate between micro- and macroadenomas and to assess their clinical utility. Methods: We present a novel, multilevel Bayesian logistic regression approach to compute observationally constrained gender-specific prolactin thresholds in a large cohort of prolactinoma patients (N = 133) with respect to dichotomized adenoma size. The robustness of the approach is examined with an ensemble machine learning approach (a so-called super learner), where the observed differences in prolactin and adenoma size between female and male patients are preserved and the initial sample size is artificially increased tenfold. Results: The framework results in a global prolactin threshold of 239.4 µg/L (95% credible interval: 44.0-451.2 µg/L) to discriminate between micro- and macroadenomas. We find evidence of gender-specific prolactin thresholds of 211.6 µg/L (95% credible interval: 29.0-426.2 µg/L) for women and 1,046.1 µg/L (95% credible interval: 582.2-2,325.9 µg/L) for men. Global (that is, gender-independent) thresholds result in a high sensitivity (0.97) and low specificity (0.57) when evaluated among men as most prolactin values are above the global threshold. Applying male-specific thresholds results in a slightly different scenario, with a high specificity (0.99) and moderate sensitivity (0.74). The male-dependent prolactin threshold shows large uncertainty and features some dependency on the choice of priors, in particular for small sample sizes. The augmented datasets demonstrate that future, larger cohorts are likely able to reduce the uncertainty range of the prolactin thresholds. Conclusions: The proposed framework represents a significant advancement in patient-centered care for treating prolactinoma patients by introducing gender-specific thresholds. These thresholds enable tailored treatment strategies by distinguishing between micro- and macroadenomas based on gender. Specifically, in men, a negative diagnosis using a universal prolactin threshold can effectively rule out a macroadenoma, while a positive diagnosis using a male-specific prolactin threshold can indicate its presence. However, the clinical utility of a female-specific prolactin threshold in our cohort is limited. This framework can be easily adapted to various biomedical settings with two subgroups having imbalanced average biomarkers and outcomes of interest. Using machine learning techniques to expand the dataset while preserving significant observed imbalances presents a valuable method for assessing the reliability of gender-specific threshold estimates. However, external cohorts are necessary to thoroughly validate our thresholds.

Are biomarkers expression and clinical-pathological factors predictive markers of the efficacy of neoadjuvant chemotherapy for locally advanced cervical cancer?

INTRODUCTION: To predict the overall pathologic response to neoadjuvant chemotherapy (NACT) of patients with locally advanced cervical cancer (LACC) creating a prediction model based on clinical-pathological factors and biomarkers (p53, Bcl1 and Bcl2) and to evaluate the prognostic outcomes of NACT. MATERIALS AND METHODS: This is a retrospective study of 88 consecutive patients with LACC who underwent NACT followed by nerve sparing surgery with retroperitoneal lymphadenectomy at National Cancer Institute of Milan, between January 2000 and June 2013. Clinical pathologic data were retrieved from the institutional database. Biomarkers (p53, Bcl1 and Bcl2) were evaluated before and after NACT in the specimen. To investigate their role as predictors of response, we tried several statistical machine learning algorithms. RESULTS: Responders to NACT showed a 5-years survival between 100%(CR) and 85.7%(PR). Clinical factors were the most important predictor of response. Age, BMI and grade represented the most important predictors of response at random forest analysis. Tree-based boosting revealed that after adjusting for other prognostic factors, age, grade, BMI and tumor size were independent predictors of response to NACT, while p53 was moderately related to response to NACT. Area under the curve (crude estimate): 0.871. Whereas Bcl1 and Bcl2, were not predictors for response to NACT. The final logistic regression reported that grade was the only significant predictor of response to NACT. CONCLUSION: Combined model that included clinical pathologic variables plus p53 cannot predict response to NACT. Despite this, NACT remain a safe treatment in chemosensitive patients avoiding collateral sequelae related to chemo-radiotherapy.

NALIRIFOX, FOLFIRINOX, and Gemcitabine With Nab-Paclitaxel as First-Line Chemotherapy for Metastatic Pancreatic Cancer: A Systematic Review and Meta-Analysis.

