Future Perspective: Carbon Ion Radiotherapy for Head and Neck and Skull Base Malignancies.

Head and neck and base of skull malignancies are challenging for surgical and radiotherapy treatment due to the density of sensitive tissues. Carbon ion radiotherapy (CIRT) is a form of heavy particle therapy that uses accelerated carbon ions to treat malignancies that may be radioresistant or in challenging anatomic locations. CIRT has an increased biological effectiveness (ie, increased cell killing) at the end of the range of the carbon beam (ie, within the target tissue) but not in the entrance dose. This increased biological effectiveness can overcome the effects of radioresistant tumors, tissue hypoxia, and the need for radiotherapy fractionation.

Antibiotics Prophylaxis for Endoscopic Endonasal Approach for Skull Base Tumor Surgery: A Meta-Analysis.

BACKGROUND: The regimen of prophylactic antibiotic for endoscopic endonasal skull base surgery (EE-SBS) varies considerably depending on surgeons and their institutes. The purpose of the present meta-analysis is to assess the effect of antibiotic regimens on EE-SBS surgery for anterior skull base tumor. METHODS: The PubMed, Embase, Web of Science, and Cochrane clinical trial databases were systematically searched through October 15, 2022. RESULTS: The 20 included studies were all retrospective. The studies included a total of 10,735 patients who underwent EE-SBS for skull base tumor. The proportion of patients with postoperative intracranial infection across all 20 studies was 0.9% (95% confidence interval [CI] 0.5%-1.3%). The proportion of postoperative intracranial infection in the multiple antibiotics group did not show statistically significant difference to that of the single antibiotic agent group (proportion: 0.6%, 95% CI 0%-1.4% vs. proportion: 1%, 95% CI 0.6%-1.5%, respectively, P = 0.39). The ultra-short duration maintenance group showed lower incidence of postoperative intracranial infection, although it did not reach statistical significance (ultra-short group: 0.7%, 95% CI 0.5%-0.9%; short duration: 1.8%, 95% CI 0.5%-3%; and long duration: 1%, 95% CI 0.2%-1.9%, P = 0.22) The combination of the multiple antibiotics group did not show meaningful low incidence of postoperative intracranial infection (antibiotics combination group: 0.6%, 95% CI 0%-1.4%; cefazolin single group: 0.8%, 95% CI 0%-1.6%; and single antibiotics other than cefazolin: 1.2%, 95% CI 0.7%-1.7%, P = 0.22). CONCLUSIONS: Multiple antibiotics did not show superiority compared with single antibiotic agent. Also, long maintenance duration of antibiotics did not reduce the incidence of postoperative intracranial infection.

Proton and carbon ion beam treatment with active raster scanning method in 147 patients with skull base chordoma at the Heidelberg Ion Beam Therapy Center-a single-center experience.

BACKGROUND: This study aimed to compare the results of irradiation with protons versus irradiation with carbon ions in a raster scan technique in patients with skull base chordomas and to identify risk factors that may compromise treatment results. METHODS: A total of 147 patients (85 men, 62 women) were irradiated with carbon ions (111 patients) or protons (36 patients) with a median dose of 66 Gy (RBE (Relative biological effectiveness); carbon ions) in 4 weeks or 74 Gy (RBE; protons) in 7 weeks at the Heidelberg Ion Beam Therapy Center (HIT) in Heidelberg, Germany. The median follow-up time was 49.3 months. All patients had gross residual disease at the beginning of RT. Compression of the brainstem was present in 38%, contact without compression in 18%, and no contact but less than 3 mm distance in 16%. Local control and overall survival were evaluated using the Kaplan-Meier Method based on scheduled treatment (protons vs. carbon ions) and compared via the log rank test. Subgroup analyses were performed to identify possible prognostic factors. RESULTS: During the follow-up, 41 patients (27.9%) developed a local recurrence. The median follow-up time was 49.3 months (95% CI: 40.8-53.8; reverse Kaplan-Meier median follow-up time 56.3 months, 95% CI: 51.9-60.7). No significant differences between protons and carbon ions were observed regarding LC, OS, or overall toxicity. The 1­year, 3­year, and 5­year LC rates were 97%, 80%, and 61% (protons) and 96%, 80%, and 65% (carbon ions), respectively. The corresponding OS rates were 100%, 92%, and 92% (protons) and 99%, 91%, and 83% (carbon ions). No significant prognostic factors for LC or OS could be determined regarding the whole cohort; however, a significantly improved LC could be observed if the tumor was > 3 mm distant from the brainstem in patients presenting in a primary situation. CONCLUSION: Outcomes of proton and carbon ion treatment of skull base chordomas seem similar regarding tumor control, survival, and toxicity. Close proximity to the brainstem might be a negative prognostic factor, at least in patients presenting in a primary situation.

