In vivo and in vitro inhibition of osteosarcoma growth by the pan Bcl-2 inhibitor AT-101.

Osteosarcoma (OS) is the most common primary malignant bone tumor and mainly affects children and adolescents. The OS five-year survival rate remains very low. Thus, novel therapeutic protocols for the treatment of OS are needed. Several approaches targeting deregulated signaling pathways have been proposed. The antitumoral effects of polyphenols, which are naturally occurring compounds with potent antioxidant and anti-inflammatory activity, have been investigated in different tumors. Gossypol, which is a natural polyphenolic aldehyde isolated from the seeds of the cotton plant, has been shown to exert antitumoral activity in leukemia and lymphoma and in breast, head and neck, colon and prostate cancers. Therefore, in this study, we evaluated the effect of AT-101, which is the (-) enantiomer and more active form of gossypol, on the growth of human and murine OS cells in vitro and in vivo. Several clinical trials employing AT-101 have been performed, and some clinical trials are ongoing. Our results showed for the first time that AT-101 significantly inhibits OS cell growth in a dose- and time-dependent manner, inducing apoptosis and necrosis and partially activating autophagy. Our results demonstrated that AT-101 inhibits prosurvival signaling pathways depending on Akt, p38 MAPK and JNK. In addition, treatment with AT-101 increases the survival of OS-bearing mice. Overall, these results suggest that AT-101 is a candidate chemo-supportive molecule for the development of novel chemotherapeutic protocols for the treatment of OS.

Polyphenols as Immunomodulatory Compounds in the Tumor Microenvironment: Friends or Foes?

Polyphenols are natural antioxidant compounds ubiquitously found in plants and, thus, ever present in human nutrition (tea, wine, chocolate, fruits and vegetables are typical examples of polyphenol-rich foods). Widespread evidence indicate that polyphenols exert strong antioxidant, anti-inflammatory, anti-microbial and anti-cancer activities, and thus, they are generally regarded to as all-purpose beneficial nutraceuticals or supplements whose use can only have a positive influence on the body. A closer look to the large body of results of years of investigations, however, present a more complex scenario where polyphenols exert different and, sometimes, paradoxical effects depending on dose, target system and cell type and the biological status of the target cell. Particularly, the immunomodulatory potential of polyphenols presents two opposite faces to researchers trying to evaluate their usability in future cancer therapies: on one hand, these compounds could be beneficial suppressors of peri-tumoral inflammation that fuels cancer growth. On the other hand, they might suppress immunotherapeutic approaches and give rise to immunosuppressive cell clones that, in turn, would aid tumor growth and dissemination. In this review, we summarize knowledge of the immunomodulatory effects of polyphenols with a particular focus on cancer microenvironment and immunotherapy, highlighting conceptual pitfalls and delicate cell-specific effects in order to aid the design of future therapies involving polyphenols as chemoadjuvants.

Surgical treatment of primary trapezio-metacarpal osteoarthritis by trapeziectomy and ligament reconstruction without tendon interposition. Long-term results of 50 cases.

BACKGROUND: Primary trapezio-metacarpal osteoarthritis can be painful and disabling. Surgical treatment is used when conservative treatment, such as splinting or oral analgesics, fails. The purpose of this study was to report the long-term outcomes obtained in 40 patients (50 thumbs) surgically treated for thumb osteoarthritis by trapeziectomy and ligament reconstruction without tendon interposition. MATERIALS AND METHODS: Forty patients (50 thumbs), with severe trapezio-metacarpal osteoarthritis, surgically treated by trapeziectomy and ligament reconstruction without tendon interposition were reviewed after an average follow-up of 8 years. All patients were women. At follow-up, clinical results were evaluated on the basis of the DASH score, possible presence of pain and the following criteria: palmar abduction of the thumb, carpometacarpal joint opposition of the thumb (Kapandji), extension of the metacarpophalangeal joint and strength of the hand. RESULTS: The DASH score improved from 42.65 (preoperatively) to 16 (at follow-up), and most patients were asymptomatic. Palmar abduction of the thumb averaged 57 mm. Carpometacarpal joint opposition averaged 8.8. Metacarpophalangeal extension was abnormally increased in 86% of the cases. The strength of the operated hand was comparable to the contralateral side in 46 cases. Radiographic examinations showed a slight proximal migration of the first metacarpal bone (< 3 mm) in all cases but mild signs of carpometacarpal osteoarthritis in only 4 cases. CONCLUSIONS: Based on the reported experience, we believe that primary trapezio-metacarpal osteoarthritis surgically treated by trapeziectomy and ligament reconstruction without tendon interposition allows good long-term results. LEVEL OF EVIDENCE: Therapeutic IV.

