Hybrid Therapy (Surgery and Radiosurgery) for the Treatment of Renal Cell Carcinoma Spinal Metastases.

BACKGROUND: The management of spinal metastatic renal cell carcinoma (mRCC) is controversial regarding extent of resection and radiation dosing. OBJECTIVE: To determine outcomes in patients treated with hybrid therapy (separation surgery plus adjuvant stereotactic body radiation therapy [SBRT]) for mRCC. METHODS: A retrospective study of a prospectively collected cohort of patients undergoing hybrid therapy for mRCC between 2003 and 2017 was performed. SBRT was delivered as high-dose single-fraction, high-dose hypofractionated, or low-dose hypofractionated. Extent of disease, clinical and operative outcomes, and complications data were collected, and associations with overall survival (OS) and progression-free survival were determined. RESULTS: Ninety patients with mRCC with high-grade epidural spinal cord compression (ESCC grades 2 and 3) were treated. Metastases were widespread, oligometastatic, and solitary in 56%, 33%, and 11% of patients, respectively. SBRT delivered was high-dose single-fraction, high-dose hypofractionated, and low-dose hypofractionated in 24%, 56%, and 20% of patients, respectively. The 1-yr cumulative incidence of major complications was 3.4% (95% confidence interval [CI]: 0.0%-7.2%). The median follow-up was 14.2 mo for the entire cohort and 38.3 mo for survivors. The 1-yr cumulative incidence of progression was 4.6% (95% CI: 0.2%-9.0%), which translates to a local control rate of 95.4% (95% CI: 91.0%-99.8%) 1 yr after surgery. The median OS for the cohort was 14.8 mo. CONCLUSION: These data support the use of hybrid therapy as a safe and effective strategy for the treatment of renal cell spine metastases.

Identification and surgical ligation of spinal CSF-venous fistula.

BACKGROUND: CSF-venous fistulas (CVF) may cause incapacitating positional headaches resulting from spontaneous intracranial hypotension/hypovolemia (SIH). Their etiology remains unknown, although unrecognized local trauma may precipitate SIH. In addition, they are diagnostically challenging despite various imaging tools available. Here, we present CVF identification using magnetic resonance myelography (MRM) and elaborate on their surgical management techniques. METHODS: Retrospective charts of confirmed and treated CVF patients with attention to their diagnostic imaging modalities and management techniques were further reviewed. RESULTS: Six cases were identified of which three are presented here. There were two females and one male patient. All had fistulas on the left side. Two were at T7-T8 while the third was at T9-T10 level. Two underwent hemilaminotomies at the T7-T8 while the third underwent a foraminotomy at T9 level to access the fistula site. All CVF were closed with a combination of an aneurysm clip and a silk tie. On follow-up, all had complete resolution of symptoms with no evidence of recurrence. CONCLUSION: Of the various imaging modalities available, MRM is particularly sensitive in localizing CVF spinal nerve level and their laterality. In addition, the technique of aneurysm clip ligation and placement of a silk tie is curative for these lesions.

Endonasal Endoscopic Fenestration of Rathke's Cleft Cysts: Whether to Leave the Fenestration Open or Closed?

Introduction Rathke's cleft cysts (RCC) are generally treated with transsphenoidal fenestration and cyst drainage. If no cerebrospinal fluid (CSF) leak is created, the fenestration can be left open. If CSF is encountered, a watertight closure must be created to prevent postoperative CSF leak, though sellar closure has theoretically been linked with higher recurrence rate. In this study, we investigate the relationship between sellar closure, rate of postoperative CSF leak, and RCC recurrence. Methods Retrospective review of a prospective database of all endoscopic endonasal RCC fenestrations and cases were divided based on closure. The "open" group included patients who underwent fenestration of the RCC, whereas the "closed" group included patients whose RCC was treated with fat and a rigid buttress ± a nasoseptal flap. The rate of intra- and postoperative CSF leak and radiographic recurrence was determined. Results The closed group had a higher rate of suprasellar extension (odds ratio [OR]: 8.0, p = 0.032) and intraoperative CSF leak ( p ≤ 0.001). There were 54.8% intraoperative CSF leaks and no postoperative CSF leaks. Radiologic recurrence rate for the closed group (35.0%) was three times higher than the open group (9.1%; risk ratio [RR] = 3.85, p = 0.203), but not powered to show significance. None of the radiologic recurrences required reoperation. Conclusion Maintaining a patent fenestration between an RCC and the sphenoid sinus is important in reducing the rate of radiographic recurrence. Closure of the fenestration may be required to prevent CSF leak. While closure increases the rate of radiographic recurrence, reoperation for recurrent RCC is still an uncommon event.

