SAKK57/16 Nab-paclitaxel and Gemcitabine in Soft Tissue Sarcoma (NAPAGE): a phase I/II trial.

BACKGROUND: To determine whether the combination of nab-paclitaxel with gemcitabine has activity in patients with pretreated soft tissue sarcoma (STS). PATIENTS AND METHODS: NAPAGE is a phase Ib/II clinical trial investigating the combination of nab-paclitaxel (nab-pc) with gemcitabine employing two cohorts. One of a dose-de-escalation phase and one of expansion. In phase I, nab-pc was given at 150 mg/m2 in combination with gemcitabine 1000 mg/m2 every two weeks, until disease progression or unacceptable toxicity. This dose was recommended for phase II (RP2D), as there was no dose limiting toxicity (DLT) or discontinuations due to adverse events (AEs). The primary endpoint of the phase II was progression-free rate (PFR) at 3 months (H0: 20%, H1:40%). The secondary endpoints included progression free survival (PFS), overall survival (OS), AEs, objective response and patient-reported outcomes (PRO). Efficacy analysis was by intention to treat. RESULTS: The 3-month PFR was 56.4% (95% confidence interval CI: 39.6-72.2%). The 3-month and 6-month PFS were 58.4% (95% CI: 41.3-72.1%) and 44.6% (95% CI: 28.4-59.5%), respectively. Median PFS was 5.3 months (95% CI: 1.4-8.2) and median OS was 12.8 months (95% CI: 10.5-39.2). The most common treatment-related grade ≥ 3 AE were neutropenia (18%), followed by anemia (2.6%), hypertension (2.6%) and alanine aminotransferase increase (2.6%). Grade 1 and grade 2 peripheral sensory neuropathy (PNP) occurred in 15.4% and 20.5%, respectively. No grade 3-4 PNP was reported. CONCLUSIONS: Combining nab-pc and gemcitabine is safe. Promising activity is observed in pretreated STS patients with manageable toxicity. This regimen should be considered for further exploration.

Radiotherapy-induced anti-tumor immune response and immune-related adverse events in a case of recurrent nasopharyngeal carcinoma undergoing anti-PD-1 immunotherapy.

BACKGROUND: Treatment of recurrent nasopharyngeal carcinoma is a challenging clinical problem. We report the case of a 46 year old male showing excellent response and signs of immunostimulation following re-re-irradiation for recurrent nasopharyngeal carcinoma under systemic treatment with pembrolizumab. CASE PRESENTATION: Patient was first diagnosed with locoregionally advanced, non-keratinizing nasopharyngeal carcinoma in 2010. After achieving complete remission following induction chemotherapy and concurrent curative chemoradiation, the patient subsequently developed distant and locoregionally recurrent disease. He received various treatments (neck dissection, radiotherapy to a bony metastasis, palliative chemotherapy, stereotactic re-irradiation of local recurrence) before initiation of anti- PD-1 immunotherapy with pembrolizumab in January of 2016. Following marked local progression 6 months thereafter, we performed re-re-irradiation of the recurrent tumor after careful evaluation and treatment planning. While treatment was well tolerated, the patient subsequently developed marked clinical and radiological signs of immunostimulation with mucosal irritation and swelling of lacrimal and salivary glands as described in the report. Immunotherapy with pembrolizumab was reinitiated, with re- staging showing excellent response with regression of all tumorous lesions. At the time of this report, following near complete recovery of inflammatory symptoms, the patient remains in excellent condition and free from recurrence under treatment with pembrolizumab. CONCLUSIONS: To our knowledge, we report the first observation of a combined effect of immunotherapy and radiotherapy in a patient with recurrent nasopharyngeal carcinoma. Demonstrating distinct signs of immunostimulation as well as excellent tumor response in a heavily pretreated patient progressing under anti-PD-1 immunotherapy, the case adds to the rising paradigm of an immunostimulatory effect of radiotherapy in patients undergoing treatment with immune checkpoint inhibitors.

Cetuximab induced aseptic meningitis.