Lower limb lengthening over an intramedullary nail: a long-term follow-up study of 28 cases.

BACKGROUND: Limb lengthening using an external fixator requires a long period of external fixation and may be associated with several complications such as axial deformity, fracture of the regenerated bone, and joint stiffness. With the goal of reducing the time of external fixation as well as some of these complications, we performed femoral or tibial lengthening over an intramedullary nail, according to Paley's technique, in 28 patients, followed up after a mean period of 8 years. MATERIALS AND METHODS: Twenty-eight patients treated for lower limb discrepancy by limb lengthening over an intramedullary nail were reviewed from 5 to 11 years after healing of regenerated bone. There were 20 femurs and 8 tibiae, with average age at surgery of 14.2 years and average length inequality of 6.1 cm for femurs and 5.3 cm for tibiae. RESULTS: The mean lengthening was 5.8 cm for femurs and 4.8 cm for tibiae. The mean period of radiographic consolidation of the regenerated bone was 6 months for femoral lengthening and 4.5 months for tibial lengthening. At follow-up, we observed 8 excellent results, 15 good results, 4 fair results, and 1 poor result, based on Paley's evaluation criteria. The main complications were one deep infection, one nonunion of the distracted segment, one breakage of the distal fiche of the external fixator, and one breakage of both distal locking screws of the intramedullary nail. DISCUSSION: We believe that limb lengthening over an intramedullary nail still represents a good method to treat limb length discrepancy because it reduces the time of external fixation, prevents axial deformities and fractures of regenerated bone, and allows early rehabilitation. The new intramedullary lengthening nails, which theoretically are the ideal device for treating limb length inequality, are still very expensive and need longer follow-up for definitive evaluation. LEVEL OF EVIDENCE: 4.

The role of body mass index in high- and low-velocity trauma causing knee injury associated with popliteal artery lesions.

BACKGROUND: Among arterial traumas, osteoarticular traumas are particularly dangerous, and those involving the popliteal artery are associated with a high amputation rate. Despite representing a minority of arterial traumas, with an incidence that varies considerably by population and geographic location, traumatic lesions of the popliteal artery are challenging. This study aimed to verify the impact of body mass index (BMI) on arterial trauma damage and patient outcomes. METHODS: Data were retrospectively collected from the electronic medical reports of all patients with osteoarticular and vascular associated lesions treated in the emergency operating room at our institution between 1 January 2005 and 1 May 2022. Forty-one patients presented with lower limb arterial trauma (43.2%); popliteal artery lesions occurred in 11 of these patients (26.8%), who were eligible for inclusion in the study. The lesion mechanism was dislocation by high-velocity trauma in 9 patients and dislocation by low-velocity trauma in 3 patients. All 7 males (63.6%) experienced high-velocity trauma, and 2 of the 3 females experienced low-velocity trauma. Only one patient had an isolated popliteal artery lesion associated with fractures in the leg or the contralateral limb. Patients with low-velocity trauma were older than 54 years, while those with high-velocity trauma were aged 22 to 71 years. RESULTS: In 10/11 patients (90.9%), revascularization was performed after osteoarticular stabilization and reduction of the dislocation or fracture. Intraoperative angiography was selectively used. Two patients required above-the-knee amputation after the procedure: one due to infection of the surgical access point and the other due to severe soft tissue injury. One patient died during hospitalization due to trauma-related complications and comorbidities. CONCLUSIONS: High-velocity trauma and low-velocity trauma in patients with a body mass index > 35 kg/m2 and knee lesions are associated with popliteal artery lesions. Revascularization success is not associated with high- or low-velocity trauma.