Prevalence and Outcome of Anterior and Middle Cranial Fossae Encephaloceles without Cerebrospinal Fluid Leak or Meningitis.

BACKGROUND: With advances in imaging techniques, encephaloceles, meningoceles, and meningoencephaloceles are occasionally discovered incidentally. These can be located in anterior cranial fossa (ACF), mostly protruding into sphenoid and ethmoid sinuses, or middle cranial fossa (MCF), protruding into the temporal bone. We reviewed a large series of cranial computed tomography and magnetic resonance imaging scans to identify the prevalence of asymptomatic encephaloceles, meningoceles, and meningoencephaloceles and describe their outcome. METHODS: We retrospectively reviewed a database of all magnetic resonance imaging and computed tomography scans done at Weill Cornell Medicine for any reason between 2003 and 2018. Encephaloceles, meningoceles, or meningoencephaloceles were confirmed on 72 scans. Of these, chart reviews were performed to identify incidentally discovered cases with symptoms other than cerebrospinal fluid leak, and chart reviews and phone calls were conducted to determine patient demographics, treatment, and outcome. RESULTS: There were 18 incidental cases for a prevalence of 0.0074%, of which 6 were located in ACF, and 12 were located in MCF. The mean age for ACF cases was 39 ± 15.9 years and for MCF cases was 49.5 ± 19.8 years. There were no leaks in any cases after the encephaloceles were discovered. Eleven of 12 (91.6%) MCF cases were treated conservatively, while 3 of 6 (50%; P = 0.083) ACF cases were treated surgically. CONCLUSIONS: This study showed that encephaloceles, meningoceles, and meningoencephaloceles without cerebrospinal fluid leak or meningitis in MCF were more often conservatively managed with observation only, whereas these entities in ACF were often repaired prophylactically. Incidentally discovered encephaloceles have a relatively benign natural history and do not precipitously leak.

Clinical trials using molecular stratification of pediatric brain tumors.

Brain cancer is now the leading cause of cancer death in children and adolescents, surpassing leukemia. The heterogeneity and invasiveness of pediatric brain tumors have historically made them difficult to treat. Although surgical intervention and standard of care therapies such as radiation and chemotherapy have improved the outlook for those affected, results are often transient and lend themselves to tumor recurrence or resistance. There also still exists a subset of brain tumors which remain unresponsive to treatment altogether. Therefore, there is great need for new therapeutic approaches. With the recent advent of molecularly-driven technologies, many of these complex tumors can now be classified by integrating molecular profiling data with clinical information such as demographics and outcomes. This new knowledge has allowed for the molecular stratification of pediatric brain tumors into distinct subgroups and the identification of molecular targets, which is changing how these children are treated, namely in the setting of clinical trials. Notable examples include reduced doses of radiation and chemotherapy in the wingless-activated subgroup of medulloblastoma, which has a favorable prognosis, and novel experimental drugs targeting BRAF alterations in low-grade gliomas and dopamine receptors in high-grade gliomas. In this review, we highlight several key previous and ongoing clinical trials that utilize molecular stratifications and targets for the treatment of pediatric brain tumors.

Low incidence of true Sternberg's canal defects among lateral sphenoid sinus encephaloceles.