We report a 67-year-old man with recurrent advanced oropharyngeal squamous cell carcinoma who developed aseptic meningitis, with first symptoms arising approximately 9hours after the first administration of cetuximab, and review the literature to identify key signs and symptoms of this condition. Cetuximab is a monoclonal antibody targeting the epidermal growth factor receptor which has been rarely associated with aseptic meningitis. Besides the case description, a MEDLINE search was performed. In five patients identified in the literature and our patient, the leading signs and symptoms included headache, neck stiffness and high fever developing within a few hours of the first cetuximab administration. Cerebrospinal fluid (CSF) analysis revealed severe pleocytosis (range: 528-2300/µl) with dominance of neutrophils (⩾87%). Clinical recovery within 1-2weeks was accompanied by normalization of CSF cell count within 4-7days. Re-challenge with cetuximab at a reduced dose caused recurrent aseptic meningitis in one of three patients. In summary, aseptic meningitis is a rare complication after first cetuximab exposure that the clinician should be aware of. CSF analysis is the key to diagnosis and recovery is usually complete within days to weeks after withdrawal of the drug. Re-challenge may be considered but bears the risk of recurrence.

Uncommon case of brain metastasis in a patient with a history of heavy smoking.

Primary sarcomas of the aorta are extremely uncommon. Depending on histomorphology and immunohistochemical pattern, intimal sarcomas can show angiosarcomatous differentiation. Here, we describe the case of a 60-year-old woman with a primary intimal sarcoma of the aortic arch and signs of cerebral metastatic disease as the initial manifestation. After the patient experienced the onset of severe headaches, ataxia, and left-sided weakness, magnetic resonance imaging showed several brain lesions. Histologic assessment of a brain biopsy specimen revealed a malignant tumour composed of large pleomorphic cells that were positive for pancytokeratin and CD10. Radiation to the brain did not significantly improve the patient's symptoms, and cranial computed tomography (ct) imaging revealed several metastases, indicating lack of response. Because of the patient's smoking history, the presence of central nervous system and skeletal metastases on combined positron-emission tomography and ct imaging, and the focal pan-cytokeratin positivity of the tumour, carcinoma of the lung was favoured as the primary tumour. Despite chemotherapy with cisplatin and etoposide, the patient's neurologic symptoms and general condition deteriorated rapidly, and she died within a few days. At autopsy, an undifferentiated intimal sarcoma of the aortic arch was diagnosed. The primary tumour in the aorta consisted of large pleomorphic cells. Immunohistochemical analysis of the aortic tumour and brain metastases demonstrated diffuse positivity for vimentin and p53 and focal S-100 staining. In summary, we report a challenging case of advanced intimal sarcoma of the aortic arch with brain and bone metastases at initial presentation. Our report demonstrates the difficulties in diagnosing and treating this disease, and the need for multicentre studies to accrue more patients for investigations of optimal therapy.

Treatment concepts of oral cancer.

The mortality of oral cancer (OC) has shown only moderate improvement over recent decades. Treatment of OC remains mainly surgical with increasing contributions from radio- and chemotherapy. Early diagnosis and adequate management improves patient prognosis whilst lymphatic spread worsens the prognosis significantly. Copious extirpation of the tumour achieving tumour-free margins, as well as the effective removal of affected or suspect lymph nodes are vital steps to ensure long-term survival. Reconstructive ablities have improved to such an extent that many patients can be fully integrated in society after treatment. New modalities such as intensity modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) ensures selective radiation and significantly contributes to improved quality of life. Photodynamic therapy and other targeted therapy options will play an increasingly important role in the future.

[123I-Metaiodobenzylguanidine- (MIBG-) scintigraphy: paradoxical positivity in an oncocytic adrenocortical carcinoma]. / 123I-Methyljodbenzylguanidin- (MIBG-) Szintigraphie: Paradoxe Nuklidspeicherung eines onkozytären Nebennierenrindenkarzinoms.

(123)I-metaiodobenzylguanidine (MIBG), a radio-labeled catecholamine analogue, is used for the imaging of pheochromocytoma based on the selective uptake of MIBG by chromaffin tissues. MIBG scintigraphy displays high sensitivity (90%) and specificity (close to 100%). In contrast, the false-positive uptake of MIBG by adrenal cortical carcinoma is rare. Here, we report a metastatic oncocytic adrenal cortical carcinoma with MIBG uptake used for therapeutic purposes.

Streptobacillus moniliformis endocarditis in an HIV-positive patient.

Streptobacillus moniliformis is the causative agent of rat bite fever, with endocarditis being a rare but well-documented complication. We report the case of an HIV-positive man who acquired S. moniliformis endocarditis through a rat bite. No predisposing cardiac lesion was known. He was treated with ceftriaxone 2 g/day i.v. for 3 weeks, gentamicin 120 mg/day i.v. for 2 weeks and penicillin 24x10(6) units/day for 1 week. At the end of the antibiotic therapy he suffered a generalized Candida albicans infection, which was treated with fluconazole for 1 week. He was subsequently discharged in a satisfactory condition.