Unresectable Clival Giant Cell Tumor, Tumor Control With Denosumab After Relapse: A Case Report and Systematic Review of the Literature.

Giant cell tumors (GCTs) of the skull base are rare entities. Although considered histologically benign, GCTs are locally aggressive with a high rate of local recurrence. The present case describes a 14-year-old girl with a clival GCT who underwent long-term therapy with denosumab after local relapse. To our knowledge, it is the second case described with a follow-up term >2 years from the start of denosumab and who did not receive any other adjuvant treatment besides denosumab. The patient achieved a local control of the disease. According to the few available data, radical excision with adjuvant therapy helps in long-term control in uncommon sites, such as the skull. However, the definitive treatment is still controversial because of their rarity and few follow-up data. The present case highlights the benefit of denosumab and its safety as long-term therapy and contributes to the existing literature with analysis and evaluation of the management strategies and prognosis.

Higher cMET dependence of sacral compared to clival chordoma cells: contributing to a better understanding of cMET in chordoma.

Chordomas are rare slow growing, malignant bone tumors of the axial skeleton with no approved medical treatment. As the majority of chordomas express cMET and its ligand, HGF, and crosstalks between EGFR and MET-signaling exist, we aimed to explore cMET activity in chordoma cell lines and clinical samples. We investigated nine chordoma patients and four chordoma cell lines for cMET expression. Two clival and two sacral chordoma cell lines were tested for chromosomal abnormalities of the MET gene locus; we studied the influence of HGF on the autocrine secretion and migration behavior, as well as protein expression and phosphorylation. Two MET/ALK inhibitors were investigated for their effects on cell viability, cell cycle, cyclin alterations, apoptosis, and downstream signaling pathways. Moderate and strong expression of membrane and cytoplasmic cMET in chordoma patients and cell lines used, as well as concentration-dependent increase in phospho cMET expression after HGF stimulation in all four chordoma cell lines was shown. U-CH2, MUG-Chor1, and UM-Chor1 are polysomic for MET. Chordoma cell lines secreted EGF, VEGF, IL-6, and MMP9 upon HGF-stimulation. Sacral cell lines showed a distinct HGF-induced migration. Both inhibitors dose-dependently inhibited cell growth, induce apoptosis and cell-cycle arrest, and suppress downstream pathways. Heterogeneous responses obtained in our in vitro setting indicate that cMET inhibitors alone or in combination with other drugs might particularly benefit patients with sacral chordomas.

Pneumatosis intestinalis in a radioactive iodine-refractory metastasic thyroid papillary carcinoma with BRAFV600E mutation treated with dabrafenib-trametinib: a case report.

BACKGROUND: Pneumatosis intestinalis (PI) is a rare entity which refers to the presence of gas within the wall of the small bowel or colon which is a radiographic sign. The etiology and clinical presentation are variable. Patients with PI may present either with chronic mild non-specific symptoms or with acute abdominal pain with peritonitis. Some cases of intestinal pneumatosis have been reported as adverse events of new oncological treatments such as targeted therapies that are widely used in multiple tumors. CASE PRESENTATION: A 59-year-old caucasian female with radioactive iodine-refractory metastatic thyroid papillary carcinoma with BRAFV600E mutation was treated with dabrafenib and trametinib as a compassionate use. After 4 months treatment, positron emission tomography-computed tomography (PET-CT) showed PI. At the time of diagnosis, the patient was asymptomatic without signs of peritonitis. The initial treatment was conservative and no specific treatment for PI was needed. Unfortunately, after dabrafenib-trametinib withdrawal, the patient developed tumor progression with significant clinical worsening. CONCLUSIONS: This case report is, in our knowledge, the first description of PI in a patient treated with dabrafenib-trametinib. Conservative treatment is feasible if there are no abdominal symptoms.

