Neoadjuvant targeted molecular therapies in patients undergoing nephrectomy and inferior vena cava thrombectomy: is it useful?

Objective

To assess the effect of neoadjuvant targeted molecular therapies (TMTs) on size and level of inferior vena cava tumor thrombi and to evaluate their impact on surgical management.

Methods

We retrospectively analyzed the data of 14 patients treated for a clear cell renal cell carcinoma with inferior vena cava thrombi by neoadjuvant TMT before nephrectomy. Clinical, pathological and perioperative data were gathered retrospectively at each institution. The primitive tumor size and the thrombus size were defined by computed tomography before TMT. The tumor thrombus level was defined according to the Novick’s classification.

Results

Before TMT, thrombus level was staged I for 1 (7 %), II for 10 (72 %) and III (21 %) for 3 patients. First-line therapy was sunitinib in 11 cases and sorafenib in 3 cases. Median therapy duration was two cycles (1–5). Three patients experienced major adverse effects (grade III) during TMT. Following TMT, 6 (43 %) patients had a measurable decrease, 6 (43 %) had no change, and 2 (14 %) had an increase in the thrombus. One patient (7 %) had a downstage of thrombus level, 12 (85 %) had stable thrombi, and 1 (7 %) had an upstage. Regarding primary tumor, 7 (50 %), 5 (36 %) and 2 (14 %) patients had a decrease, stabilization and an increase in tumor size, respectively.

Conclusion

Neoadjuvant TMT appears to have limited effects on renal tumor thrombi. This retrospective study failed to demonstrate a significant impact of neoadjuvant TMT on surgical management of clear cell renal cell carcinoma with inferior vena cava tumor thrombi.     

Extracorporeal lithotripsy endoscopically controlled by ureterorenoscopy (LECURS): a new concept for the treatment of kidney stones—first clinical experience using digital ureterorenoscopes

Purpose

To evaluate the feasibility and usefulness of extracorporeal lithotripsy endoscopically controlled by simultaneous flexible ureterorenoscopy (LECURS) and combined with Holmium laser lithotripsy for kidney stones surgery.

Methods

Retrograde flexible ureteroscopy allowed stone visualization and intrarenal relocation when possible. Extracorporeal schock wave lithotripsy (ESWL) was performed under direct vision allowing constant focal zone adjustment for optimal stone fragmentation. Holmium laser lithotripsy was used simultaneously when necessary. Post-operative assessment included ultrasound at day one and abdominal CT scan 3 weeks later to evaluate for residual fragments.

Results

Six patients with kidney stones were recruited including 3 with relative contraindication to ESWL. One patient had a stone beyond an infundibular stenosis and 2 had multiple stones in a horseshoe kidney with an uretero-pelvic junction (UPJ) stricture. A 100 % stone fragmentation rate was obtained. Post-operative ultrasound was normal in 5 patients and showed slight peri-renal infiltration in the other. One patient developed an obstructive pyelonephritis requiring antibiotics and changing a double J to a ureteral catheter. No other complications were noted. Three patients (50 %) were stone free after LECURS. Three patients underwent a second-look procedure for small (<3 mm) retained residual fragments. No damage was seen with the digital ureteroscopes, laser fibers or stone baskets.

Conclusions

This initial experience with LECURS has shown to be feasible and safe. This opens the opportunity for further evaluation of this approach in order to improve outcomes of both approaches.     

Delayed presentation of deep penetrating trauma to the subaxial cervical spine

Purpose

To present a rare case of deep penetrating neck trauma in which a retained foreign body in the cervical spine (a broken knife blade) resulted in delayed radicular injury. We describe the surgical management using a retrojugular approach.

Case report

Our patient sustained a stab wound to the supraclavicular triangle from a small pocketknife. He was initially managed in a local hospital by simple primary wound closure without any radiological examinations, and was discharged home. The patient re-consulted in a delayed fashion with mild local persistent neck pain. Subsequent radiological investigations revealed a foreign body (the broken blade of a pocket knife) embedded in the left neural foramen between the C6 and C7 vertebrae penetrating the disc space. The blade was lying between the left C7 nerve root and the ipsilateral vertebral artery (VA) at the transition of V1 and V2 segments. Initial neurological evaluation was normal. Some days later, the patient developed a delayed left C7 radicular deficit. We undertook urgent exploration along the wound corridor through a retrojugular, transforaminal approach with successful removal of the blade.

Discussion

To our knowledge, this is a unique case where a retained foreign body penetrated the soft tissues of the neck, embedding deep in the vertebral column without vascular, aerodigestive or significant primary neurological injury, while causing delayed neck pain and delayed onset radicular injury. We describe our surgical management for removal of the retained blade. The retrojugular approach gives excellent access to all of the important anatomical structures of the neck from an anterolateral approach.

