Direct Integration of 3D Printing and Cryogel Scaffolds for Bone Tissue Engineering.

Cryogels, known for their biocompatibility and porous structure, lack mechanical strength, while 3D-printed scaffolds have excellent mechanical properties but limited porosity resolution. By combining a 3D-printed plastic gyroid lattice scaffold with a chitosan-gelatin cryogel scaffold, a scaffold can be created that balances the advantages of both fabrication methods. This study compared the pore diameter, swelling potential, mechanical characteristics, and cellular infiltration capability of combined scaffolds and control cryogels. The incorporation of the 3D-printed lattice demonstrated patient-specific geometry capabilities and significantly improved mechanical strength compared to the control cryogel. The combined scaffolds exhibited similar porosity and relative swelling ratio to the control cryogels. However, they had reduced elasticity, reduced absolute swelling capacity, and are potentially cytotoxic, which may affect their performance. This paper presents a novel approach to combine two scaffold types to retain the advantages of each scaffold type while mitigating their shortcomings.

Randomized Phase II Trial Comparing Bevacizumab Plus Carboplatin and Paclitaxel With Carboplatin and Paclitaxel Alone in Previously Untreated Locally Advanced or Metastatic Non-Small-Cell Lung Cancer.

PURPOSE: To investigate the efficacy and safety of bevacizumab plus carboplatin and paclitaxel in patients with advanced or recurrent non-small-cell lung cancer. PATIENTS AND METHODS: In a phase II trial, 99 patients were randomly assigned to bevacizumab 7.5 (n = 32) or 15 mg/kg (n = 35) plus carboplatin (area under the curve = 6) and paclitaxel (200 mg/m2) every 3 weeks or carboplatin and paclitaxel alone (n = 32). Primary efficacy end points were time to disease progression and best confirmed response rate. On disease progression, patients in the control arm had the option to receive single-agent bevacizumab 15 mg/kg every 3 weeks. RESULTS: Compared with the control arm, treatment with carboplatin and paclitaxel plus bevacizumab (15 mg/kg) resulted in a higher response rate (31.5% v 18.8%), longer median time to progression (7.4 v 4.2 months) and a modest increase in survival (17.7 v 14.9 months). Of the 19 control patients that crossed over to single-agent bevacizumab, five experienced stable disease, and 1-year survival was 47%. Bleeding was the most prominent adverse event and was manifested in two distinct clinical patterns; minor mucocutaneous hemorrhage and major hemoptysis. Major hemoptysis was associated with squamous cell histology, tumor necrosis and cavitation, and disease location close to major blood vessels. CONCLUSION: Bevacizumab in combination with carboplatin and paclitaxel improved overall response and time to progression in patients with advanced or recurrent non-small-cell lung cancer. Patients with nonsquamous cell histology appear to be a subpopulation with improved outcome and acceptable safety risks.

A Rare Presentation of Intraosseous Sarcoidosis of the Mandible Presenting as Peri-Implantitis: A Case Report and Literature Review.

We describe a rare case of intraosseous sarcoidosis initially presenting as peri-implantitis, perform a review and analysis of 27 cases of intraosseous sarcoidosis, and provide a clinical review of this condition. We searched the literature for patients presenting with intraosseous sarcoidosis of the jaw through June 2020 using key phrases. Additional papers were included via a search of references and citing papers. Data including patient demographic characteristics and diagnostic tests were manually extracted from the cases and then qualitatively coded by the authors. Descriptive statistical analysis was performed to elucidate general themes and characteristics. A total of 27 cases, dating as early as 1943 and as recent as this case, were identified in the literature, including our case. The average age of these patients was 39 years old, with a range of 16 to 75 years. Eighteen (67%) cases were identified as female and nine (33%) as male. Fourteen cases were reported with localized mandibular involvement. Ten had maxillary disease; 3 cases were generalized to both regions. Nine cases presented anteriorly, 12 posteriorly, and 6 extended across both regions. Eight patients received surgical interventions, such as tooth extractions or lesion removal. Five patients received nonsurgical interventions, such as steroids. Ten patients received combination therapy, often involving surgical intervention and steroid therapy. Our patient had an unusual presentation of intraosseous sarcoidosis mimicking peri-implantitis. To our knowledge, no case in the English literature describes a patient with sarcoidosis presenting with peri-implantitis. Based on the literature review and analysis of our patient's experience, sarcoidosis should be considered on the differential diagnosis for patients with persistent, nonhealing bony lesions in the maxillofacial region, particularly when patients have not been exposed to osteoclast inhibitory therapy or radiation. Pathologic analysis of bone and surrounding tissue in these scenarios is essential.

