Protection of cultured malignant cells from mitoxantrone cytotoxicity by low extracellular pH: A possible mechanism for chemoresistance in vivo

In malignant tumors the distribution of pH values is shifted to lower values (range, pH 5.8–7.4) as compared to normal tissues (range, pH 6.9–7.4) or peripheral blood (pH 7.35–7.45). We have investigated whether the cytotoxic effect of the anthracenedione anti-cancer drug mitoxantrone (MX) on malignant cells in culture is dependent on changes of extracellular pH. The clonogenic fraction of M1R rat mammary carcinoma cells was measured after exposure to MX at an extracellular pH (pH_e) of 6.5–7.4. At pH_e 6.8 (approximately the average pH measured in a number of malignant tumors in vivo) the clonogenic fraction of M1R cells exposed to MX (0.1 μg/ml) only decreased to 1 × 10⁻¹ as compared to 2.5 × 10⁻⁴ at pH_e 7.4, corresponding to a 400-fold inhibition of MX cytotoxicity at reduced environmental pH. The H⁺ ion-mediated resistance of M1R cells to MX could be partially reversed by verapamil, suggesting that a reduced microenvironmental pH possibly interferes with intracellular MX accumulation. Therefore, drugs like MX may not be effective in the elimination of cells in acidic tumor areas. Moreover, investigations on anti-cancer drug activity in vitro at what is frequently referred to as ‘physiological pH’ may be irrelevant in terms of the cytotoxic effects of the respective agents at the pH values prevailing in malignant tissues in vivo.     

Lymphedema and wound healing

The lymphatic system is a widespread vascular network that plays a vital role in homeostasis of the extracellular space. The role of the lymphatics is often neglected and the aim of this article is to emphasize the important contribution the lymphatics make to maintenance of cell equilibrium and normal wound healing. The most important role of the lymphatics is the control of the interstitial microcirculation. The lymphatic vessels remove from the extravascular space macromolecules and particulate matter too large to reenter the blood capillaries. If these materials are not removed, the osmotic and hydrostatic forces within the tissues change and disease results. Failure of the lymphatics leads to pollution of the tissues because of the excesses of protein, other macromolecules, and fluid around the cells. The lymphatics are the pathway for exit of T lymphocytes and Langerhans cells. The immunologic processes that occur in the skin need the lymphatic system to function. Macrophages and Langerhans cells leaving the skin travel in the lymphatics to lymph nodes where they are recognized and induce an immunologic response. Contact dermatitis cannot develop without the lymphatics, as cellular immunity cannot develop without lymphatics directing antigen from the skin to the lymph node. Patients with lymphedema are prone to develop secondary infection as the lymphatics are the normal pathway for clearance of bacteria from the interstitium.     

Giant cell tumour of bone in the denosumab era

Giant cell tumour of bone (GCTB) is an intermediate locally aggressive primary bone tumour, occurring mostly at the meta-epiphysis of long bones. Overexpression of receptor activator of nuclear factor kappa-B ligand (RANKL) by mononuclear neoplastic stromal cells promotes recruitment of numerous reactive multinucleated osteoclast-like giant cells, causing lacunar bone resorption. Preferential treatment is curettage with local adjuvants such as phenol, alcohol or liquid nitrogen. The remaining cavity may be filled with bone graft or polymethylmethacrylate (PMMA) bone cement; benefits of the latter are a lower risk of recurrence, possibility of direct weight bearing and early radiographic detection of recurrences. Reported recurrence rates are comparable for the different local adjuvants (27–31%). Factors increasing the local recurrence risk include soft tissue extension and anatomically difficult localisations such as the sacrum. When joint salvage is impossible, en-bloc resection and endoprosthetic joint replacement may be performed. Local tumour control on the one hand and maintenance of a functional native joint and quality of life on the other hand are the main pillars of surgical treatment for this disease. Current knowledge and development in the fields of imaging, functional biology and systemic therapy are forcing us into a paradigm shift from a purely surgical approach towards a multidisciplinary approach. Systemic therapy with denosumab (RANKL inhibitor) or zoledronic acid (bisphosphonates) blocks, respectively inhibits, bone resorption by osteoclast-like giant cells. After use of zoledronic acid, stabilisation of local and metastatic disease has been reported, although the level of evidence is low. Denosumab is more extensively studied in two prospective trials, and appears effective for the optimisation of surgical treatment. Denosumab should be considered in the standard multidisciplinary treatment of advanced GCTB (e.g. cortical destruction, soft tissue extension, joint involvement or sacral localisation) to facilitate surgery at a later stage, and thereby aiming at immediate local control. Even though several questions concerning optimal treatment dose, duration and interval and drug safety remain unanswered, denosumab is among the most effective drug therapies in oncology.     