Chevron osteotomy with lateral release and adductor tenotomy for hallux valgus.

BACKGROUND: Distal chevron osteotomy is a procedure widely performed for the surgical treatment of painful hallux valgus. The risks and benefits of a lateral capsular release and adductor tenotomy combined with chevron osteotomy are still debated. The aim of our study was to report the clinical and radiographic outcomes of this combined procedure in mild and moderate incongruent bunion deformities, with a hallux valgus angle (HVA) up to 40 degrees and an intermetatarsal angle (IMA) up to 20 degrees. MATERIALS AND METHODS: Forty-two patients (52 feet) who consecutively underwent chevron osteotomy combined with lateral release and adductor tenotomy were reviewed 24-36 months after surgery. The mean age of the patients was 53.5 (range, 43 to 64) years. All the deformities were mild to moderate, with a mean preoperative value of 28 degrees in the HVA (range, 16 degrees to 40 degrees) and of 13 degrees in the IMA (range, 9 degrees to 20 degrees). RESULTS: At followup, the AOFAS hallux score improved from an average of 46 to an average of 88. The HVA and IMA had an average postoperative decrease respectively of 12 degrees and 6 degrees; lateral sesamoid displacement decreased by a mean of 15%. In no case did we observe infection or nonunion of the osteotomy. In one case, painless avascular necrosis of the first metatarsal head developed. CONCLUSION: Our short-term results show that distal chevron osteotomy combined with lateral release and adductor tenotomy is a feasible surgical option to address mild to moderate hallux valgus deformity, even with an IM angle between 15 and 20 degrees. Clinical and radiographic outcomes are generally good and patient satisfaction is generally high.

Tönnis triple pelvic osteotomy for the management of late residual acetabular dysplasia: mid-term to long-term follow-up study of 54 patients.

The authors reviewed 54 (58 hips) patients with acetabular dysplasia following developmental dislocation of the hip (DDH), treated by triple pelvic osteotomy according to the Tönnis technique. The aim of our study was to report the long-term clinical and radiographic results of the operation at a mean follow-up of 12 years (from 7 to 20). At diagnosis, all the hips were painful, the Wiberg angle measured less than 20°, and no radiographic signs of osteoarthritis were present. At follow-up, 82.7% of the operated hips showed either excellent or good results, according to Harris, and the Wiberg angle measured an average of 34° (from 26° to 45°). We encountered five complications: one acetabular malrotation and four asymptomatic ischial nonunions. In conclusion, we believe that, although Bernese periacetabular osteotomy is nowadays considered the gold standard for the surgical treatment of the dysplastic hip following DDH, Tönnis osteotomy represents a good treatment option: it is technically easy, enables direct visualization of the three osteotomies, leads to few complications, and its learning curve is short. The absence of radiographic signs of osteoarthritis and hip congruency before surgery are the basic requirements to achieve a successful result.

Isolated Madelung's deformity: long-term follow-up study of five patients treated surgically.

Five patients with isolated Madelung's deformity were reviewed with an average follow-up of 34 years after surgery. All the patients were female and their average age at surgery was 12.7 years, whereas the average age at follow-up was 53 years. The deformity was bilateral in four patients and unilateral in one, for a total of nine deformities. At diagnosis, in all the patients the typical radial deviation of the hand was observed, with dorsal prominence of the distal end of the ulna. Pain and limitation of the range of motion were present in all the wrists except two, which were painless but presented marked functional impairment. In no patient did we observe growth disorders of the other bones or deformities typical of osteochondrodysplasias. Surgical correction was sought by both the families and the patients mainly for functional reasons, although cosmetic improvement was also expected. The operation consisted of closing-wedge osteotomy of the distal radial metaphysis and either shortening osteotomy or resection of the distal ulna. At follow-up, the range of motion of the wrists was improved, and all the patients were pain-free and satisfied with the final results. No significant radiographic osteoarthritis was present in any of the operated wrists, although four of the five patients were above 50 years of age.

Treatment of recalcitrant atrophic non-union of the humeral shaft with BMP-7, autologous bone graft and hydroxyapatite pellets.