Penetrating Midface Trauma: A Case Report, Review of the Literature, and a Diagnostic and Management Protocol.

PURPOSE: Penetrating facial trauma is an uncommon injury, but patients who present with these dramatic situations require special consideration. We describe the case of a young man who had been shot with an arrow that deeply penetrated his midface as well as report the results of a literature review of penetrating midface injuries. The information gathered was used to create a diagnostic protocol for patients who sustain such injuries. METHODS: A PubMed search up to October 2019 using several key phrases was performed, and 623 unique articles were evaluated. Excluding firearm injuries to the midface, there were 57 unique cases that involved penetrating midface injuries. Clinical and imaging data were compiled and evaluated with descriptive statistical analysis. RESULTS: The average patient age was 27 years, with a male predilection. The most common reported etiology was accidental trauma (54%), and a knife was the most common weapon of injury (30%). The most common (32%) specific location of trauma was within the orbital region, including the canthus or the eyelid. In all cases where the patient had not died immediately, surgery was used to remove the penetrating object. We found that computed tomography was the most commonly obtained imaging study (39% of cases). Radiographs were the sole imaging in 28% of the cases, with angiography (16%) and magnetic resonance imaging (10%) used less frequently in management. In 28% of the cases, deep structures, such as the carotid artery, sphenoid sinus, or skull base, were involved in the injury. In 25% of the cases, there was injury to the central nervous system. Death occurred in 8.8% of the cases. Postoperative complications occurred in at least 21% of the cases. Statistical analysis also revealed a significant correlation between antibiotic use and full recovery. Penetration of the object posterior to the maxillary sinus was correlated with incomplete recovery or death. CONCLUSIONS: Based on all case reports collected, a Dartmouth Penetrating Midface Protocol was developed to aid the practitioner who may happen to be responsible for these dramatic life-threatening injuries. The Dartmouth Penetrating Midface Protocol is based on the type of imaging available at the treating facility, the neurologic and hemodynamic stability of the patient, and the depth of penetration beyond the posterior wall of the maxillary sinus.

A Phase III study of zanubrutinib plus rituximab versus bendamustine plus rituximab in transplant-ineligible, untreated mantle cell lymphoma.

Mantle cell lymphoma is an aggressive B-cell malignancy. Current frontline chemoimmunotherapies produce high response rates but relapse is inevitable. Furthermore, the elderly and those with comorbidities are precluded from standard regimens and stem cell transplant, leaving them with limited options. Targeted therapies, including Bruton tyrosine kinase inhibitors, are an effective treatment strategy in mantle cell lymphoma. Zanubrutinib is a potent next-generation Bruton tyrosine kinase inhibitor that has demonstrated complete and sustained Bruton tyrosine kinase occupancy, minimal off-target effects and favorable pharmacokinetic/pharmacodynamic properties. Described herein is an ongoing Phase III study comparing the efficacy and safety of zanubrutinib plus rituximab followed by zanubrutinib monotherapy versus bendamustine plus rituximab followed by observation in transplant-ineligible patients with previously untreated mantle cell lymphoma. Clinical Trial Registration: NCT04002297 (ClinicalTrials.gov).

Zanubrutinib for the treatment of patients with Waldenström macroglobulinemia: 3 years of follow-up.

