Structural evidence for the roles of divalent cations in actin polymerization and activation of ATP hydrolysis.

The structure of the actin filament is known at a resolution that has allowed the architecture of protein components to be unambiguously assigned. However, fully understanding the chemistry of the system requires higher resolution to identify the ions and water molecules involved in polymerization and ATP hydrolysis. Here, we find experimental evidence for the association of cations with the surfaces of G-actin in a 2.0-Šresolution X-ray structure of actin bound to a Cordon-Bleu WH2 motif and in previously determined high-resolution X-ray structures. Three of four reoccurring divalent cation sites were stable during molecular dynamics (MD) simulations of the filament, suggesting that these sites may play a functional role in stabilizing the filament. We modeled the water coordination at the ATP-bound Mg2+, which also proved to be stable during the MD simulations. Using this model of the filament with a hydrated ATP-bound Mg2+, we compared the cumulative probability of an activated hydrolytic water molecule approaching the γ-phosphorous of ATP, in comparison with G-actin, in the MD simulations. The cumulative probability increased in F-actin in line with the activation of actin's ATPase activity on polymerization. However, inclusion of the cations in the filament lowered cumulative probability, suggesting the rate of hydrolysis may be linked to filament flexibility. Together, these data extend the possible roles of Mg2+ in polymerization and the mechanism of polymerization-induced activation of actin's ATPase activity.

Durvalumab with or without tremelimumab in patients with recurrent or metastatic head and neck squamous cell carcinoma: EAGLE, a randomized, open-label phase III study.

BACKGROUND: Targeting the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis has demonstrated clinical benefit in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Combining immunotherapies targeting PD-L1 and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) has shown evidence of additive activity in several tumor types. This phase III study evaluated the efficacy of durvalumab (an anti-PD-L1 monoclonal antibody) or durvalumab plus tremelimumab (an anti-CTLA-4 monoclonal antibody) versus standard of care (SoC) in R/M HNSCC patients. PATIENTS AND METHODS: Patients were randomly assigned to receive 1 : 1 : 1 durvalumab (10 mg/kg every 2 weeks [q2w]), durvalumab plus tremelimumab (durvalumab 20 mg/kg q4w plus tremelimumab 1 mg/kg q4w × 4, then durvalumab 10 mg/kg q2w), or SoC (cetuximab, a taxane, methotrexate, or a fluoropyrimidine). The primary end points were overall survival (OS) for durvalumab versus SoC, and OS for durvalumab plus tremelimumab versus SoC. Secondary end points included progression-free survival (PFS), objective response rate, and duration of response. RESULTS: Patients were randomly assigned to receive durvalumab (n = 240), durvalumab plus tremelimumab (n = 247), or SoC (n = 249). No statistically significant improvements in OS were observed for durvalumab versus SoC [hazard ratio (HR): 0.88; 95% confidence interval (CI): 0.72-1.08; P = 0.20] or durvalumab plus tremelimumab versus SoC (HR: 1.04; 95% CI: 0.85-1.26; P = 0.76). The 12-month survival rates (95% CI) were 37.0% (30.9-43.1), 30.4% (24.7-36.3), and 30.5% (24.7-36.4) for durvalumab, durvalumab plus tremelimumab, and SoC, respectively. Treatment-related adverse events (trAEs) were consistent with previous reports. The most common trAEs (any grade) were hypothyroidism for durvalumab and durvalumab plus tremelimumab (11.4% and 12.2%, respectively), and anemia (17.5%) for SoC. Grade ≥3 trAE rates were 10.1%, 16.3%, and 24.2% for durvalumab, durvalumab plus tremelimumab, and SoC, respectively. CONCLUSION: There were no statistically significant differences in OS for durvalumab or durvalumab plus tremelimumab versus SoC. However, higher survival rates at 12 to 24 months and response rates demonstrate clinical activity for durvalumab. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02369874.

Advances in Structural Biology and the Application to Biological Filament Systems.