Recalcitrant humeral non-union is a disabling condition that is extremely difficult to treat. The use of BMP-7 has been proposed to improve bone healing. This is a report of the results obtained in 12 patients with recalcitrant humeral non-union treated using stable fixation with a long locking compression plate and BMP-7, autologous bone graft and hydroxyapatite pellets applied at the non-union site. Patients had up to three surgical attempts at non-union healing prior to our treatment. The average time from the initial fracture to our surgery was 5.2 years. Average follow-up was 5.3 years. At follow-up, non-union had healed in all patients by an average of 7.3 months. All the patients were very satisfied with their final results, despite a restricted range of motion of the elbow and a moderate muscular atrophy, which was frequently observed. Our study shows that BMP-7 associated with autologous bone grafting and hydroxyapatite pellets after stable fixation is an effective adjuvant to stimulate bone healing in the treatment of recalcitrant humeral non-union.

Laceration of a branch of the profunda femoris artery caused by a spike of the displaced lesser trochanter in an inter-trochanteric femoral fracture. A case report.

INTRODUCTION: Injury of femoral vessels is an extremely rare complication in intertrochanteric femoral fractures. In most cases reported, the vascular lesion involves the superficial femoral artery, whereas in very few cases does it involve the profunda femoris artery. PRESENTATION OF CASE: We report a case of acute bleeding due to laceration of a perforating branch of the profunda femoris artery caused by a sharp fragment of the displaced lesser trochanter in an intertrochanteric femoral fracture; the lesion was treated by transcatheter embolization. DISCUSSION: The arterial injury may be iatrogenic, occurring during intramedullary internal fixation, or less frequently, the injury may be due to the fracture itself, caused by a sharp bone fragment that damages the profunda femoris artery or one of its perforating branches. CONCLUSION: We believe that intertrochanteric femoral fractures with avulsed lesser trochanter are at risk for femoral vessel injuries caused by the displaced bone spike, and we advise meticulous clinical and laboratory monitoring pre- and post-operatively to prevent serious complications.

Osteochondrosis of the accessory ossification centre of the medial malleolus.

We report a case of a painful accessory ossification centre of the medial malleolus in an 11-year-old girl who was not involved in sports activities. The patient was treated conservatively, with complete clinical and radiographic healing of the medial malleolus 6 months after the first presentation. We ruled out the uncommon pathological conditions causing chronic pain in the medial malleolus during skeletal growth, such as traction apophysitis of the medial malleolus, osteochondrosis, osteochondritis or avascular necrosis of the distal tibial epiphysis. We speculate that this painful condition may be classified as an osteochondrosis of the accessory ossification centre of the medial malleolus.

Modified Murray Technique for Carpal Navicular Nonunion.

The authors report the results of long-term follow-up in 29 patients treated for non-union of the carpal navicular with a modified Murray technique performed through a lateral approach. Mean patient age at surgery was 22.5 years. Average time from injury to surgery for nonunion was 18 months. In 5 cases, mild signs of osteoarthritis of the radioscaphoid joint (scaphoid nonunion advanced collapse [SNAC] stage I) were present before surgery, and in 2 cases, radiographic signs of avascular necrosis of the proximal nonunion fragment were evident. In all cases, a corticocancellous nonvascularized bone graft taken from the distal part of the ipsilateral radius was used. Mean follow-up was 11.2 years. Nonunion had healed in 93.1% of cases. At follow-up, the 2 patients in whom nonunion had not healed had severe painful osteoarthritis of the wrist (SNAC stage IV). Twenty patients were asymptomatic, and 5 had occasional pain in the wrist. Wrist range of motion was restricted in all patients compared with the contralateral side. Mild osteoarthritis was observed in 6 patients (SNAC stage I). The average Disabilities of the Arm, Shoulder and Hand score was 8.7 of 100. The modified Murray technique is reliable for treating nonunion of the carpal navicular. The union rate is high, and the incidence of wrist osteoarthritis is low compared with other studies. Early diagnosis and treatment of nonunion (a short interval between fracture and surgery) can minimize the risk of degenerative joint disease. Avascular necrosis of the proximal fragment is not an absolute contraindication to surgery.

Two-stage surgical treatment of complex femoral deformities with severe coxa vara in polyostotic fibrous dysplasia.