Inhibitors of Bruton's tyrosine kinase (BTK) have established therapeutic activity in patients with Waldenström macroglobulinemia (WM). Zanubrutinib, a potent and selective BTK inhibitor, was evaluated in a phase 1/2 study in patients with WM who were either treatment-naïve (TN) or had relapsed/refractory (R/R) disease. Patients had disease requiring treatment per International Workshop on Waldenström Macroglobulinemia (IWWM) criteria. Treatment was 160 mg of oral zanubrutinib twice daily (n = 50) or 320 mg once daily (n = 23). Efficacy endpoints included overall response rate (ORR) and very good partial response/complete response (VGPR/CR) rates per IWWM-6 criteria (with modification of VGPR definition published previously). Between September 2014 and March 2018, 77 patients (24 TN and 53 R/R) began treatment. At a median follow-up of 36.0 months for patients with R/R disease and 23.5 months for TN, 72.7% remained on treatment. Reasons for treatment discontinuation included any adverse events in 13.0% of patients (1 treatment related), disease progression (10.4%), and other (3.9%). The ORR was 95.9%, and the VGPR/CR rate was 45.2%, which increased over time: 20.5% at 6 months, 32.9% at 12 months, and 43.8% at 24 months. Estimated 3-year progression-free survival rate was 80.5%, and overall survival rate was 84.8%. Adverse events of interest included contusion (32.5%, all grade 1), neutropenia (18.2%), major hemorrhage (3.9%), atrial fibrillation/flutter (5.2%), and grade 3 diarrhea (2.6%). Long-term treatment with single-agent zanubrutinib resulted in deep and durable responses in some patients with WM. The safety profile of long-term zanubrutinib therapy in these patients was acceptable. This trial was registered at www.clinicaltrials.gov as #NCT02343120.

An Anatomic Predisposition to Mandibular Angle Fractures.

PURPOSE: To investigate a predisposition to mandibular angle fractures, a retrospective study was performed in which fractured mandibles were compared with healthy mandibles with no history of fracture. Other investigations of angle fracture risk have exclusively studied patients with existing fractures. In addition, the risk has not been comprehensively explained in conjunction with the specific features of mandibular anatomy. We sought to characterize any anatomic variations between the jaws that had fractured and those that had never fractured. MATERIALS AND METHODS: Healthy mandibles with no history of fracture were physically measured at the William M. Bass Skeletal Collection at the University of Tennessee, Knoxville and compared with fractured mandibles from computed tomography (CT) scans at the Dartmouth Hitchcock Medical Center. A total of 52 healthy mandibles and 44 CT scans were evaluated. MATLAB machine learning algorithms (MathWorks, Natick, MA) were used to compare the study populations and isolate those anatomic features that differed between healthy and fractured mandibles. RESULTS: Machine learning classifiers were able to differentiate between male and female jaws, with the condylion-gnathion distance the most distinguishing feature. The 6 most common anatomic features that differed between healthy and fractured mandibles were the 1) retromolar space, 2) perimeter of the cross-section just proximal to the second molar, 3) breadth of the ramal cross-section, 4) thickness of the oblique ridge, 5) transgonial angle, and 6) location of the ipsilateral mental foramen. The presence of third molars was also related to fracture risk, with third molars present in 72.7% of the fractured mandibles versus 26.9% of unfractured mandibles. Of the fractured mandibles with third molars present, 87.5% had the fracture running directly through the tooth or its socket. CONCLUSIONS: The results from the present study have provided evidence that anatomic differences exist between mandibles that sustain angle fractures and those that do not. Although much of the morphology was found to be interdependent, the fracture risk could be accurately predicted using 6 anatomic features. Understanding these mandibular variations and identifying patients vulnerable to mandibular fracture could provide clinicians with additional objective information. Furthermore, using the methods demonstrated in our study, future research could focus on developing an algorithm that includes these unique anatomic features in the hope of assisting surgeons in providing tailored treatment for mandibular angle fractures according to patient-specific morphology.

Crystal structures and rotational dynamics of a two-dimensional metal halide perovskite (OA)2PbI4.

The extended charge carrier lifetime in metal halide perovskites is responsible for their excellent optoelectronic properties. Recent studies indicate that the superb device performance in these materials is intimately related to the organic cation dynamics. Here, we focus on the investigation of the two-dimensional hybrid perovskite, (C8H17NH3)2PbI4 (henceforth, OA+ = C8H17NH3 +). Using elastic and quasielastic neutron scattering techniques and group theoretical analysis, we studied the structural phase transitions and rotational modes of the C8H17NH3 + cation in (OA)2PbI4. Our results show that, in the high-temperature orthorhombic (T > 310 K) phase, the OA+ cation exhibits a combination of a twofold rotation of the NH3-CH2 head group about the crystal c-axis with a characteristic relaxation time of ∼6.2 ps, threefold rotations (C3) of NH3 and CH3 terminal groups, and slow librations of the other atoms. Contrastingly, only the C3 rotation is present in the intermediate-temperature orthorhombic (238 K < T < 310 K) and low-temperature monoclinic (T < 238 K) phases.