A rare case of Meckel's cave primary lymphoma: a case report and elaboration of the diagnostic algorithm.

Management of lesions involving Meckel's cave can represent a challenge for neurosurgeons, because of the deep-seated location and the surrounding complex neurovascular structures. Very small lesions arising from MC are generally asymptomatic and radiological follow-up with head MRI and PET-CT is sufficient to control these lesions. In rare cases, the rapid increase in the size of lesions and the alteration of the neurologic status make early histological characterization mandatory in the plethora of lesions arising from Meckel's cave; a very small percentage is represented by central nervous system lymphomas. Primary diffuse large B-cell lymphoma is the most commonly found. Aggressive surgery, in case of suspicious Meckel's cave lesions, is strongly discouraged, because this procedure may increase the risk of postoperative deficit and provides no survival benefit compared with biopsy alone. The aim of the present paper is to report a very rare case of primary Meckel's cave diffuse large B-cell lymphoma (only seven cases were described in literature) and standardize an operative algorithm to avoid the risks of an incorrect surgical conduct.

Stereotactic radiosurgery as a primary treatment for metastatic skull base alveolar soft part sarcoma: a case report.

Alveolar soft part sarcoma (ASPS) is a rare malignancy that typically arises in the trunk or extremities and preferentially metastasises to the brain. Radical resection is generally recommended for cranial metastatic ASPS, but stereotactic radiosurgery (SRS) is a recognised alternative for tumours in surgically challenging locations. Here, we present the case of a 22-year-old female, who underwent SRS and systemic therapy with pazopanib for a metastatic ASPS in the left temporal bone. The tumour was successfully controlled without further intervention over 23 months following SRS, which should be considered for metastatic ASPS when surgical resection is not appropriate.

Treatment Options for Recurrent Anterior Skull Base Tumors.

Malignancies of the anterior skull base are rare and recur in 40-80% of treated cases, varying with substantial variance according to histology, stage at primary diagnosis, and other factors. Most recurrences manifest within 2-5 years after primary treatment, but some histologies can relapse even decades after the first presentation. Management of recurrent anterior skull base tumors is challenging and a wide variety of treatment options are available. Similar to the primary setting, surgery is the mainstay of treatment. However, only few patients are likely to be suitable for salvage surgery after restaging. In this scenario, non-surgical options such as re-irradiation with photon or heavy particles may play a role, although the potential toxicity and benefits of treatment needs to be considered on a case-by-case basis. Moreover, stereotactic technologies are emerging as an adjunct valuable tool to minimize side effects. Chemotherapy is acquiring a relevant role in the primary treatment of sinonasal malignant lesions involving the anterior skull base in the neoadjuvant setting or in combination with radiotherapy, but evidence of its efficacy in the treatment of the recurrent/metastatic disease is very limited. The specific drugs employed vary considerably and need to be paralleled with the biology of the different histologies.

Clinical outcomes and toxicities of pazopanib administered orally in crushed form: Case reports and review of the literature.

Cancer treatment has changed dramatically with the development of oral targeted therapies. Pazopanib, an oral VEGF tyrosine kinase inhibitor, is currently approved for advanced renal cell carcinoma, advanced soft tissue sarcoma, and is being studied for various tumor types. Due to the potential of increased exposure to pazopanib when crushed, pazopanib should be given as an intact whole tablet. Thus, in patients with difficulty swallowing medications or feeding tubes, pazopanib is usually not considered to be an option. Here, we describe two cases which show the administration of crushed pazopanib was feasible and had apparent clinical activity.

Spontaneous regression of a clival chordoma. Case report.

In this case report, we present a rare and previously unreported case of spontaneous regression of a histologically consistent clival chordoma. At the time of diagnosis, imaging demonstrated a T2 hyperintense and T1 isointense midline skull base mass, centered in the nasopharynx, with scalloping of the ventral clivus consistent with a chordoma measuring 3.1 × 1.9 × 3.0 cm (8.84 cm3). On pre-operative imaging 2 months later, with no intervening therapy, the mass had regressed by 61.7% to a size of 2.3 × 2.1 × 1.4 cm (3.38 cm3). The patient self-administered several herbal supplements and animal oils which may have contributed to tumor regression. The purpose of this report is to document this rare occurrence and provide a comprehensive description of the case details and list of the various medications, herbs, and supplements used prior to this rare event.