BACKGROUND: In patients with polyostotic fibrous dysplasia with extensive femoral involvement, severe coxa vara may cause complex femoral deformities that are difficult to treat with a single-stage surgical procedure. We evaluated the results of treatment of such patients with a two-stage procedure. METHODS: Eleven patients with polyostotic fibrous dysplasia and severe coxa vara (including one who required bilateral treatment and one who required repeat treatment) were treated surgically at a mean age of fourteen years and four months. A two-stage surgical procedure was planned to correct the deformity. The first stage involved correction of the coxa vara and fixation with a hip plate. The second stage involved correction of a shepherd's crook deformity if present and definitive fixation with an interlocking cervicodiaphyseal nail. All patients were evaluated clinically and radiographically at a mean of four years and seven months after the second-stage procedure. RESULTS: The femoral neck-shaft angle averaged 83° before surgery and was corrected to a mean of 130° after the first-stage procedure. In two patients, cutout of the hip screw-plate caused acute postoperative loss of correction (by 40° in one patient and 20° in the other). After the second-stage procedure, the neck-shaft angle was either fully corrected or improved and the shepherd's crook deformity was fully corrected in all patients. At the time of the latest follow-up, the mean neck-shaft angle was 124°, with a mean loss of correction of 5° relative to the angle measured at the end of the second-stage procedure. The mean estimated blood loss was 625 mL in the first stage and 979 mL in the second. CONCLUSIONS: The two-stage surgical procedure designed to treat patients with polyostotic fibrous dysplasia with complex femoral deformity and severe coxa vara restored a nearly normal femoral alignment that was maintained at a mean of four years and seven months of follow-up. The clinical benefits were pain relief in all of the patients and gait normalization or improvement in most. The estimated blood loss was substantial in both stages. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Valgus extension femoral osteotomy to treat "hinge abduction" in Perthes' disease.

PURPOSE: "Hinge abduction" is a complication of Perthes' disease caused by impingement of the extruded superolateral portion of the femoral head against the lateral lip of the acetabulum. Catterall first described femoral valgus extension osteotomy (VGEO) to treat this condition. We report the results of this operation in 16 cases of Perthes' disease with "hinge abduction". METHODS: Sixteen hips in 16 patients affected by Perthes' disease and "hinge abduction" were operated on at a mean age of 10.1 years and followed up an average of 6.5 years later. Before surgery, the mean Iowa hip score was 44.4 points. Preoperative radiographs were taken with the affected hip in maximum adduction in order to calculate the amount of valgus correction. The osteotomy was performed between the greater and the lesser trochanter, and it was fixed with a hip plate. RESULTS: All the osteotomies healed uneventfully. At follow-up, no patient complained of pain and hip abduction ranged from 20° to 45°. Four out of the 16 patients had a moderate limp, and 12 had an improvement in gait pattern compared to preoperatively. At follow-up, the Iowa hip score totaled a mean of 83.6 points, with a statistically significant improvement in comparison to the preoperative evaluation. At follow-up, two hips were classified as Stulberg II-III, ten hips as Stulberg III, and four as Stulberg IV. CONCLUSIONS: In our hands, VGEO was an effective procedure to treat "hinge abduction" in severe Perthes' disease with satisfactory results. The main limitation of our study is its short follow-up.

Post-traumatic malunion of the proximal phalanx of the finger. Medium-term results in 24 cases treated by "in situ" osteotomy.

We report the clinical and radiographic medium-term results obtained for 20 patients (24 fingers) treated surgically for post-traumatic malunion of the proximal phalanx of the finger. In all cases we performed a corrective osteoclasia or osteotomy at the site of malunion, followed by miniplate and screw fixation or by screw fixation only. The corrective osteoclasia was performed when malalignment was addressed within six weeks after injury. Two patients who had two fractures underwent additional surgery (tenolysis and/or capsulolysis) to improve function and ROM. At the final follow-up, at a mean of 24 months after corrective surgery, good or excellent clinical and radiographic results were obtained in all the patients. The pseudoclaw deformity disappeared in all cases in which a volar angulation deformity was present. An average improvement of about 30% in the range of motion of the MP and PIP joints was observed; only 4 patients complained of mild pain at the maximum degrees of articular excursion of the MP and PIP joints. All the patients presented an improvement in grip strength. The mean DASH score in our series was 5 points. In two of the four cases treated by an intra-articular corrective osteotomy, mild radiographic signs of osteoarthritis at the MP joint were present. The data for this study confirm that "in situ" osteotomy stabilized by miniplates and/or screws is an effective procedure to correct post-traumatic malunions of the proximal phalanges of the fingers.