Structural biology has experienced several transformative technological advances in recent years. These include: development of extremely bright X-ray sources (microfocus synchrotron beamlines and free electron lasers) and the use of electrons to extend protein crystallography to ever decreasing crystal sizes; and an increase in the resolution attainable by cryo-electron microscopy. Here we discuss the use of these techniques in general terms and highlight their application for biological filament systems, an area that is severely underrepresented in atomic resolution structures. We assemble a model of a capped tropomyosin-actin minifilament to demonstrate the utility of combining structures determined by different techniques. Finally, we survey the methods that attempt to transform high resolution structural biology into more physiological environments, such as the cell. Together these techniques promise a compelling decade for structural biology and, more importantly, they will provide exciting discoveries in understanding the designs and purposes of biological machines.

Activity and safety of afatinib in a window preoperative EORTC study in patients with squamous cell carcinoma of the head and neck (SCCHN).

Background: To investigate the activity and safety of afatinib in the preoperative treatment of squamous cell carcinoma of the head and neck (SCCHN). Patients and methods: This study was an open-label, randomized, multicenter, phase II window of opportunity trial. Treatment-naïve SCCHN patients selected for primary curative surgery were randomized (5 : 1 ratio) to receive afatinib during 14 days (day -15 until day -1) before surgery (day 0) or no treatment. Tumor biopsies, 2-[fluorine-18]-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET), and magnetic resonance imaging (MRI) were carried out at diagnosis and just before surgery. The primary end point was metabolic FDG-PET response (according to EORTC guidelines). Other end points included response assessment based on the Response Evaluation Criteria In Solid Tumors (RECIST) v1.1, dynamic contrast-enhanced (DCE)-MRI, diffusion weighted (DW)-MRI, safety, and translational research (TR). Results: Thirty patients were randomized: 25 to afatinib and 5 to control arm. Of the 23 eligible patients randomized to afatinib, 16 (70%; 95% CI: 47% to 87%) patients had a partial metabolic FDG-PET response (PMR). Five patients (22%; 95% CI: 8% to 44%) showed a partial response by RECISTv1.1. Responses assessed via DCE-MRI and DWI-MRI did not show a strong association with PMR or RECIST. One patient discontinued afatinib after 11 days for grade 3 diarrhea with subsequent renal failure and 24 days delay in surgery. No grade 4 toxicities or surgical comorbidities related to afatinib were reported. TR results indicated that PMR was more frequent in the tumors with high Cluster3-hypoxia score expression and with TP53 wild type. Conclusion: Afatinib given for 2 weeks to newly diagnosed SCCHN patients induces a high rate of FDG-PET partial metabolic response and partial response according to RECISTv1.1. Afatinib can be safely administered before surgery. Although exploratory, the hypoxic gene signature needs further investigations as a predictive biomarker of afatinib activity. Clinical trial registration: ClinicalTrials.gov: NCT01538381.

Incidence of medication-related osteonecrosis of the jaw in patients treated with both bone resorption inhibitors and vascular endothelial growth factor receptor tyrosine kinase inhibitors.

BACKGROUND: Several case reports and small case series have suggested a higher incidence of medication-related osteonecrosis of the jaw (MRONJ) in patients treated concomitantly with bone resorption inhibitors (BRIs) and vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs), as compared to patients treated with BRIs alone. We aimed to assess ONJ-incidence in patients exposed concomitantly to BRIs and VEGFR-TKIs. PATIENTS AND METHODS: We reviewed the records of all patients who received VEGFR-TKIs concomitantly with BRIs. Patients, who were treated with BRIs without VEGFR-TKI, served as a control group. Endpoints of the study were total MRONJ-incidence, MRONJ-incidence during the first and second year of exposure, and time-to-ONJ-incidence. RESULTS: Ninety patients were treated concomitantly with BRIs and VEGFR-TKIs with a median BRI-exposure of 5.0 months. Total MRONJ-incidence was 11.1%. During the first year of BRI-exposure (with a median concomitant exposure of 4.0 months), 6 out of 90 patients (6.7%) developed a MRONJ, compared to 1.1% in the control group (odds ratio 5.9; 95%CI 2.0-18.0; p = 0.0035). In Kaplan-Meier estimates, time-to-ONJ-incidence was significantly shorter in patients treated with BRIs and VEGFR-TKIs compared to BRIs alone (hazard ratio 9.5; 95%CI 3.1-29.6; p < 0.0001). MRONJs occurred earlier in patients treated concomitantly compared to patients treated with BRIs only (after a median exposure of 4.5 and 25.0 months, respectively; p = 0.0033). CONCLUSION: With a global MRONJ-incidence of 11%, patients receiving concomitant treatment with VEGFR-TKIs and BRIs have a five to ten times higher risk for development of MRONJ compared to patients treated with BRIs alone.