BACKGROUND: Spontaneous sphenoid sinus cerebrospinal fluid (CSF) encephaloceles have been postulated to arise from a persistent Sternberg's canal. However, recent evidence has questioned this embryological etiology. We examined the anatomic location of a series of lateral sphenoid sinus encephaloceles to determine if they corresponded with the location of Sternberg's canal. METHODS: We queried a prospectively acquired database of surgically treated spontaneous CSF leaks and identified those arising from the sphenoidal sinus. Images were reviewed to characterize the leaks with respect to the foramen rotundum (FR) and the vidian canal (VC). Four leak types were classified of which Type I (medial to FR and VC entering nasopharynx) was theoretically located in the precise location of Sternberg's canal. Type II was medial to FR; Type III was lateral to FR; Type IV passed through an enlarged FR into sphenoid sinus. Demographic data were analyzed. RESULTS: Of 103 repaired CSF leaks, 17 arose from the lateral sphenoid sinus. There were no true Type I leaks, 3 Type II leaks, 12 Type III leaks, and 2 Type IV leaks. No differences were found with respect to sphenoid pneumatization, BMI, age, sex, arachnoid pits, or postoperative leak between different types. CONCLUSIONS: No evidence was found to support the existence of a classic Sternberg canal CSF leak, supporting the hypothesis that most sphenoid spontaneous leaks likely occur secondary to chronically elevated ICP. Rare cases may be related to a weakness in the sphenoid wall in the region of Sternberg's canal.

pH-dependent thermodynamic intermediates of pHLIP membrane insertion determined by solid-state NMR spectroscopy.

The applications of the pH low insertion peptide (pHLIP) in cancer diagnosis and cross-membrane cargo delivery have drawn increasing attention in the past decade. With its origin as the transmembrane (TM) helix C of bacteriorhodopsin, pHLIP is also an important model for understanding how pH can affect the folding and topogenesis of a TM α-helix. Protonations of multiple D/E residues transform pHLIP from an unstructured coil at membrane surface (known as state II, at pH ≥ 7) to a TM α-helix (state III, pH ≤ 5.3). While these initial and end states of pHLIP insertion have been firmly established, what happens at the intervening pH values is less clear. However, the intervening pH range is most relevant to pHLIP-cell interactions in the acidic extracellular tumor environment (and in the endosomes within cells). Here, using advanced solid-state NMR spectroscopy with palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine unilamellar vesicles as the model membrane, we systematically examined the state of pHLIP-membrane interactions (in terms of the membrane locations of D/E residues, as well as lipid dynamics) at the intervening pH values of 6.4, 6.1, and 5.8, along with the known states at pH 7.4 and 5.3. Thermodynamic intermediate states distinct from the initial and end states were discovered to exist at each of the intervening pH examined. They support a multistage model of pHLIP insertion in which the D/E titrations occur in a defined sequence at distinct intermediate pH values. This multistage model has important ramifications in pHLIP applications.

Protonation-Driven Membrane Insertion of a pH-Low Insertion Peptide.

The pH-low insertion peptide (pHLIP) inserts into membranes and forms a transmembrane (TM) α-helix in response to slight acidity, and has shown great potential for cancer diagnosis and treatment. As a lead, pHLIP is challenging to optimize because the mechanism of its pH-dependent membrane interactions is not completely understood. Within pHLIP there are multiple D/E residues which could sense the pH change, the particular role played by each of them in the protonation-driven insertion process is not clear. The precise location of the TM helix within the pHLIP sequence is also unknown. In this work, solid-state NMR spectroscopy is used to address these central questions. Tracing backbone conformations revealed that the TM helix spans from A10 to D33 with a break at T19 to P20. Residue-specific pKa values of D31, D33, D25, and D14 were determined to be 6.5, 6.3, 6.1, and 5.8, respectively, and define the sequence of protonations which lead to insertion. Furthermore, possible intermediate states which disrupt membranes at pH 6.4 were proposed based on tryptophan fluorescence quenching and NMR data.