A randomized phase II trial of nab-paclitaxel and gemcitabine with tarextumab or placebo in patients with untreated metastatic pancreatic cancer.

PURPOSE: Notch signaling dysregulation is implicated in the development of pancreatic adenocarcinoma (PDAC). Tarextumab is a fully human IgG2 antibody that inhibits Notch2/3 receptors. PATIENTS AND METHODS: Aphase 2, randomized, placebo-controlled, multicenter trial evaluated the activity of tarextumab in combination with nab-paclitaxel and gemcitabine in patients with metastatic PDAC. Patients were stratified based on ECOG performance score and Ca 19-9 level and randomized 1:1 to nab-paclitaxel, gemcitabine with either tarextumab or placebo. Based on preclinical and phase Ib results suggesting a positive correlation between Notch3 gene expression and tarextumab anti-tumor activity, patients were also divided into subgroups of low, intermediate, and high Notch3 gene expression. Primary endpoint was overall survival (OS) in all and in patients with the three Notch3 gene expression subgroups (≥25th, ≥50% and ≥75% percentiles); secondary end points included progression-free survival (PFS), 12-month OS, overall response rate (ORR), and safety and biomarker investigation. RESULTS: Median OS was 6.4 months in the tarextumab group vs 7.9 months in the placebo group (HR = 1.34 [95% CI = 0.95, 1.89], P = .0985). No difference observed in OS in the Notch3 gene expression subgroups. PFS in the tarextumab-treated group (3.7 months) was significantly shorter compared with the placebo group (5.5 months) (hazard ratio was 1.43 [95% CI = 1.01, 2.01]; P = .04). Grade 3 diarrhea and thrombocytopenia were more common in the tarextumab group. CONCLUSIONS: The addition of tarextumab to nab-paclitaxel and gemcitabine did not improve OS, PFS, or ORR in first-line metastatic PDAC, and PFS was specifically statistically worse in the tarextumab-treated patients. CLINICAL TRIAL REGISTRY NO: NCT01647828.

A Rare Case of Odontogenic Chronic Suppurative Otitis Media.

Common causes of chronic suppurative otitis media (CSOM) include persistence of acute otitis media, cholesteatoma, and eustachian tube dysfunction. We describe a patient who presented with CSOM of several years duration refractory to medical management. Ultimately, a dental abscess was found on computed tomography (CT) to be the source of concurrent ipsilateral maxillary sinusitis and mastoiditis. Extraction of the molar abscess resulted in complete resolution of her CSOM and need to be on antibiotics. To our knowledge, this is the first report of an odontogenic cause of chronic suppurative otitis media.

The application of group sequential stopping boundaries to evaluate the treatment effect of an experimental agent across a range of biomarker expression.

Using stopping boundaries developed for group sequential trials, we control the overall type 1 error for a series of tests that evaluate the treatment effect of an experimental agent in each of several predefined marker subgroups. We then go on to present a procedure based on these group sequential stopping boundaries that provides strong control of type 1 error for testing a series of hypothesis regarding the treatment effect over a range of marker expression. Finally this use of group sequential procedures to control the type 1 error in biomarker subset testing will be compared with some other benchmark procedures in a simulation.

Chemical Identification at the Solid-Liquid Interface.

Solid-liquid interfaces are decisive for a wide range of natural and technological processes, including fields as diverse as geochemistry and environmental science as well as catalysis and corrosion protection. Dynamic atomic force microscopy nowadays provides unparalleled structural insights into solid-liquid interfaces, including the solvation structure above the surface. In contrast, chemical identification of individual interfacial atoms still remains a considerable challenge. So far, an identification of chemically alike atoms in a surface alloy has only been demonstrated under well-controlled ultrahigh vacuum conditions. In liquids, the recent advent of three-dimensional force mapping has opened the potential to discriminate between anionic and cationic surface species. However, a full chemical identification will also include the far more challenging situation of alike interfacial atoms (i.e., with the same net charge). Here we demonstrate the chemical identification capabilities of dynamic atomic force microscopy at solid-liquid interfaces by identifying Ca and Mg cations at the dolomite-water interface. Analyzing site-specific vertical positions of hydration layers and comparing them with molecular dynamics simulations unambiguously unravels the minute but decisive difference in ion hydration and provides a clear means for telling calcium and magnesium ions apart. Our work, thus, demonstrates the chemical identification capabilities of dynamic AFM at the solid-liquid interface.