TPF plus cetuximab induction chemotherapy followed by biochemoradiation with weekly cetuximab plus weekly cisplatin or carboplatin: a randomized phase II EORTC trial.

BACKGROUND: Our aim was to test the safety of cetuximab added to chemoradiation with either cisplatin or carboplatin after prior induction chemotherapy. METHODS: Patients with stage III/IV unresectable, squamous cell carcinoma of the head and neck received up to four cycles of TPF-E (cisplatin and docetaxel 75 mg/m2 on day 1 followed by 5-FU 750 mg/m2/day as a continuous infusion on days 1-5 plus cetuximab at a loading dose of 400 mg/m2 followed by a weekly dose of 250 mg/m2), with prophylactic antibiotics but no growth factors. Patients not progressing after four cycles of TPF-E were randomly assigned to radiotherapy (70 Gy over 7 weeks in 2 Gy fractions) and weekly cetuximab with either weekly cisplatin 40 mg/m2 or carboplatin, AUC of 1.5 mg/ml/min. Primary endpoint was feasibility. RESULTS: Forty-seven patients were recruited. One patient did not start TPF (hypersensitivity reaction during the cetuximab loading dose). Induction TPF-E was discontinued in 12 patients due to toxicity (6 patients), medical decision (2), death (1), patient refusal (1), protocol violation (1), co-morbidity (1). Three further patients were not randomized [progressive disease (1), protocol violation (1), toxicity and co-morbidity (1)]. Of particular interest are three patients who suffered from bowel perforation, one patient who died as results of pneumonia and septic shock, and a second patient who was found dead at home 12 days after starting TPF-E (cause of death unknown). Weekly cisplatin and carboplatin was stopped early in seven and four patients, respectively. Radiotherapy was stopped in two patients with cisplatin and interrupted in one patient with cisplatin and four patients with carboplatin. CONCLUSIONS: The addition of cetuximab to full dose TPF induction chemotherapy led to unacceptable complications and premature closing of the study. Only 34 out of 46 patients completed four cycles of TPF-E and only 30 started biochemoradiation.

Biomarkers predict enhanced clinical outcomes with afatinib versus methotrexate in patients with second-line recurrent and/or metastatic head and neck cancer.

BACKGROUND: In the phase III LUX-Head & Neck 1 (LUX-H&N1) trial, second-line afatinib significantly improved progression-free survival (PFS) versus methotrexate in patients with recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Here, we evaluated association of prespecified biomarkers with efficacy outcomes in LUX-H&N1. PATIENTS AND METHODS: Randomized patients with R/M HNSCC and progression following ≥2 cycles of platinum therapy received afatinib (40 mg/day) or methotrexate (40 mg/m2/week). Tumor/serum samples were collected at study entry for patients who volunteered for inclusion in biomarker analyses. Tumor biomarkers, including p16 (prespecified subgroup; all tumor subsites), EGFR, HER2, HER3, c-MET and PTEN, were assessed using tissue microarray cores and slides; serum protein was evaluated using the VeriStrat® test. Biomarkers were correlated with efficacy outcomes. RESULTS: Of 483 randomized patients, 326 (67%) were included in the biomarker analyses; baseline characteristics were consistent with the overall study population. Median PFS favored afatinib over methotrexate in patients with p16-negative [2.7 versus 1.6 months; HR 0.70 (95% CI 0.50-0.97)], EGFR-amplified [2.8 versus 1.5 months; HR 0.53 (0.33-0.85)], HER3-low [2.8 versus 1.8 months; HR 0.57 (0.37-0.88)], and PTEN-high [1.6 versus 1.4 months; HR 0.55 (0.29-1.05)] tumors. Afatinib also improved PFS in combined subsets of patients with p16-negative and EGFR-amplified tumors [2.7 versus 1.5 months; HR 0.47 (0.28-0.80)], and patients with p16-negative tumors who were EGFR therapy-naïve [4.0 versus 2.4 months; HR 0.55 (0.31-0.98)]. PFS was improved in afatinib-treated patients who were VeriStrat 'Good' versus 'Poor' [2.7 versus 1.5 months; HR 0.71 (0.49-0.94)], but no treatment interaction was observed. Afatinib improved tumor response versus methotrexate in all subsets analyzed except for those with p16-positive disease (n = 35). CONCLUSIONS: Subgroups of HNSCC patients who may achieve increased benefit from afatinib were identified based on prespecified tumor biomarkers (p16-negative, EGFR-amplified, HER3-low, PTEN-high). Future studies are warranted to validate these findings. CLINICAL TRIAL REGISTRATION: NCT01345682.