Macroprolactinoma clival ectópico: una forma rara de presentación de adenoma hipofisario / Ectopic clival macroprolactinoma: a rare presentation of pituitary adenoma

Los adenomas pituitarios son los tumores hipofisarios más frecuentes siendo una entidad rara cuando se trata de adenomas ectópicos, es decir, sin conexión con la glándula pituitaria. Se cree que derivan de células residuales del tracto de migración embriológico desde la bolsa de Rathke. Su presentación clínica es muy variable porque depende de la producción hormonal y del efecto masa en estructuras adyacentes. Generalmente suponen un reto diagnóstico debido a su baja frecuencia, la clínica variable de presentación y que no presentan características específicas en las pruebas de imagen. Generalmente el diagnóstico se realiza de manera retrospectiva tras la resección quirúrgica. Presentamos el caso de un varón de 56 años que se presentó con unos valores de prolactina de 6647.5 ng/ml (2.2-17.7) con clínica de hipogonadismo aislada que se resolvió con tratamiento médico sin precisar resección quirúrgica, con una disminución de la densidad radiológica y estabilización del tamaño y sin clínica compresiva ni alteración visual.

Pituitary adenomas are the most common hypophyseal tumors being a rare entity when they are ectopic, without connection to the pituitary gland. They are thought to arise from residual cells in the migration tract from Rathke´s pouch. Its clinical presentation is variable depending on the hormonal production and the pressure effect on adjacent structures. They usually are a diagnostic challenge due to their low frequency, wide range of clinical presentation and not showing specific features on imaging techniques. The diagnosis is made usually retrospectively after surgical resection. We report the case of a 56 years old male that presented with a prolactine value of 6647.5 ng/ml (2.2-17.7) and isolated hypogonadism symptoms that resolved with medical treatment without surgery, diminishing the radiological density and stabilizing the size without having compresive symptoms nor visual disturbances.

Periorbital dermatitis in patients receiving docetaxel in combination chemotherapy.

Recognition of new cutaneous side effects of combination chemotherapy can help prevent unnecessary cessation or reduction of cancer therapy. Periorbital rash has not been found with docetaxel alone, but here, we report it as a result of combination chemotherapy. A series of three patients who received docetaxel in combination with other chemotherapies developed clinically near-identical, distinctive periorbital rashes. Rashes resolved by resolving underlying docetaxel-induced epiphora in conjunction with ophthalmological consultation, topical skin-directed care, and in some cases, chemotherapy dose reduction. It is important for dermatologists and oncologists to recognise the increased severity of cutaneous reactions when docetaxel is used in combination chemotherapy.

Imatinib and everolimus in patients with progressing advanced chordoma: A phase 2 clinical study.

BACKGROUND: We present the results of an academic phase 2 study on imatinib plus everolimus in patients who have progressive advanced chordoma. METHODS: In January 2011, 43 adult chordoma patients were enrolled in the study and received imatinib 400 mg/day and everolimus 2.5 mg/day until progression or limiting toxicity. Eligible patients had progressed in the 6 months before study entry. PDGFRB, S6, and 4EBP1 expression and phosphorylation were evaluated by way of immunohistochemistry and/or western blotting. The primary endpoint was the overall response rate (ORR) according to Choi criteria. Secondary endpoints were RECIST 1.1 response, progression-free survival (PFS), overall survival (OS), correlation between S6/4EBP1 phosphorylation and response. RESULTS: Thirteen of 43 patients were pretreated with imatinib. Among 40 of the 43 patients who were evaluable by Choi criteria, the best responses were 9 with partial response (ORR, 20.9%), 24 with stable disease (SD) (ORR, 55.8%), and 7 with progressive disease (ORR, 16.3%). Forty-two patients were evaluable by RECIST criteria, with 1 partial response (ORR, 2.3%), 37 stable disease (ORR, 86%), and 4 progressive disease (ORR, 9.3%). The median PFS according to Choi criteria was 11.5 months (range, 4.6-17.6 months), and 58.8% and 48.1% of patients were progression-free at 9 and 12 months, respectively. The median PFS by RECIST criteria was 14 months; the median OS was 47.1 months. When assessable, S6/4EBP1 was phosphorylated in a high and moderate/low proportion of tumor cells in responsive and nonresponsive patients, respectively. Toxicity caused a temporary and definitive treatment discontinuation in 60.5% and 30.2% of patients, respectively. CONCLUSIONS: Imatinib plus everolimus showed a limited activity in progressing advanced chordoma. Interestingly, the amount of tumor cells activated for mammalian target of rapamycin effectors correlated with the response. Toxicity was not negligible.

