Phase II Window Study of Olaparib Alone or with Cisplatin or Durvalumab in Operable Head and Neck Cancer.

Purpose: We conducted a phase II randomized noncomparative window of opportunity (WOO) trial to evaluate the inhibition of cellular proliferation and the modulation of immune microenvironment after treatment with olaparib alone or in combination with cisplatin or durvalumab in patients with operable head and neck squamous cell carcinoma (HNSCC). Experimental Design: Forty-one patients with HNSCC were randomized to cisplatin plus olaparib (arm A), olaparib alone (arm B), no treatment (arm C) or durvalumab plus olaparib (arm D). The primary endpoint was to evaluate the percentage of patients in each arm that achieved a reduction of at least 25% in Ki67. Secondary endpoints included objective response rate (ORR), safety, and pathologic complete response (pCR) rate. Paired baseline and resection tumor biopsies and blood samples were evaluated for prespecified biomarkers. Results: A decrease in Ki67 of at least 25% was observed in 44.8% of treated patients, as measured by quantitative immunofluorescence. The ORR among treated patients was 12.1%. pCR was observed in 2 patients. Two serious adverse events occurred in 2 patients.Programmed death ligand 1 (PD-L1) levels [combined positive score (CPS)] were significantly higher after treatment in arms A and D. Expression of CD163 and colony-stimulating factor 1 receptor (CSF1R) genes, markers of M2 macrophages, increased significantly posttreatment whereas the expression of CD80, a marker of M1 macrophages, decreased. Conclusion: Preoperative olaparib with cisplatin or alone or with durvalumab was safe in the preoperative setting and led to decrease in Ki67 of at least 25% in 44.8% of treated patients. Olaparib-based treatment modulates the tumor microenvironment leading to upregulation of PD-L1 and induction of protumor features of macrophages. Significance: HNSCC is characterized by defective DNA repair pathways and immunosuppressive tumor microenvironment. PARP inhibitors, which promote DNA damage and "reset" the inflammatory tumor microenvironment, can establish an effective antitumor response. This phase II WOO trial in HNSCC demonstrated the immunomodulatory effects of PARP inhibitor-induced DNA damage. In this chemo-naïve population, PARP inhibitor-based treatment, reduced tumor cell proliferation and modulated tumor microenvironment. After olaparib upregulation of PD-L1 and macrophages, suggests that combinatorial treatment might be beneficial. Synopsis: Our WOO study demonstrates that preoperative olaparib results in a reduction in Ki67, upregulation of PD-L1 CPS, and induction of protumor features of macrophages in HNSCC.

Late-presenting developmental dysplasia of the hip treated with the modified Hoffmann-Daimler functional method.

BACKGROUND: The general consensus is that nonoperative treatment of developmental dysplasia of the hip should not be attempted for patients in whom previous treatment of the disease has failed, those in whom the disease was neglected, or those in whom the disease presented late. In such cases, it is believed that the optimum period for hip remodeling has passed and that operative methods are preferable. The purpose of the present study was to report the efficacy of a modified form of the Hoffmann-Daimler method for the treatment of late-presenting developmental dysplasia of the hip. MATERIALS: We retrospectively reviewed the records of sixty-nine patients (ninety-five hips) with neglected developmental dysplasia of the hip who had been managed nonoperatively with a modification of the Hoffmann-Daimler method from 1971 to 2000. With this method, the patient wears a flexion harness (Phase A), during which time the femoral head is gradually reduced, followed by an abduction splint (Phase B), during which time the reduced hip remodels. We have modified the original method by introducing new treatment strategies. The study group included nine boys and sixty girls. The average age of the patients was sixteen months (range, six to forty-four months) at the start of treatment and 11.5 years (range, six to twenty-nine years) at the time of the latest follow-up. Radiographs were assessed to determine the acetabular index, the Severin classification, and the presence of evidence of osteonecrosis of the proximal femoral epiphysis. Hips that were rated as Severin class I or class II were classified as satisfactory, whereas those that were rated as Severin class III or class IV were classified as unsatisfactory. RESULTS: On the basis of the most recent follow-up radiographs, eighty-eight (93%) of the dislocated hips were classified as satisfactory (sixty-seven were rated as Severin class I and twenty-one were rated as Severin class II) and seven were classified as unsatisfactory (six were rated as Severin class III and one was rated as Severin class IV). No hip was rated as Severin class V or VI. The average acetabular index was 40 degrees +/- 7.4 degrees prior to the onset of treatment and 24 degrees +/- 5.7 degrees at the end of treatment. No redislocations or other complications were noted. Osteonecrosis was noted in six of the ninety-five hips. CONCLUSIONS: Late-presenting or neglected developmental dysplasia of the hip can be successfully treated with use of a modified Hoffmann-Daimler method. The high rate of successful reduction, the low prevalence of osteonecrosis and residual dysplasia, and the limited complications may make this modified method a safe alternative to surgical treatment. LEVEL OF EVIDENCE: Therapeutic Level IV.