Afatinib versus methotrexate in older patients with second-line recurrent and/or metastatic head and neck squamous cell carcinoma: subgroup analysis of the LUX-Head & Neck 1 trial.

BACKGROUND: In the phase III LUX-Head & Neck 1 (LHN1) trial, afatinib significantly improved progression-free survival (PFS) versus methotrexate in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients progressing on/after platinum-based therapy. This report evaluates afatinib efficacy and safety in prespecified subgroups of patients aged ≥65 and <65 years. PATIENTS AND METHODS: Patients were randomized (2:1) to 40 mg/day oral afatinib or 40 mg/m(2)/week intravenous methotrexate. PFS was the primary end point; overall survival (OS) was the key secondary end point. Other end points included: objective response rate (ORR), patient-reported outcomes, tumor shrinkage, and safety. Disease control rate (DCR) was also assessed. RESULTS: Of 483 randomized patients, 27% (83 afatinib; 45 methotrexate) were aged ≥65 years (older) and 73% (239 afatinib; 116 methotrexate) <65 years (younger) at study entry. Similar PFS benefit with afatinib versus methotrexate was observed in older {median 2.8 versus 2.3 months, hazard ratio (HR) = 0.68 [95% confidence interval (CI) 0.45-1.03], P = 0.061} and younger patients [2.6 versus 1.6 months, HR = 0.79 (0.62-1.01), P = 0.052]. In older and younger patients, the median OS with afatinib versus methotrexate was 7.3 versus 6.4 months [HR = 0.84 (0.54-1.31)] and 6.7 versus 6.2 months [HR = 0.98 (0.76-1.28)]. ORRs with afatinib versus methotrexate were 10.8% versus 6.7% and 10.0% versus 5.2%; DCRs were 53.0% versus 37.8% and 47.7% versus 38.8% in older and younger patients, respectively. In both subgroups, the most frequent treatment-related adverse events were rash/acne (73%-77%) and diarrhea (70%-80%) with afatinib, and stomatitis (43%) and fatigue (31%-34%) with methotrexate. Fewer treatment-related discontinuations were observed with afatinib (each subgroup 7% versus 16%). A trend toward improved time to deterioration of global health status, pain, and swallowing with afatinib was observed in both subgroups. CONCLUSIONS: Advancing age (≥65 years) did not adversely affect clinical outcomes or safety with afatinib versus methotrexate in second-line R/M HNSCC patients. CLINICAL TRIAL REGISTRATION: NCT01345682 (ClinicalTrials.gov).

Comparison of diagnostic accuracy of (111)In-pentetreotide SPECT and (68)Ga-DOTATOC PET/CT: A lesion-by-lesion analysis in patients with metastatic neuroendocrine tumours.

OBJECTIVES: To compare the diagnostic accuracy of (111)In-pentetreotide-scintigraphy with (68)Ga-DOTATOC-positron emission tomography (PET)/computed tomography (CT) in patients with metastatic-neuroendocrine tumour (NET) scheduled for peptide receptor radionuclide therapy (PRRT). Incremental lesions (ILs) were defined as lesions observed on only one modality. METHODS: Fifty-three metastatic-NET-patients underwent (111)In-pentetreotide-scintigraphy (24 h post-injection; planar+single-photon emission CT (SPECT) abdomen) and whole-body (68)Ga-DOTATOC-PET/CT. SPECT and PET were compared in a lesion-by-lesion and organ-by-organ analysis, determining the total lesions and ILs for both modalities. RESULTS: Significantly more lesions were detected on (68)Ga-DOTATOC-PET/CT versus (111)In-pentetreotide-scintigraphy. More specifically, we observed 1,098 lesions on PET/CT (range: 1-105; median: 15) versus 660 on SPECT (range: 0-73, median: 9) (p<0.0001), with 439 PET-ILs (42/53 patients) and one SPECT-IL (1/53 patients). The sensitivity for PET/CT was 99.9 % (95 % CI, 99.3-100.0), for SPECT 60.0 % (95 % CI, 48.5-70.2). The organ-by-organ analysis showed that the PET-ILs were most frequently visualized in liver and skeleton. CONCLUSION: Ga-DOTATOC-PET/CT is superior for the detection of NET-metastases compared to (111)In-pentetreotide SPECT. KEY POINTS: Somatostatin receptor PET is superior to SPECT in detecting NET metastases. PET is the scintigraphic method for accurate depiction of NET tumour burden. The sensitivity of PET is twofold higher than the sensitivity of SPECT.