Importance: The NAPOLI 3 trial showed the superiority of fluorouracil, leucovorin, liposomal irinotecan, and oxaliplatin (NALIRIFOX) over the combination of gemcitabine and nab-paclitaxel (GEM-NABP) as first-line treatment of metastatic pancreatic ductal adenocarcinoma (PDAC). Analyses comparing NALIRIFOX and GEM-NABP with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) have not yet been reported. Objective: To derive survival, response, and toxic effects data from phase 3 clinical trials and compare NALIRIFOX, FOLFIRINOX, and GEM-NABP. Data Sources: After a systematic search of PubMed, Scopus, Embase, and American Society of Clinical Oncology and European Society for Medical Oncology meetings' libraries, Kaplan-Meier curves were extracted from phase 3 clinical trials conducted from January 1, 2011, until September 12, 2023. Study Selection: Phase 3 clinical trials that tested NALIRIFOX, FOLFIRINOX, or GEM-NABP as first-line treatment of metastatic PDAC and reported overall survival (OS) and progression-free survival (PFS) curves were selected. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses of Individual Participant Data reporting guidelines. Data Extraction And Synthesis: Individual patient OS and PFS data were extracted from Kaplan-Meier plots of original trials via a graphic reconstructive algorithm. Overall response rates (ORRs) and grade 3 or higher toxic effects rates were also collected. A pooled analysis was conducted, and results were validated via a network meta-analysis. Main Outcomes and Measures: The primary end point was OS. Secondary outcomes included PFS, ORR, and toxic effects rates. Results: A total of 7 trials with data on 2581 patients were analyzed, including 383 patients treated with NALIRIFOX, 433 patients treated with FOLFIRINOX, and 1756 patients treated with GEM-NABP. Median PFS was longer in patients treated with NALIRIFOX (7.4 [95% CI, 6.1-7.7] months) or FOLFIRINOX (7.3 [95% CI, 6.5-7.9] months; [HR], 1.21 [95% CI, 0.86-1.70]; P = .28) compared with patients treated with GEM-NABP (5.7 [95% CI, 5.6-6.1] months; HR vs NALIRIFOX, 1.45 [95% CI, 1.22-1.73]; P < .001). Similarly, GEM-NABP was associated with poorer OS (10.4 [95% CI, 9.8-10.8]; months) compared with NALIRIFOX (HR, 1.18 [95% CI, 1.00-1.39]; P = .05], while no difference was observed between FOLFIRINOX (11.7 [95% CI, 10.4-13.0] months) and NALIRIFOX (11.1 [95% CI, 10.1-12.3] months; HR, 1.06 [95% CI, 0.81-1.39]; P = .65). There were no statistically significant differences in ORR among NALIRIFOX (41.8%), FOLFIRINOX (31.6%), and GEM-NABP (35.0%). NALIRIFOX was associated with lower incidence of grade 3 or higher hematological toxic effects (eg, platelet count decreased 1.6% vs 11.8% with FOLFIRINOX and 10.8% with GEM-NABP), but higher rates of severe diarrhea compared with GEM-NABP (20.3% vs 15.7%). Conclusions and Relevance: In this systematic review and meta-analysis, NALIRIFOX and FOLFIRINOX were associated with similar PFS and OS as first-line treatment of advanced PDAC, although NALIRIFOX was associated with a different toxicity profile. Careful patient selection, financial toxic effects consideration, and direct comparison between FOLFIRINOX and NALIRIFOX are warranted.

EpiDiP/NanoDiP: a versatile unsupervised machine learning edge computing platform for epigenomic tumour diagnostics.

DNA methylation analysis based on supervised machine learning algorithms with static reference data, allowing diagnostic tumour typing with unprecedented precision, has quickly become a new standard of care. Whereas genome-wide diagnostic methylation profiling is mostly performed on microarrays, an increasing number of institutions additionally employ nanopore sequencing as a faster alternative. In addition, methylation-specific parallel sequencing can generate methylation and genomic copy number data. Given these diverse approaches to methylation profiling, to date, there is no single tool that allows (1) classification and interpretation of microarray, nanopore and parallel sequencing data, (2) direct control of nanopore sequencers, and (3) the integration of microarray-based methylation reference data. Furthermore, no software capable of entirely running in routine diagnostic laboratory environments lacking high-performance computing and network infrastructure exists. To overcome these shortcomings, we present EpiDiP/NanoDiP as an open-source DNA methylation and copy number profiling suite, which has been benchmarked against an established supervised machine learning approach using in-house routine diagnostics data obtained between 2019 and 2021. Running locally on portable, cost- and energy-saving system-on-chip as well as gpGPU-augmented edge computing devices, NanoDiP works in offline mode, ensuring data privacy. It does not require the rigid training data annotation of supervised approaches. Furthermore, NanoDiP is the core of our public, free-of-charge EpiDiP web service which enables comparative methylation data analysis against an extensive reference data collection. We envision this versatile platform as a useful resource not only for neuropathologists and surgical pathologists but also for the tumour epigenetics research community. In daily diagnostic routine, analysis of native, unfixed biopsies by NanoDiP delivers molecular tumour classification in an intraoperative time frame.

Dietary intervention for tertiary prevention in head and neck squamous cell carcinoma survivors: clinical and translational results of a randomized phase II trial.