     

The screening of Alzheimer’s patients with CSF biomarkers,modulates the distribution of APOE genotype: impact on clinical trials

Polymorphism of the apolipoprotein E gene (APOE) plays a role in the level of neuropathological lesions and in drug response in Alzheimer’s disease (AD). The aim of this study was to investigate whether the selection of AD patients based on cerebrospinal fluid (CSF) biomarkers assessment may be biased by their APOE distribution. We studied the relationships between APOE genotype and CSF biomarkers levels in a total of 432 patients (AD, n = 244; non-AD, n = 188) explored for cognitive disorders. We studied the distribution of APOE genotypes among AD patient subgroups selected by various cut-offs of CSF biomarkers. Strategies of screening based on CSF Aβ1–42 lead to overselection of ε4/ε4 patients in the AD group. Screening based on tau levels did not change Apoe4 distribution in the AD group. CSF Aβ1–42 discriminated better AD patients with at least one ε4 than AD patients with no ε4. A strong allele-effect relationship was detected between APOE genotype and CSF amyloid-β (Aβ1–42) in AD patients. Selecting AD patients on CSF amyloid levels only may create an overselection of ε4/ε4 carriers, and might potentially bias the population of patients included in clinical trial studies.     

Nephron-sparing surgery is superior to radical nephrectomy in preserving renal function benefit even when expanding indications beyond the traditional 4-cm cutoff

ObjectivesTo analyze to what extent partial nephrectomy (PN) is superior to radical nephrectomy (RN) in preserving renal function outcome in relation to tumor size indication.Methods and materialsClinical data from 973 patients operated at 9 academic institutions were retrospectively analyzed. Glomerular filtration rate (GFR) before and after surgery was calculated with the abbreviated Modification of the Diet in Renal Disease equation. For a fair comparison between the 2 techniques, all imperative indications for PN were excluded. A shift to a less favorable GFR group following surgery was considered clinically significant.ResultsMedian age at diagnosis was 60 years (19–91). Tumor size was smaller than 4 cm in 665 (68.3%) cases and larger than 4 cm in 308 (31.7%) cases. PN and RN were performed in 663 (68.1%) and 310 (31.9%) patients, respectively. In univariate analysis, patients undergoing PN had a smaller risk for developing significant GFR change following surgery than those undergoing RN did. This was true for tumors≤4 cm (P = 0.0001) and for tumors>4 cm (P = 0.0001). In multivariate analysis, the following criteria were independent predictive factors for developing significant postoperative GFR loss: the use of RN (P = 0.0001), preoperative GFR<60 ml/min (P = 0.0001), tumor size≥4 cm (P = 0.0001), and older age at diagnosis (P = 0.0001).ConclusionsThe renal function benefit carried out by elective PN over RN persists even when expanding nephron-sparing surgery indications beyond the traditional 4-cm cutoff.     

Profiling of drugs and environmental chemicals for functional impairment of neural crest migration in a novel stem cell-based test battery

Developmental toxicity in vitro assays have hitherto been established as stand-alone systems, based on a limited number of toxicants. Within the embryonic stem cell-based novel alternative tests project, we developed a test battery framework that allows inclusion of any developmental toxicity assay and that explores the responses of such test systems to a wide range of drug-like compounds. We selected 28 compounds, including several biologics (e.g., erythropoietin), classical pharmaceuticals (e.g., roflumilast) and also six environmental toxicants. The chemical, toxicological and clinical data of this screen library were compiled. In order to determine a non-cytotoxic concentration range, cytotoxicity data were obtained for all compounds from HEK293 cells and from murine embryonic stem cells. Moreover, an estimate of relevant exposures was provided by literature data mining. To evaluate feasibility of the suggested test framework, we selected a well-characterized assay that evaluates ‘migration inhibition of neural crest cells.’ Screening at the highest non-cytotoxic concentration resulted in 11 hits (e.g., geldanamycin, abiraterone, gefitinib, chlorpromazine, cyproconazole, arsenite). These were confirmed in concentration–response studies. Subsequent pharmacokinetic modeling indicated that triadimefon exerted its effects at concentrations relevant to the in vivo situation, and also interferon-β and polybrominated diphenyl ether showed effects within the same order of magnitude of concentrations that may be reached in humans. In conclusion, the test battery framework can identify compounds that disturb processes relevant for human development and therefore may represent developmental toxicants. The open structure of the strategy allows rich information to be generated on both the underlying library, and on any contributing assay.