Cisplatin, 5-fluorouracil, and cetuximab (PFE) with or without cilengitide in recurrent/metastatic squamous cell carcinoma of the head and neck: results of the randomized phase I/II ADVANTAGE trial (phase II part).

BACKGROUND: Recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN) overexpresses αvß5 integrin. Cilengitide selectively inhibits αvß3 and αvß5 integrins and is investigated as a treatment strategy. PATIENTS AND METHODS: The phase I/II study ADVANTAGE evaluated cilengitide combined with cisplatin, 5-fluorouracil, and cetuximab (PFE) in R/M-SCCHN. The phase II part reported here was an open-label, randomized, controlled trial investigating progression-free survival (PFS). Patients received up to six cycles of PFE alone or combined with cilengitide 2000 mg once (CIL1W) or twice (CIL2W) weekly. Thereafter, patients received maintenance therapy (cilengitide arms: cilengitide plus cetuximab; PFE-alone arm: cetuximab only) until disease progression or unacceptable toxicity. RESULTS: One hundred and eighty-two patients were treated. Median PFS per investigator read was similar for CIL1W + PFE, CIL2W + PFE, and PFE alone (6.4, 5.6, and 5.7 months, respectively). Accordingly, median overall survival and objective response rates were not improved with cilengitide (12.4 months/47%, 10.6 months/27%, and 11.6 months/36%, respectively). No clinically meaningful safety differences were observed between groups. None of the tested biomarkers (expression of integrins, CD31, Ki-67, vascular endothelial growth factor receptor 2, vascular endothelial-cadherin, type IV collagen, epidermal growth factor receptor, or p16 for human papillomavirus) were predictive of outcome. CONCLUSION: Neither of the cilengitide-containing regimens demonstrated a PFS benefit over PFE alone in R/M-SCCHN patients.

A randomized, phase II study of afatinib versus cetuximab in metastatic or recurrent squamous cell carcinoma of the head and neck.

BACKGROUND: Afatinib is an oral, irreversible ErbB family blocker that has shown activity in epidermal growth factor receptor (EGFR)-mutated lung cancer. We hypothesized that the agent would have greater antitumor activity compared with cetuximab in recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients, whose disease has progressed after platinum-containing therapy. PATIENTS AND METHODS: An open-label, randomized, phase II trial was conducted in 43 centers; 124 patients were randomized (1 : 1) to either afatinib (50 mg/day) or cetuximab (250 mg/m(2)/week) until disease progression or intolerable adverse events (AEs) (stage I), with optional crossover (stage II). The primary end point was tumor shrinkage before crossover assessed by investigator (IR) and independent central review (ICR). RESULTS: A total of 121 patients were treated (61 afatinib, 60 cetuximab) and 68 crossed over to stage II (32 and 36 respectively). In stage I, mean tumor shrinkage by IR/ICR was 10.4%/16.6% with afatinib and 5.4%/10.1% with cetuximab (P = 0.46/0.30). Objective response rate was 16.1%/8.1% with afatinib and 6.5%/9.7% with cetuximab (IR/ICR). Comparable disease control rates were observed with afatinib (50%) and cetuximab (56.5%) by IR; similar results were seen by ICR. Most common grade ≥3 drug-related AEs (DRAEs) were rash/acne (18% versus 8.3%), diarrhea (14.8% versus 0%), and stomatitis/mucositis (11.5% versus 0%) with afatinib and cetuximab, respectively. Patients with DRAEs leading to treatment discontinuation were 23% with afatinib and 5% with cetuximab. In stage II, disease control rate (IR/ICR) was 38.9%/33.3% with afatinib and 18.8%/18.8% with cetuximab. CONCLUSION: Afatinib showed antitumor activity comparable to cetuximab in R/M HNSCC in this exploratory phase II trial, although more patients on afatinib discontinued treatment due to AEs. Sequential EGFR/ErbB treatment with afatinib and cetuximab provided sustained clinical benefit in patients after crossover, suggesting a lack of cross-resistance.