Chronic osteomyelitis of the pelvis in children and adolescents.

Osteomyelitis of the pelvis is rare in children as well as in adults. This explains why the diagnosis is often missed, so that the infection becomes chronic. The authors report five chronic paediatric cases, seen between 1993 and 2003. The diagnosis was initially missed in two patients. In two others, the osteomyelitis was recognised but insufficiently treated, so that it also became chronic. The fifth patient developed exogenous osteomyelitis 6 months after an open pelvic fracture. The bone scan was useful for the differential diagnosis, but laboratory and radiographic findings were not. Treatment was the same for all patients, including wide surgical debridement, antibiotic therapy and prolonged immobilisation. Four patients were free of symptoms at the last clinical evaluation, after an average follow-up period of 7 years. Only one patient had a recurrence 3 months postoperatively and was re-operated. This study demonstrates that surgical treatment of chronic pelvic osteomyelitis in children and adolescents yields encouraging results.

Post-traumatic cystic lesion following fracture of the radius.

Post-traumatic cystic lesions are an uncommon complication of fractures in children. They are benign, asymptomatic, non-expansive and tend to resolve spontaneously. Their cause seems to be the invasion of bone-marrow fat by subperiosteal hematoma, which may be visible on radiographs during fracture consolidation of the newly formed subperiosteal bone. The case we present is of cyst formation following a fracture of the distal radius and we evaluate the role of yellow bone marrow in the pathogenesis of the cyst. Its typical features clear differentiation from other lesions, preventing unnecessary and, possibly, invasive examinations.

Neovascularization and other histopathologic findings in an autogenous saphenous vein wrap used for recalcitrant carpal tunnel syndrome: a case report.

A patient suffering from recalcitrant carpal tunnel syndrome despite 4 surgical decompressions was treated successfully with revision carpal tunnel release, neurolysis, and autogenous saphenous vein wrapping of the median nerve. When he subsequently developed compression of the common digital nerve to the middle finger his carpal tunnel was re-explored and the previously applied vein graft underwent a biopsy examination. Histopathologic analysis of the biopsy specimen was remarkable for neovascularization of the vein graft and structural transformation of the vein endothelium, neither of which has been reported in vein wrapping of the upper extremity.

Radial tunnel syndrome.

True neurogenic radial tunnel syndrome is an uncommon condition caused by entrapment of the radial or posterior interosseous nerve. It is a subjective pain syndrome with rare motor findings. The chief complaint is generally pain at the dorsal aspect of the upper forearm; any weakness is usually secondary to pain. Electrodiagnostic studies are unreliable in radial tunnel syndrome. Although previous studies have found a high rate of good results, the authors believe that a high rate of morbidity is associated with both the disease and its treatment. Based on their results they suggest that great caution has to be taken before performing radial tunnel release, and strict adherence to the indications should be noted during the preoperative examination. A trial of nonsurgical treatment is warranted in all patients. Patients who do not respond or continue to progress despite conservative treatment are candidates for surgical decompression. Based on the recent literature, surgical decompression leads to approximately 60 to 70% good and excellent results.