Preoperative Cytoreduction of Clival Giant Cell Tumor: An Effective Replication of the Systemic Modality in the Skull Base.

BACKGROUND: Giant cell tumors (GCTs) are benign tumors with a predilection for the epimetaphyseal region of the long bones. GCTs involving the skull base are rare, and only a few available cases have been reported. Surgical gross total resection is the recommended method of treatment for GCTs. In the case of skull base tumors, it is very difficult to achieve such a result by direct surgical resection alone without any morbidities. Denosumab is a fully humanized monoclonal anti-receptor activator of nuclear factor-κB ligand antibody that has been recently approved by the Food and Drug Administration for the treatment of GCTs that are surgically unresectable, metastatic, and have a high risk of progression and recurrence. Denosumab has been used in many cases involving the long bones. However, in cases of skull base GCTs, only a limited number of cases have been reported. In addition, in such cases, it was used as postoperative chemotherapy owing to subtotal resection. CASE DESCRIPTION: For the present patient, we adopted a unique approach in which denosumab was administered as neoadjuvant chemotherapy to reduce the size of the tumor to a resectable level. Subsequently, surgical resection was performed with good functional and histopathological outcomes. CONCLUSIONS: Our findings emphasize the use of denosumab as a neoadjuvant treatment routinely for all cases of skull base GCTs to achieve safe and complete excision of the tumor.

Chordoma: a case series and review of the literature.

BACKGROUND: Chordoma is a rare malignant tumor of the skull base and axial skeleton, with an incidence of less than 0.1/100,000 per year. Patients with advanced chordoma have a poor prognosis due to locoregional recurrence with infiltration and destruction of surrounding bone and soft tissue. Cytotoxic chemotherapy or other systemic therapies have not been proven to be effective for these diseases. Therefore, several molecularly targeted therapies have been proposed as potentially beneficial, including tyrosine kinase inhibitors such as imatinib, sorafenib, lapatinib, and others. CASE PRESENTATION: We present three cases of advanced chordoma treated with molecular targeted therapies: a 52-year-old Caucasian man, a 72-year-old Caucasian woman, and a 38-year-old Caucasian woman. CONCLUSIONS: Chordoma has few systemic treatment options and they have limited benefit. Randomized trials with large patient numbers are unfeasible in this rare disease. Targeted therapy might be a reasonable alternative treatment for chordoma. Still, new treatment strategies are needed for this rare disease.

Cerebrospinal Fluid Leak Rhinorrhea after Systemic Erlotinib Chemotherapy for Metastatic Lung Cancer: A Familiar Problem from an Unfamiliar Culprit.

BACKGROUND: Cerebrospinal fluid (CSF) rhinorrhea after medical therapy for pituitary prolactinoma is a rare but well-described phenomenon. To our knowledge, no CSF leaks have been reported after targeted medical treatment of pituitary or anterior skull base metastases. We report this unusual case to raise awareness of spontaneous CSF leaks in the setting of skull base metastatic disease. CASE PRESENTATION: A 66-year-old woman presented with epidermal growth factor receptor-mutant stage IV adenocarcinoma of the lung. Headache workup revealed a large sellar and clival lesion consistent with metastatic disease. Systemic erlotinib chemotherapy was initiated with a robust positive response. Approximately 1 week after chemotherapy initiation, the patient noted clear discharge from the right nostril. Her oncologist first diagnosed her with allergic rhinitis, but she presented with meningitis 4 days after diagnosis of CSF leak and was admitted for intravenous antibiotics and definitive repair of a CSF leak via an endoscopic endonasal approach. An erosion of bone and dura was found at the dorsum sellae where tumor had regressed due to the chemotherapy. A multilayer skull base repair was made uneventfully, and she recovered fully with no leakage seen at 2-month follow-up. CONCLUSIONS: All members of the treatment team should be aware of this possibility of CSF leak after initiation of systemic chemotherapy and tumor regression and urgently refer patients for repair if a leak should develop before the development of meningitis.