Role of GRB2-associated binder 1 in epidermal growth factor receptor-induced signaling in head and neck squamous cell carcinoma.

The epidermal growth factor receptor (EGFR) plays an important role in the pathogenesis of head and neck squamous cell carcinoma (HNSCC). Despite the high expression of EGFR in HNSCC, EGFR inhibitors have only limited success as monotherapy. The Grb2-associated binder (GAB) family of adaptor proteins acts as docking/scaffolding molecules downstream of tyrosine kinase receptors. We hypothesized that GAB1 may amplify EGFR-induced signaling in HNSCCs and therefore could play a role in the reduced sensitivity of HNSCC to EGFR inhibitors. We used representative human HNSCC cell lines overexpressing wild type EGFR, and expressing GAB1 but not GAB2. We demonstrated that baseline Akt and MAPK signaling were reduced in HNSCC cells in which GAB1 expression was reduced. Furthermore, the maximal EGF-induced activation of the Akt and MAPK pathway was reduced and delayed, and the duration of the EGF-induced activation of these pathways was reduced in cells with GAB1 knock-down. In agreement with this, HNSCC cells in which GAB1 levels were reduced showed an increased sensitivity to the EGFR inhibitor gefitinib. Our work demonstrates that GAB1 plays an important role as part of the mechanism of by which EGFR induces induced activation of the MAPK and AKT pathway. Our results identify GAB1 as an amplifier of the EGFR-initiated signaling, which may also interfere with EGFR degradation. These findings support the emerging notion that reducing GAB1 function may sensitize HNSCC to EGFR inhibitors, hence representing a new therapeutic target HNSCC treatment in combination with EGFR targeting agents.

Defining pseudoprogression in glioblastoma multiforme.

BACKGROUND AND PURPOSE: Pseudoprogression is a frequent phenomenon observed since the introduction of postoperative therapy with radiotherapy and temozolomide (RT/TMZ) in glioblastoma multiforme (GBM) patients. However, the criteria defining pseudoprogression, its incidence, the time of occurrence and its impact on therapy and outcome remain poorly defined. METHODS: The objective of this study is to compare two sets of criteria (liberal and stringent), defining pseudoprogression, in a cohort of patients treated before and after the introduction of RT/TMZ in the standard postoperative treatment. This retrospective review includes 136 unselected and consecutively treated patients with pathologically diagnosed GBM. RESULTS: Pseudoprogression was observed in 10 (12%) cases applying the stringent criteria, and in 18 (23%) patients when using the liberal criteria, in the cohort treated with RT/TMZ. Pseudoprogression was observed in only one patient treated with RT alone. The median time to pseudoprogression was 4 weeks after the end of RT. Patients with pseudoprogression had a median survival time of 28 months, compared with 12 months for patients without pseudoprogression. CONCLUSIONS: The incidence of pseudoprogression after RT/TMZ strongly depends on the applied criteria. However, regardless of the stringency of the criteria, the impact on survival remains the same.

Cyclophosphamide, doxorubicin, and cisplatin in advanced salivary gland cancer.

OBJECTIVES: Advanced salivary gland cancer is a rare disease that comprises different histopathological tumour types; correspondingly, data on palliative systemic treatment are scarce. Combination chemotherapy with cyclophosphamide, doxorubicin, and cisplatin (CAP) has been reported to induce a reasonable response rate, although fewer than 100 cases have been described. We conducted a retrospective review of advanced salivary gland cancer patients treated with CAP. METHODOLOGY: Fifteen consecutive patients with recurrent, locally advanced, or metastatic progressive salivary gland cancer treated with CAP were identified over a five-year period. The mean age at start of treatment was 53.5 years, and the male/female ratio was 11/4. The most common histological subtypes were adenoid cystic carcinoma and adenocarcinoma not otherwise specified (NOS), with the parotid gland as the most frequently affected anatomical site. RESULTS: A response rate of 60% was achieved, with one complete and eight partial responses and six stable diseases according to RECIST criteria. No patient progressed under treatment. An average of 5.4 treatment cycles were administered; median time to progression after ending CAP was 6.6 months, and median overall survival was 15.1 months. Patients with adenocarcinoma NOS appeared to benefit more than patients with adenoid cystic carcinoma, but had a shorter time to progression. Except for neutropenia with neutropenic fever and alopecia, no NCI-CTC grade III or IV toxicity was observed. CONCLUSION: This retrospective study confirms the clinically meaningful efficacy of CAP in advanced adenocarcinomas NOS of the salivary gland in routine practice, with acceptable safety levels.