Background: There is a strong need for preventive approaches to reduce the incidence of recurrence, second cancers, and late toxicities in head and neck squamous cell carcinoma (HNSCC) survivors. We conducted a randomized controlled trial (RCT) to assess a dietary intervention as a non-expensive and non-toxic method of tertiary prevention in HNSCC survivors. Methods: Eligible participants were disease-free patients with HNSCC in follow-up after curative treatments. Subjects were randomized 1:1 to receive a highly monitored dietary intervention plus the Word Cancer Research Fund/American Institute for Cancer Research recommendations for cancer prevention (intervention arm) or standard-of-care recommendations (control arm). The planned sample size for the event-free survival evaluation (primary endpoint) was not reached, and the protocol was amended in order to investigate the clinical (nutritional and quality-of-life questionnaires) and translational study [plasma-circulating food-related microRNAs (miRNAs)] as main endpoints, the results of which are reported herein. Results: One hundred patients were screened, 94 were randomized, and 89 were eligible for intention-to-treat analysis. Median event-free survival was not reached in both arms. After 18 months, nutritional questionnaires showed a significant increase in Recommended Food Score (p = 0.04) in the intervention arm vs. control arm. The frequency of patients with and without a clinically meaningful deterioration or improvement of the C30 global health status in the two study arms was similar. Food-derived circulating miRNAs were identified in plasma samples at baseline, with a significant difference among countries. Conclusion: This RCT represented the first proof-of-principle study, indicating the feasibility of a clinical study based on nutritional and lifestyle interventions in HNSCC survivors. Subjects receiving specific counseling increased the consumption of the recommended foods, but no relevant changes in quality of life were recorded between the two study arms. Food-derived plasma miRNA might be considered promising circulating dietary biomarkers.

Safety and antitumor activity of metformin plus lanreotide in patients with advanced gastro-intestinal or lung neuroendocrine tumors: the phase Ib trial MetNET2.

In retrospective studies, metformin use has been associated with better clinical outcomes in diabetic patients with advanced, well-differentiated neuroendocrine tumors (WDNETs). However, prospective evidence of metformin safety and activity is lacking. Here, we conducted the first-in-human phase Ib MetNET2 trial to investigate the safety and antitumor activity of metformin in combination with the somatostatin analog lanreotide autogel (ATG) in both diabetic and non-diabetic patients with advanced WDNETs of the gastrointestinal (GI) or thoracic tract. Enrolled patients received lanreotide ATG 120 mg plus oral metformin, up to a maximum dosage of 2550 mg/day. We enrolled 20 patients, of whom 18 (90%) and 2 (10%) had WDNETs of the GI and thoracic tract, respectively. Fourteen patients (70%) were non-diabetic. With a 5% incidence of SAEs, the study met its primary objective of demonstrating treatment safety. With a median follow-up of 39 months (95% CI 28-NE), median PFS was 24 months (95% CI 16-NE), with 12-month and 24-month PFS probability of 75% (95% CI 58-97) and 49% (95% CI 31-77), respectively. We found no statistically significant PFS differences between diabetic and non-diabetic patients. Among exploratory analyses, the presence of tumor genomic alterations in DNA damage pathways was associated with trend towards worse PFS, whereas a precocious reduction of HOMA-IR index and plasma cholesterol concentration showed a trend towards an association with better PFS. In conclusion, metformin plus lanreotide ATG is a safe and well tolerated combination treatment that is associated with promising antitumor activity in both non-diabetic and diabetic patients with WDNETs, and that warrants further investigation in larger clinical trials.

Peripheral blood lymphocytes predict clinical outcomes in hormone receptor-positive HER2-negative advanced breast cancer patients treated with CDK4/6 inhibitors.

Background: Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6i) combined with Endocrine Therapy (ET) are the standard treatment for patients with Hormone Receptor-positive/HER2-negative advanced breast cancer (HR+/HER2- aBC). Objectives: While CDK4/6i are known to reduce several peripheral blood cells, such as neutrophils, lymphocytes and platelets, the impact of these modulations on clinical outcomes is unknown. Design: A multicenter, retrospective-prospective Italian study. Methods: We investigated the association between baseline peripheral blood cells, or their early modifications (i.e. 2 weeks after treatment initiation), and the progression-free survival (PFS) of HR+/HER2- aBC patients treated with ETs plus CDK4/6i. Random Forest models were used to select covariates associated with patient PFS among a large list of patient- and tumor-related variables. Results: We evaluated 638 HR+/HER2- aBC patients treated with ET plus CDK4/6i at six Italian Institutions between January 2017 and May 2021. High baseline lymphocyte counts were independently associated with longer PFS [median PFS (mPFS) 20.1 versus 13.2 months in high versus low lymphocyte patients, respectively; adjusted Hazard Ratio (aHR): 0.78; 95% confidence interval (CI): 0.66-0.92; p = 0.0144]. Moreover, patients experiencing a lower early reduction of lymphocyte counts had significantly longer PFS when compared to patients undergoing higher lymphocyte decrease (mPFS 18.1 versus 14.5 months; aHR: 0.82; 95% CI: 0.73-0.93; p = 0.0037). Patients with high baseline lymphocytes and undergoing a lower reduction, or even an increase, of lymphocyte counts during CDK4/6i therapy experienced the longest PFS, while patients with lower baseline lymphocytes and undergoing a higher decrease of lymphocytes had the lowest PFS (mPFS 21.4 versus 11 months, respectively). Conclusion: Baseline and on-treatment modifications of peripheral blood lymphocytes have independent prognostic value in HR+/HER2- aBC patients. This study supports the implementation of clinical strategies to boost antitumor immunity in patients with HR+/HER2- aBC treated with ETs plus CDK4/6i.