Alveolar Differentiation Drives Resistance to KRAS Inhibition in Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD), commonly driven by KRAS mutations, is responsible for 7% of all cancer mortality. The first allele-specific KRAS inhibitors were recently approved in LUAD, but the clinical benefit is limited by intrinsic and acquired resistance. LUAD predominantly arises from alveolar type 2 (AT2) cells, which function as facultative alveolar stem cells by self-renewing and replacing alveolar type 1 (AT1) cells. Using genetically engineered mouse models, patient-derived xenografts, and patient samples, we found inhibition of KRAS promotes transition to a quiescent AT1-like cancer cell state in LUAD tumors. Similarly, suppressing Kras induced AT1 differentiation of wild-type AT2 cells upon lung injury. The AT1-like LUAD cells exhibited high growth and differentiation potential upon treatment cessation, whereas ablation of the AT1-like cells robustly improved treatment response to KRAS inhibitors. Our results uncover an unexpected role for KRAS in promoting intratumoral heterogeneity and suggest that targeting alveolar differentiation may augment KRAS-targeted therapies in LUAD. SIGNIFICANCE: Treatment resistance limits response to KRAS inhibitors in LUAD patients. We find LUAD residual disease following KRAS targeting is composed of AT1-like cancer cells with the capacity to reignite tumorigenesis. Targeting the AT1-like cells augments responses to KRAS inhibition, elucidating a therapeutic strategy to overcome resistance to KRAS-targeted therapy. This article is featured in Selected Articles from This Issue, p. 201.

Alveolar differentiation drives resistance to KRAS inhibition in lung adenocarcinoma.

Lung adenocarcinoma (LUAD), commonly driven by KRAS mutations, is responsible for 7% of all cancer mortality. The first allele-specific KRAS inhibitors were recently approved in LUAD, but clinical benefit is limited by intrinsic and acquired resistance. LUAD predominantly arises from alveolar type 2 (AT2) cells, which function as facultative alveolar stem cells by self-renewing and replacing alveolar type 1 (AT1) cells. Using genetically engineered mouse models, patient-derived xenografts, and patient samples we found inhibition of KRAS promotes transition to a quiescent AT1-like cancer cell state in LUAD tumors. Similarly, suppressing Kras induced AT1 differentiation of wild-type AT2 cells upon lung injury. The AT1-like LUAD cells exhibited high growth and differentiation potential upon treatment cessation, whereas ablation of the AT1-like cells robustly improved treatment response to KRAS inhibitors. Our results uncover an unexpected role for KRAS in promoting intra-tumoral heterogeneity and suggest targeting alveolar differentiation may augment KRAS-targeted therapies in LUAD. Significance: Treatment resistance limits response to KRAS inhibitors in LUAD patients. We find LUAD residual disease following KRAS targeting is composed of AT1-like cancer cells with the capacity to reignite tumorigenesis. Targeting the AT1-like cells augments responses to KRAS inhibition, elucidating a therapeutic strategy to overcome resistance to KRAS-targeted therapy.

Prognostic Factors for Attempted Finger Replantation and Revascularisation after Traumatic Amputation: A 16-Year Retrospective Cohort Study.

Background: The aim of this study was to evaluate the impact of variant factors on finger replantation and revascularisation after traumatic amputation, which also included duty shift and the level of main operator. Methods: To determine the prognostic factors for the survival rate of finger replantation and revascularisation after traumatic finger amputation, we retrospectively reviewed the cases of finger replantation conducted from January 2001 to December 2017. Data collected consisted of the basic information of the patients, trauma-related factors, details of the operation and treatment outcomes. Descriptive statistics and data analysis was performed to assess outcomes. Results: In total, 150 patients with 198 replanted digits were enrolled in this study. The median age of the participants was 42.5 years, and 132 (88%) patients were men. The overall successful replantation rate was 86.4%. Seventy-three (36.9%) digits had Yamano type 1 injury; 110 (55.6%), Yamano type 2 injury and 15 (7.6%), Yamano type 3 injury. In total, 73 (36.9%) digits were completely amputated and 125 (63.1%) were not. Half of the replantation procedures (101, 51.0%) were performed during night shift (16:00-00:00), 69 (34.8%) during day shift (08:00-16:00) and 28 (14.1%) during graveyard shift (00:00-08:00). Multivariate logistic regression demonstrated that the trauma mechanism and type of amputation (complete vs. incomplete) significantly affect the survival rate of replantation. Conclusions: The trauma mechanism and type of amputation (complete vs. incomplete) significantly affect the survival rate of replantation. Other factors including duty shift and the level of operator did not reach statistically significance. Further studies must be conducted to validate the results of the current study. Level of Evidence: Level III (Prognostic).