Low-Intensity Pulsed Ultrasound-Induced Spinal Fusion is Coupled with Enhanced Calcitonin Gene-Related Peptide Expression in Rat Model

Low-intensity pulsed ultrasound (LIPUS) has been found to accelerate fracture healing. In this study, we analyzed the role of calcitonin gene-related peptide (CGRP) in a rat spinal fusion model treated with LIPUS. The results revealed that LIPUS significantly increases bone formation, and the process was coupled with elevated CGRP innervation. CGRP was located in fibrous tissue, closely surrounding the allograft and newly formed cartilage. The density of CGRP peaked at week 3 after surgery in both the control (non-LIPUS-treated) and LIPUS-treated groups. These results suggest that LIPUS might accelerate spinal fusion by promoting sensory nerve fiber innervation.     

颈前路减压植骨融合器械的设计及临床应用

目的 设计颈前路减压用相应器械并临床应用。方法 设计新型环锯锯芯、双环锯定位器、后纵韧带切除钩及“U”形骨凿等器械并临床应用56例脊髓型颈椎病,其中13例伴有神经根型颈椎病,7例合并后纵韧带骨化;43例为单间隙病变,11例为双间隙病变,2例三间隙病变。均采用新型环锯锯芯定位引导,双环锯减压,以后纵韧带切除钩切除后纵韧带,并以“U”形骨凿切取髂骨骨块行前路植骨融合、钢板内固定术(AO或Orion)。结果 除1例因髂骨骨凿使用不当致髂骨骨块压缩骨折外,其余55例使用本套器械操作者均手术顺利,无神经并发症,无植骨移位及塌陷。结论 新型环锯锯芯、双环锯定位器、后纵韧带切除钩及“U”形骨凿等器械应用于颈前路减压术具有设计合理、操作简便、使用安全等优点。     

脊髓前动脉损伤后脊髓病理演变的实验研究

目的观察脊髓前动脉损伤后脊髓组织形态学演变过程,研究病理机制.方法以家犬为实验模型,损伤脊髓前动脉后进行肉眼、光镜和电镜动态观察,定量测定坏死神经元.结果脊髓前动脉损伤2h运动神经元变性,轴索病变,6h神经元坏死,24h脊髓水肿达到高峰,7d髓内出血最明显.在脊髓前动脉损伤节段,24h 30%～40%的运动神经元坏死,3d达80%,7d以后95%以上.病变均位于脊髓2/3.脊髓前动脉损伤节段变性坏死最严重,相邻节段其次,尾侧脊髓坏死量逐渐减少.结论脊髓前动脉损伤后脊髓缺血性病变是渐进和不可逆的,可引起广泛节段脊髓病变.     

Combined multi-lobed flaps: A series of 39 extensive hand and multi-digit injuries one-staged reconstructions using modified designs of ALT,DPA and chimeric linking flaps