Neglected fracture of the medial humeral epicondyle that was entrapped into the elbow joint: a case report.

The objective of this paper is to report clinical and radiographic long-term results of a neglected fracture of the medial humeral epicondyle, which was entrapped into the elbow joint. At follow-up, 48 years after the trauma, the patient complained of occasional discomfort around the elbow, but the joint had a normal range of motion and good stability. Radiographs showed that the epicondylar fragment was fused to the medial border of the olecranon. The authors conclude that an old fracture of the medial humeral epicondyle, presenting a fusion of the fragment to the olecranon with normal range of motion and without pain, may be managed expectantly.

Immediate continuous passive motion after internal fixation of an ankle fracture.

BACKGROUND: Surgical treatment is usually mandatory in displaced bimalleolar and trimalleolar fractures. Some authors have recommended early mobilization of the ankle joint after surgical treatment of these lesions. In this study, we evaluate the effect of immediate postoperative continuous passive motion in the management of displaced bimalleolar and trimalleolar fractures treated surgically. MATERIALS AND METHODS: Two series of 22 patients each, who had had a Weber type A, B or C ankle fracture treated surgically, were followed up at least 10 years after the injury. In the first series, immediately after surgery, a continuous passive motion machine was applied to the operated ankle for 3 weeks, whereas in the second series, after surgery a plaster splint or a plaster cast was applied for 3 weeks. RESULTS: At follow-up, all patients were evaluated clinically and radiographically using the AOFAS Ankle Hindfoot Score System (Kitaoka, Foot Ankle 15:349-353, 1994). The average final score for the first series of patients was 95.7 points (range 87-100 points, standard deviation 3.42 points). Of this series, at radiographic examination, in two patients we observed minor signs of osteoarthritis of the ankle joint. The average final score for the second series was 88 points (range 68-100 points, standard deviation 10.60 points). At radiographic examination, in six patients we observed minor signs of osteoarthritis of the ankle joint, whereas in another one the osteoarthritis was severe. CONCLUSIONS: Continuous passive motion started immediately after surgery seems to be an effective method both for allowing complete and quick recovery of the range of motion of the ankle and for reducing the risk of early degenerative joint disease. Immediate passive ankle motion can be applied only after adequate reduction and stable internal fixation.

Anterior tibial tendon transfer in relapsing congenital clubfoot: long-term follow-up study of two series treated with a different protocol.

Two series of patients with relapsing congenital clubfoot were treated by transfer of the anterior tibial tendon to the third cuneiform under the extensor retinaculum. The two series were reviewed at the end of skeletal growth to evaluate the effectiveness of the surgical procedure. The first series included 19 clubfeet and the second 16. The two series of clubfeet were initially treated by two different manipulative techniques and two different complementary soft tissue release operations. In relapsing clubfeet, the foot dorsiflexion/eversion activity of the tibialis anterior was suppressed and the muscle functioned as an invertor. At follow-up the functional results of the second series of patients, in whom the relapsing deformity was passively correctable at the time of surgery, were better than those of the first series of patients, in whom the relapsing deformity was sometimes less passively correctable. None of the operated patients had a further relapse. In both series, the angles formed by the longitudinal axis of the navicular and the first cuneiform, the calcaneus and the fifth metatarsal, and the calcaneus and the cuboid, evaluated both by plain radiographs and by CT scan, were smaller than in normal feet and in the clubfeet that did not relapse. Transfer of the anterior tibial tendon to the third cuneiform underneath the extensor retinaculum corrects and stabilizes relapsing clubfeet by restoring their normal function of foot dorsiflexion/eversion. As a consequence, the cuneiforms and the cuboid were shifted more laterally than normal, as shown by both x-rays and CT scan.