Dihydroceramide desaturase 1 (DES1) promotes anchorage-independent survival downstream of HER2-driven glucose uptake and metabolism.

Oncogenic reprogramming of cellular metabolism is a hallmark of many cancers, but our mechanistic understanding of how such dysregulation is linked to tumor behavior remains poor. In this study, we have identified dihydroceramide desaturase (DES1)-which catalyzes the last step in de novo sphingolipid synthesis-as necessary for the acquisition of anchorage-independent survival (AIS), a key cancer enabling biology, and establish DES1 as a downstream effector of HER2-driven glucose uptake and metabolism. We further show that DES1 is sufficient to drive AIS and in vitro tumorigenicity and that increased DES1 levels-found in a third of HER2+ breast cancers-are associated with worse survival outcomes. Taken together, our findings reveal a novel pro-tumor role for DES1 as a transducer of HER2-driven glucose metabolic signals and provide evidence that targeting DES1 is an effective approach for overcoming AIS. Results further suggest that DES1 may have utility as a biomarker of aggressive and metastasis-prone HER2+ breast cancer.

Dissecting the Oncogenic Roles of Keratin 17 in the Hallmarks of Cancer.

There is an unmet need to identify and validate tumor-specific therapeutic targets to enable more effective treatments for cancer. Heterogeneity in patient clinical characteristics as well as biological and genetic features of tumors present major challenges for the optimization of therapeutic interventions, including the development of novel and more effective precision medicine. The expression of keratin 17 (K17) is a hallmark of the most aggressive forms of cancer across a wide range of anatomical sites and histological types. K17 correlates with shorter patient survival, predicts resistance to specific chemotherapeutic agents, and harbors functional domains that suggest it could be therapeutically targeted. Here, we explore the role of K17 in the hallmarks of cancer and summarize evidence to date for K17-mediated mechanisms involved in each hallmark, elucidating functional roles that warrant further investigation to guide the development of novel therapeutic strategies.

Neutralizing activity to SARS-CoV-2 of convalescent and control plasma used in a randomized controlled trial.

BACKGROUND: There are limited data on the neutralizing activity of convalescent plasma (CP) administered in randomized controlled trials (RCT) of COVID-19 infection. STUDY DESIGN AND METHODS: As part of an RCT, CP was collected per FDA guidelines from individuals recovered from COVID-19 infection. CP donors had to have ≥145 optical density (OD) units (ideal target ≥300) using a semiquantitative, immunochromatographic test for IgG antibody to the nucleocapsid protein (NP) of SARS-CoV-2 (typical range 0-500 OD units). A random subset of samples [14 control plasma, 12 CP "medium-anti-NP" (145-299 OD units), and 13 CP "high" anti-NP (≥300 OD units)] were tested for neutralizing antibodies using an established viral luciferase antibody inhibition assay to detect the infection of SARS-CoV-2 pseudovirus that encoded spike protein (SARS2-Strunc ) on a human immunodeficiency virus 1 vector (NL43dEnvNanoLuc), using ACE2-expressing 293 T cells. The titer needed to neutralize 50% of viral activity (NT50) was calculated. RESULTS: The uptake of SARS-CoV-2 pseudovirus by 293TACE2 cells was inhibited by pretreatment with CP compared to control CP (p < .001) with control plasma having a median (IQR) 50% neutralization titer (NT50) of 1:28 (1:16,1:36) compared to 1:334 (1:130,1:1295) and 1:324 (1:244,1:578), for medium anti-NP and high anti-NP CP units, respectively. The neutralizing activity of CP met minimum FDA criteria with neutralizing antibody titers >1:80 in 100% of randomly selected samples, using a conservative approach that excluded non-specific binding. DISCUSSION: Plasma from donors screened using an immunochromatographic test for IgG antibody to SARS-CoV-2 NP exhibited neutralizing activity meeting FDA's minimum standard in all randomly selected COVID-19 CP units.