IntroductionThe use of multiple small flaps linked in a “chain-linked” flap microanastomosed chimeric system is recommended in distal hand and digital defects reconstruction. The aim of this study is to demonstrates our experience utilizing microsurgical fabrication, multi-lobed and linking combined flaps for the reconstruction of hand degloving injuries with complex multidigit soft tissue defects.MethodsMicroanastomosed chimeric flap systems using ALT and DPA modified designed flaps were combined in five selections to cover extensive soft tissue defects involving the hands and multiple digits of 39 patients (M:F − 36:3) from October 2009 to February 2013. Five different microsurgical combined chimeric flap systems utilised in extensive hand and multidigit injuries; innervated ALT flaps, multilobed DPA flaps, innervated ALT flap with multilobed DPA flap, innervated ALT flap with sensate ALT flap and bilobed ALT flap with multilobed DPA flap. All DPA donor sites were reconstructed using free ALT flap and anterior tibial artery propeller flap.ResultsThirty-nine combined free flap extremities reconstructions on 39 patients (M:F − 36:3) with average age 28.5 (18–45) years sustained traumatic degloving injuries, 24 from road traffic accidents and 15 from industrial devices. Five different designs of combined multi-lobed flaps have be successfully used without any peri-operative complications. Average follow-up of 12 months, all flaps survived without complications. Operated extremities showed favorable functional recovery with restoration of the diminished protective sensation on the flap through reinnervation. All flaps survived uneventfully with coverage matching the texture and color of the recipients. Donor sites healed without complication.ConclusionThe microsurgical fabrication of chimeric ALT flaps and multilobed DPA flaps is a valuable alternative for the reconstruction of hand degloving injury with complex multidigit soft tissue defects.Level of evidence: Level IV, therapeutic study.     

Laminoplasty—an underutilized procedure for cervical spondylotic myelopathy

BACKGROUND CONTENTCervical laminoplasty (LP) and laminectomy and fusion (LF) are commonly used surgical techniques for cervical spondylotic myelopathy (CSM). Several recent studies have demonstrated superior perioperative metrics and decreased overall costs with LP, yet LF is performed far more often in the United States.PURPOSETo determine the percentage of patients with CSM who are radiographically candidates for LP.STUDY DESIGNRetrospective comparative cohort study.PATIENT SAMPLEPatients >18 years old who underwent LF or LP for CSM at 2 large academic institutions from 2017 to 2019.OUTCOME MEASURESCandidacy for LP based on radiographic criteria.METHODSRadiographs were assessed by 2 spine surgeons not involved in the care of the patients to determine the C2–C7 Cobb angle and the presence and extent of cervical instability. Patients with kyphosis >13°, > 3.5 mm of listhesis on static imaging, or > 2.5 mm of motion on flexion-extension or standing-supine films were not considered candidates for LP. Intraclass coefficient (ICC) was calculated to assess the interobserver reliability of angular measurements and the presence of instability. The percentage of patients for whom LP was contraindicated was calculated.RESULTSOne hundred eight patients underwent LF while 142 underwent LP. Of the 108 patients who underwent LF, 79.6% were radiographically deemed candidates for LP, as were all 142 patients who underwent LP. The ICC for C2–C7 alignment was 0.90; there was 97% agreement with respect to the presence of instability.CONCLUSIONSIn 250 patients with CSM, 228 (91.2%) were radiographically candidates for LP. These data suggest that LP may be an underutilized procedure for the treatment for CSM.     

Anatomical feasibility of transferring the obturator and genitofemoral nerves to repair lumbosacral plexus nerve root avulsion injuries

Nerve transfer is a valid surgical procedure for restoring lower‐extremity function after lumbosacral plexus nerve root avulsion. We determined the anatomical feasibility of transferring the obturator and genitofemoral nerves for this purpose. The obturator, genitofemoral and femoral nerves, and the S1 and S2 nerve roots on both sides were exposed in 10 cadaver specimens. We traced all nerves to their origins. The lengths of the obturator and genitofemoral nerves were measured from their origins to their exits from the abdominal cavity. The transverse and longitudinal diameters of all nerves were measured. Specimens were obtained to determine the total number of myelinated fibers in each nerve. The proximal part of the left obturator nerve was anastomosed with the distal part of the right femoral nerve, between the vertebrae and the peritoneum, with an overlap of 2–3 cm. Similarly, the proximal parts of the right obturator and genitofemoral nerves were anastomosed with the ipsilateral S1 and S2 nerve roots, respectively, with an overlap of 2–4 cm. The obturator nerve contained approximately one‐third of the number of fibers (4,300–7,800) presenting in the femoral nerve (13,500–21,000). Similarly, the number of fibers found in the S1 nerve root was in the range 5,200–8,900. The genitofemoral nerve contained approximately half the number of fibers (3,000–4,500) presenting in the S2 nerve root (4,600–8,400). The obturator and genitofemoral nerves could be suitable donor nerves for repairing lumbosacral plexus nerve root avulsion. Clin. Anat. 27:783–788, 2014. © 2013 Wiley Periodicals, Inc.