Independent adjudication of symptomatic heart failure with the use of doxorubicin and cyclophosphamide followed by trastuzumab adjuvant therapy: a combined review of cardiac data from the National Surgical Adjuvant breast and Bowel Project B-31 and the North Central Cancer Treatment Group N9831 clinical trials.

PURPOSE: An independent Adjuvant Cardiac Review and Evaluation Committee (ACREC) systematically reviewed cases of symptomatic heart failure events to uniformly define the cardiac event rate across two large trials (National Surgical Adjuvant Breast and Bowel Project [NSABP] B-31 and North Central Cancer Treatment Group [NCCTG] N9831) that assessed the addition of trastuzumab to standard adjuvant chemotherapy. PATIENTS AND METHODS: The committee was composed of six independent oncologists and cardiologists. A retrospective review of patients with a cardiac event was performed by the primary investigators of the trials. The ACREC prospectively established criteria for determining a symptomatic heart failure event. Recovery status was determined from documented resolution of signs and symptoms. Potential risk factors were also assessed. RESULTS: Medical records for a total of 173 patients were reviewed: 40 in the chemotherapy-alone arm and 133 in the trastuzumab arm. Trastuzumab-treated patients had a 2.0% incidence of symptomatic heart failure events compared with 0.45% in the chemotherapy-alone arm. Complete or partial recovery was observed in 86.1% of trastuzumab-treated patients with symptomatic heart failure events. Of five patients who died, only one patient had received trastuzumab. Independent predictors for cardiac events were age older than 50 years, a low ejection fraction at the start of paclitaxel treatment, and trastuzumab treatment. CONCLUSION: The incidence of symptomatic heart failure events is 2.0% in patients treated with adjuvant trastuzumab, and the majority of these patients recover with appropriate treatment.

Health-related quality of life impact of bevacizumab when combined with irinotecan, 5-fluorouracil, and leucovorin or 5-fluorouracil and leucovorin for metastatic colorectal cancer.

PURPOSE: To compare the time to deterioration in health-related quality of life (HRQoL) in patients with previously untreated metastatic colorectal cancer receiving a 5-fluorouracil (5-FU)-based chemotherapy regimen with or without the addition of bevacizumab (BV) in two randomized, placebo-controlled studies. PATIENTS AND METHODS: Prespecified HRQoL endpoints in the phase II (Study 2192) and phase III (Study 2107) studies were time to deterioration in HRQoL, measured by the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) Colorectal Cancer Subscale (CCS), Trial Outcome Index (TOI-C), and FACT-C total score. Time to deterioration in HRQoL was evaluated for patients with baseline and postbaseline assessments, using the stratified log-rank test. RESULTS: In the pivotal phase III trial, HRQoL baseline and postbaseline CCS scores were available for 127 patients receiving irinotecan, 5-FU, and leucovorin (LV) (IFL) and 122 patients receiving IFL plus BV. The time to deterioration in HRQoL did not differ significantly between treatment groups as measured by the CCS, TOI-C, or FACT-C total score. In the phase II study, baseline and postbaseline CCS scores were available for 77 and 89 patients receiving 5-FU and LV and 5-FU and LV plus BV, respectively. In that study, the time to deterioration in HRQoL was similar between groups as measured by the CCS and TOI-C scores, but was significantly longer in the 5-FU and LV plus BV arm than in the 5-FU and LV plus placebo arm for the FACT-C total score. CONCLUSIONS: When added to 5-FU chemotherapy, BV significantly prolonged overall survival and progression-free survival without compromising HRQoL.

Quantifying the usefulness of PD biomarkers in Phase 2 screening trials of oncology drugs.

This paper develops a framework for evaluating the usefulness of a PD biomarker as a primary endpoint in a Phase 2 screening trial of an oncology drug. We judge the contribution of the PD biomarker by assessing its impact on the efficiency of the drug development process. 'Efficiency' is defined as the probability that an active drug is found to be effective in Phase 3 divided by the sum of the expected number of events in Phase 3 and the pre-Phase 2 drug development costs appropriately normalized. We show that 20 Phase 2 trials of different experimental treatments can provide a reasonable answer as to whether a PD biomarker makes a positive or negative contribution to the drug development process.