Kinase Activity in Recurring Primary Skull Base Chordomas and Chondrosarcomas: Identification of Novel Pathways of Oncogenesis and Potential Drug Targets.

BACKGROUND: Chordomas and chondrosarcomas can occur in the skull base. Currently, 45% of chordomas and 56% of chondrosarcomas recur within 5 years of surgery. The role of adjuvant therapy is highly debated. No pharmacotherapies have been approved by the U.S. Food and Drug Administration for chordomas or chondrosarcomas. High propensity for recurrence and lack of definitive adjuvant therapy necessitate additional basic science research to identify molecular anomalies associated with recurrent disease. METHODS: We pooled tumor lysates from patients based on clinical criteria into 4 groups: primary chordomas, primary chordomas that recurred, primary chondrosarcomas, and primary chondrosarcomas that recurred. We used a peptide labeling method, isobaric tags for relative and absolute quantitation, to uniquely identify each tumor group. Phosphorylated peptides were identified and quantified via mass spectroscopy to determine and predict active kinases. RESULTS: Six groups of phosphorylated peptides were associated with primary tumors that later recurred. Specific kinases associated with primary chordomas that recurred were FES and FER. Specific kinases associated with primary chondrosarcomas that recurred were FES, FER, SRC family kinases, PKC, ROCK, and mitogen-activated protein kinase signaling (JNK, ERK1, p38). CONCLUSIONS: These data provide clinicians with a means to screen skull base chordomas and chondrosarcomas to help identify tumors with a propensity to recur. Many of these kinases can be efficaciously inhibited by Food and Drug Administration-approved drugs that have not yet been used in clinical trials for treatment of skull base chordomas or chondrosarcomas. Validation of kinases identified in this study may advance treatment options for patients with these tumors.

Advanced chordoma treated by first-line molecular targeted therapies: Outcomes and prognostic factors. A retrospective study of the French Sarcoma Group (GSF/GETO) and the Association des Neuro-Oncologues d'Expression Française (ANOCEF).

BACKGROUND: To assess the role of first-line Molecular Targeted Therapies (MTTs) in Advanced chordoma (AC) patients. METHODS: Retrospective study of 80 patients treated between January 2004 and December 2015 at 15 major French Sarcoma or Neurooncology Centres. RESULTS: The sex ratio M/F was 46/34. The median age was 59 (6-86) years. The primary sites were the sacrum (50, 62.5%), mobile spine (12, 15.0%), and skull base (18, 22.5%). Metastases were present in 28 patients (36.0%). The first line of MTTs consisted of imatinib (62, 77.5%), sorafenib (11, 13.7%), erlotinib (5, 6.3%), sunitinib (1, 1.2%) and temsirolimus (1, 1.2%). The reported responses were: partial response (5, 6.3%), stable disease (58, 72.5%), or progressive disease (10, 12.5%). Symptomatic improvement was seen in 28/66 assessable patients (42.4%) and was associated with an objective response occurrence (p = 0.005), imatinib (p = 0.020) or erlotinib use (p = 0.028). The median progression-free survival (PFS) was 9.4°months (95% CI, [6.8-16.1]). Two independent factors of poor prognosis for PFS were identified: a skull-based primary location (HR = 2.5, p = 0.019), and the interval between diagnosis and MTT of <52months (HR = 2.8, p < 0.001). The median overall survival (OS) was 4.4°years (95% CI, [3.8-5.6]). Four independent factors of poor prognosis for OS were identified: the presence of liver metastases (HR = 13.2, p < 0.001), pain requiring opioids (HR = 2.9, p = 0.012), skull-based primary location (HR = 19.7, p < 0.001), and prior radiotherapy (photon alone) (HR = 2.5, p = 0.024). The PFS and OS did not significantly differ between the MTT. CONCLUSIONS: The prognostic factors identified require validation in an independent database but are potently useful to guide treatment decisions and design further clinical trials.