Altered RNA Splicing by Mutant p53 Activates Oncogenic RAS Signaling in Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is driven by co-existing mutations in KRAS and TP53. However, how these mutations collaborate to promote this cancer is unknown. Here, we uncover sequence-specific changes in RNA splicing enforced by mutant p53 which enhance KRAS activity. Mutant p53 increases expression of splicing regulator hnRNPK to promote inclusion of cytosine-rich exons within GTPase-activating proteins (GAPs), negative regulators of RAS family members. Mutant p53-enforced GAP isoforms lose cell membrane association, leading to heightened KRAS activity. Preventing cytosine-rich exon inclusion in mutant KRAS/p53 PDACs decreases tumor growth. Moreover, mutant p53 PDACs are sensitized to inhibition of splicing via spliceosome inhibitors. These data provide insight into co-enrichment of KRAS and p53 mutations and therapeutics targeting this mechanism in PDAC.

An unbiased high-throughput drug screen reveals a potential therapeutic vulnerability in the most lethal molecular subtype of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer-related deaths in the United States by 2020, due in part to innate resistance to widely used chemotherapeutic agents and limited knowledge about key molecular factors that drive tumor aggression. We previously reported a novel negative prognostic biomarker, keratin 17 (K17), whose overexpression in cancer results in shortened patient survival. In this study, we aimed to determine the predictive value of K17 and explore the therapeutic vulnerability in K17-expressing PDAC, using an unbiased high-throughput drug screen. Patient-derived data analysis showed that K17 expression correlates with resistance to gemcitabine (Gem). In multiple in vitro and in vivo models of PDAC, spanning human and murine PDAC cells, and orthotopic xenografts, we determined that the expression of K17 results in a more than twofold increase in resistance to Gem and 5-fluorouracil, key components of current standard-of-care chemotherapeutic regimens. Furthermore, through an unbiased drug screen, we discovered that podophyllotoxin (PPT), a microtubule inhibitor, showed significantly higher sensitivity in K17-positive compared to K17-negative PDAC cell lines and animal models. In the clinic, another microtubule inhibitor, paclitaxel (PTX), is used in combination with Gem as a first-line chemotherapeutic regimen for PDAC. Surprisingly, we found that when combined with Gem, PPT, but not PTX, was synergistic in inhibiting the viability of K17-expressing PDAC cells. Importantly, in preclinical models, PPT in combination with Gem effectively decreased tumor growth and enhanced the survival of mice bearing K17-expressing tumors. This provides evidence that PPT and its derivatives could potentially be combined with Gem to enhance treatment efficacy for the ~ 50% of PDACs that express high levels of K17. In summary, we reported that K17 is a novel target for developing a biomarker-based personalized treatment for PDAC.

Penalized full likelihood approach to variable selection for Cox's regression model under nested case-control sampling.

Assuming Cox's regression model, we consider penalized full likelihood approach to conduct variable selection under nested case-control (NCC) sampling. Penalized non-parametric maximum likelihood estimates (PNPMLEs) are characterized by self-consistency equations derived from score functions. A cross-validation method based on profile likelihood is used to choose the tuning parameter within a family of penalty functions. Simulation studies indicate that the numerical performance of (P)NPMLE is better than weighted partial likelihood in estimating the log-relative risk and in identifying the covariates and the model, under NCC sampling. LASSO performs best when cohort size is small; SCAD performs best when cohort size is large and may eventually perform as well as the oracle estimator. Using the SCAD penalty, we establish the consistency, asymptotic normality, and oracle properties of the PNPMLE, as well as the sparsity property of the penalty. We also propose a consistent estimate of the asymptotic variance using observed profile likelihood. Our method is illustrated to analyze the diagnosis of liver cancer among those in a type 2 diabetic mellitus dataset who were treated with thiazolidinediones in Taiwan.

Surgical Decompression or Corticosteroid Treatment of Indirect Traumatic Optic Neuropathy: A Randomized Controlled Trial.

BACKGROUND: Traumatic optic neuropathy (TON) is a rare cause of severe permanent visual impairment after injury. Traumatic optic neuropathy may occur due to sharp trauma (direct injury) that damages the optic nerve directly or due to damage from the transmitted forces after a concussive blow to the head or orbit (indirect injury). The management of indirect TON remains controversial. Either surgical decompression or mega dose corticosteroid is used for managing indirect TON. However, no consensus exists regarding the definitive treatment. MATERIALS AND METHODS: We designed a randomized controlled trial study to investigate this issue. Only patients with indirect TON and normal vision before the injury were enrolled. The patients' data were recorded, and fine cut facial computed tomography scan was performed to exclude those with retrobulbar hematoma. All the study subjects were randomly allocated to either the mega dose steroid (30 mg/kg stat and 15 mg/kg every 6 hours for 3 days) group or the surgical decompression group. The patients were followed up at 1 week, 1 month, 3 months, 6 months, and 9 months. During each follow-up, the Snellen visual acuity (VA), visual field, color change, fundus findings, and intraocular pressure were evaluated. These data were compared and analyzed using the Mann-Whitney U test and odds ratio. The short form questionnaire was used to analyze the lift quality difference between the two groups. RESULTS: Thirty patients were enrolled, 12 in the surgical group and 18 in the steroid treatment group. There were no significant differences in the improvement rate, improvement degree, and life quality between the groups. However, the odds ratios are 5, 10, 2.5, and nonavailable in the cutoff points of no light perception (NLP), light perception (LP), hand movement, and counting finger in surgery group. In steroid group, they are 1, 1, 1, 1.83 in each cutoff points. Patients with better VA than NLP had better life quality than those with NLP VA (P = 0.005). Other cutoff point groups had no significant difference. CONCLUSIONS: Patients with worse initial VA (eg, NLP and LP) had a higher chance of benefiting from surgical treatment and experiencing improvements in the life quality.