Are Phase 2 screening trials in oncology obsolete?

Phase 2 studies in Oncology are controversial because on the one hand they are substantially underpowered for making assessments of activity and on the other hand they are used as a screen to determine whether a Phase 3 trial is warranted. In this paper, we undertake a systematic assessment of the properties of a Phase 2 study in the context of a drug development program. We will show that, when considering only the efficiency of a clinical trials program, Phase 2 screening trials can substantially increase the efficiency with which drugs that provide clinical benefit are identified. However, if there are substantial costs in identifying drug candidates to test in clinical trials as there are today, then Phase 2 screening trials as a prelude to Phase 3 trials may reduce the efficiency of the drug development process as a whole. .

Utilization of tracheostomy in craniomaxillofacial trauma at a level-1 trauma center.

PURPOSE: The decision to perform a tracheostomy on patients with maxillofacial trauma is complex. There is little data exploring the role of tracheostomy in facial fracture management. We sought to profile the utilization of tracheostomy in the context of maxillofacial trauma at our institution by comparing patients who required tracheostomy with and without facial fractures versus those with facial fractures not requiring tracheostomy. MATERIALS AND METHODS: All patients admitted to the Trauma Service at Legacy Emanuel Hospital and Health Center (LEHHC), Portland, OR, from 1993 to 2003 that sustained facial fractures or underwent tracheostomy were identified and data were retrospectively reviewed using patient charts and the trauma registry. Variables such as age, gender, death, injury severity score (ISS), facial injury severity score (FISS), Glasgow coma score (GCS), intensive care days (ICU), hospital length of stay (LOS), facial fracture profile, and oral and maxillofacial surgery (OMFS) operative intervention were tabulated and analyzed. Data were divided into 3 groups for comparison: group 1 (ffxT) consisted of patients who underwent a tracheostomy procedure and repair of their facial fracture during the SAME operation by the OMFS department (N = 125); group 2 (ffxNT) were those patients who had repair of their facial fractures by OMFS and did not require a tracheostomy (N = 224); and group 3 (NffxT) were patients who did not have facial fractures but received a tracheostomy during their hospitalization (N = 259). Ten-year data were used to analyze the ffxT and 5-year data were used to analyze the ffxNT and NffxT. Analysis of variance and chi2 testing was used for statistical analysis. RESULTS: A total of 18,187 patients were admitted to the trauma LEHHC Trauma Service during the study period, of which 1,079 (5.9%) patients sustained facial fractures and 788 (4.3%) required a tracheostomy. One hundred twenty-five patients (0.69% of total; 11.6% of facial fracture) received a tracheostomy at the same time as the facial fracture repair. All patients had their facial fractures successfully managed, regardless of the type of method used to stabilize the airway. There were no known cases of tracheal stenosis, severe bleeding requiring a return to the operating room, airway obstruction, or loss of secured airway. Males were the predominate gender in all 3 groups. The NffxT group (mean, 44.9 years) was much older compared with the ffxT (mean, 36.2 years) and ffxNT (mean, 30.9 years) groups. The incidence of death was higher in the tracheostomy groups compared with 0% with the non-tracheostomy group. The ffxNT group had a statistically significant higher GCS with an average of 12.4 when compared with the tracheostomy groups (ffxT = 6.8; NffxT = 6.7). ISS was nearly the same in the tracheostomy group (ffxT = 28.45; NffxT = 30.04), but higher when compared with the ffxNT (ISS = 17.33). All 3 groups were much different in terms of LOS and ICU days, in which the NffxT group had an average hospital LOS and ICU days of 34.4 and 16.56, respectively. This was higher when compared with the ffxT (LOS = 19.71 days; ICU = 7.21 days) and ffxNT (LOS = 6.82 days; ICU = 1.33 days) groups. The FISS averaged 6.22 in the ffxT group and was higher compared with an FISS of 3.16 in the ffxNT group. Overall, the fracture profile was different between the tracheostomy and non-tracheostomy groups. There was a higher prevalence of mandibular fractures, multiple mandibular fractures, and Le Fort III fractures in the ffxT group compared with the ffxNT group. CONCLUSION: Tracheostomy is commonly performed in the context of multisystem trauma and is a safe method for airway stabilization in patients with craniomaxillofacial trauma. Multi-institutional collaboration and a prospective, randomized trial measuring outcome, resource utilization, and length of ICU stay is necessary to determine if tracheostomy is indeed of measurable benefit to patients with complex injuries.

Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab.

BACKGROUND: Although combination treatment with bevacizumab (humanized monoclonal antibody against vascular endothelial growth factor) and chemotherapy improves survival of patients with various metastatic carcinomas, an increased risk of arterial thromboembolic events has been observed in some trials. We characterized this risk by performing post hoc analyses of randomized controlled trials that evaluated combination treatment with bevacizumab and chemotherapy versus chemotherapy alone. Low-dose aspirin was permitted in these trials, and its safety was also analyzed. METHODS: Data were pooled from five randomized controlled trials that included a total of 1745 patients with metastatic colorectal, breast, or non-small-cell lung carcinoma. The risk of an arterial or venous thromboembolic event was assessed by simple incidence rates, rates per 100 person-years, and/or hazard ratios (HRs). The association between patient characteristics and risk of an arterial thromboembolic event was investigated primarily by Cox proportional hazards regression. The relationship between low-dose aspirin and bleeding was explored by incidence rates and rates per 100 person-years. RESULTS: Combined treatment with bevacizumab and chemotherapy, compared with chemotherapy alone, was associated with increased risk for an arterial thromboembolic event (HR = 2.0, 95% confidence interval [CI] = 1.05 to 3.75; P = .031) but not for a venous thromboembolic event (HR = 0.89, 95% CI = 0.66 to 1.20; P = .44). The absolute rate of developing an arterial thromboembolism was 5.5 events per 100 person-years for those receiving combination therapy and 3.1 events per 100 person-years for those receiving chemotherapy alone (ratio = 1.8, 95% CI = 0.94 to 3.33; P = .076). Development of an arterial thromboembolic event was associated with a prior arterial thromboembolic event (P<.001) or age of 65 years or older (P = .01). Baseline or on-study aspirin use was associated with modest increases in grade 3 and 4 bleeding events in both treatment groups, from 3.6% to 4.7% for bevacizumab-treated patients and from 1.7% to 2.2% for control subjects. CONCLUSIONS: Combination treatment with bevacizumab and chemotherapy, compared with chemotherapy alone, was associated with an increased risk of arterial thromboembolism but not venous thromboembolism.

An adaptive Simon Two-Stage Design for Phase 2 studies of targeted therapies.

The field of specialized medicine and clinical development programs for targeted cancer therapies are rapidly expanding. The proposed Phase 2 design allows for preliminary determination of efficacy that may be restricted to a particular sub-population defined by biomarker status (presence/absence). The design is an adaptation of the Simon Two-Stage Design. We provide examples where the adaptation can result in substantial savings in sample size and thus potentially lead to greater efficiency in decision making during the drug development process.

Endpoints for agents that slow tumor growth.

The endpoints of confirmed response and progression are widely used in oncology clinical trials. These endpoints originated at a time when agents used to treat cancer were primarily cytotoxic. Increasingly agents that are cytostatic are being investigated in combination with agents that are cytotoxic. Since tumor growth rates often depend on the volume of the tumor, combining cytotoxic agents that reduce tumor volume with cytostatic agents may mask the activity of the cytostatic agent. This paper explores the sensitivity of time to progression/progression free survival (TTP/PFS) as an endpoint for evaluating the efficacy of cytostatic drugs when combined with cytotoxic agents. Mathematical models of tumor growth are used to describe tumor growth over time. The models account for the impact of chemotherapy and an agent that slows tumor growth in the context of the Gompertzian growth kinetics. We use a clinical trial of an angiogenesis inhibitor in metastatic breast cancer as a motivating example. We demonstrate that the endpoint TTP/PFS may not be sensitive to the effects of active cytostatic agents when they are combined with chemotherapy, and measuring time to regrowth would be more sensitive to the activity of a cytostatic agent. We conclude that an active cytostatic agent may not appear effective when combined with chemotherapy and evaluated with TTP/PFS in a clinical trial.