Salvage Transoral Laser Microsurgery for Radiorecurrent Laryngeal Cancer: Indications, Limits, and Outcomes.

PURPOSE OF REVIEW: The aim of this report is to identify relevant literature reports on salvage transoral laser microsurgery (TLM); to consider its oncologic and functional outcomes, as well as reported complications; and to address indications and limitations of salvage TLM. FINDINGS: The weighted average of local control after first salvage TLM was 57%. Repeated TLM procedures for second or third recurrences were required in up to 41% of cases, resulting in a weighted average of local control with TLM alone of 67%. The rate of definite laryngeal preservation was 73%. The ultimate local control rate, including cases that required total laryngectomy, was 90%. The overall complication rate after salvage TLM was 14%. SUMMARY: Salvage TLM of radiorecurrent laryngeal cancer yields excellent oncologic outcomes. Serious complications are scarce, hospitalization times are short, and functional outcomes in terms of voice and swallowing are favorable when compared to open conservation laryngeal surgery. The key to success is an optimal patient selection.

Pain management in palliative cancer patients: a prospective observational study on the use of high dosages of transdermal buprenorphine.

INTRODUCTION: Despite guidelines and recommendations, a large proportion of patients with cancer still have inadequate pain control. Transdermal opioid administration can overcome problems such as swallowing and compliance, because only one application every three days is needed. Transdermal buprenorphine was documented to provide effective pain relief in cancer and non-cancer patients. A ceiling effect was described in animals at supratherapeutic dose levels. OBJECTIVES: This prospective observational pilot study was designed to explore the need for doses of transdermal buprenorphine beyond the recommended maximum dose of 140 microg/h, in a cohort of palliative patients with cancer pain. METHODS: 36 consecutive palliative patients with uncontrolled cancer pain were prescribed transdermal buprenorphine after having received adequate information on the disease, its evolution, the pain and the drug. They gave written informed consent for participation in this observational study. Pain intensity and use of breakthrough medication were registered by the patient and the health care provider. RESULTS: Pain was judged to be satisfactory controlled, by the patient and the health care providers, in 21 of 28 evaluable patients at a dose lower than or equal to 140 microg/h. The success rate was higher in the hospitalized patient group. The observation of adequate pain control in two patients treated with doses up to 210 microg/h supports the hypothesis that buprenorphine dose titration above 140 microg/h can be clinically effective and well tolerated. This also refutes the assumption of a clinically relevant ceiling effect. CONCLUSIONS: Transdermal buprenorphine control cancer pain in the majority of palliative patients.

A case series of embryonal rhabdomyosarcoma of the head and neck in adults.

Embryonal rhabdomyosarcoma (RMS) is a rare malignant mesenchymal tumour that is believed to arise from cells committed to a skeletal muscle lineage. The head and neck region is among the most frequent locations for embryonal RMS in adults. We present a retrospective review of seven patients treated in our institution between 2000 and 2008. The age at diagnosis ranged from 19 to 41 years. One patient received primary surgery followed by adjuvant radiotherapy. Six inoperable patients were treated along a single chemotherapy protocol: the VIA-VIP regimen (a combination of vincristine, ifosfamide and doxorubicin (VIA) in alternation with etoposide, ifosfamide and cisplatin (VIP) administered in 3-weekly cycles), followed by local therapy, involving radiation therapy and/or surgery. An objective response to chemotherapy was observed in all six patients. Three out of seven patients remain disease-free with a median follow up of 4.5 years. Although the prognosis of head and neck embryonal RMS is worse in adults than in children, a multimodality treatment combining surgery, radiotherapy and intensive chemotherapy is feasible and effective in this population.