Keratin 17 identifies the most lethal molecular subtype of pancreatic cancer.

Although the overall five-year survival of patients with pancreatic ductal adenocarcinoma (PDAC) is dismal, there are survival differences between cases with clinically and pathologically indistinguishable characteristics, suggesting that there are uncharacterized properties that drive tumor progression. Recent mRNA sequencing studies reported gene-expression signatures that define PDAC molecular subtypes that correlate with differences in survival. We previously identified Keratin 17 (K17) as a negative prognostic biomarker in other cancer types. Here, we set out to determine if K17 is as accurate as molecular subtyping of PDAC to identify patients with the shortest survival. K17 mRNA was analyzed in two independent PDAC cohorts for discovery (n = 124) and validation (n = 145). Immunohistochemical localization and scoring of K17 immunohistochemistry (IHC) was performed in a third independent cohort (n = 74). Kaplan-Meier and Cox proportional-hazard regression models were analyzed to determine cancer specific survival differences in low vs. high mRNA K17 expressing cases. We established that K17 expression in PDACs defines the most aggressive form of the disease. By using Cox proportional hazard ratio, we found that increased expression of K17 at the IHC level is also associated with decreased survival of PDAC patients. Additionally, within PDACs of advanced stage and negative surgical margins, K17 at both mRNA and IHC level is sufficient to identify the subgroup with the shortest survival. These results identify K17 as a novel negative prognostic biomarker that could inform patient management decisions.

The PHLPP2 phosphatase is a druggable driver of prostate cancer progression.

Metastatic prostate cancer commonly presents with targeted, bi-allelic mutations of the PTEN and TP53 tumor suppressor genes. In contrast, however, most candidate tumor suppressors are part of large recurrent hemizygous deletions, such as the common chromosome 16q deletion, which involves the AKT-suppressing phosphatase PHLPP2. Using RapidCaP, a genetically engineered mouse model of Pten/Trp53 mutant metastatic prostate cancer, we found that complete loss of Phlpp2 paradoxically blocks prostate tumor growth and disease progression. Surprisingly, we find that Phlpp2 is essential for supporting Myc, a key driver of lethal prostate cancer. Phlpp2 dephosphorylates threonine-58 of Myc, which renders it a limiting positive regulator of Myc stability. Furthermore, we show that small-molecule inhibitors of PHLPP2 can suppress MYC and kill PTEN mutant cells. Our findings reveal that the frequent hemizygous deletions on chromosome 16q present a druggable vulnerability for targeting MYC protein through PHLPP2 phosphatase inhibitors.

Application of Computer-Assisted Navigation System in Acute Zygomatic Fractures.

OBJECTIVE: To compare the surgical results of early treatment of zygomatic fractures with and without the use of the computer-assisted navigation system. METHODS: All patients with unilateral traumatic zygomatic fractures treated within 30 days after the injury at a single center between June 2012 and May 2017 were studied retrospectively. Primary outcome was defined by the displacement at 5 junctional sutures of zygomatic bone, the change at each point before and after the reconstruction, and the patient's subjective scoring of their appearance. Secondary outcome included the length of the operation and hospital stay, the number of incisional approaches, the fixation points, the maximal mouth opening, and the sequelae upon follow-up. RESULTS: Twenty-eight patients were enrolled in this study. Fourteen of them received surgery with the help of a computer-assisted navigation system (navigation group), and 14 patients were treated without its assistance (control group). Before the surgery, the mean displacement of each junctional suture and the mean total displacement between both groups were comparable. Postoperative computed tomography showed that the mean total displacement was significantly less for the navigation group than the control group (0.53 vs 2.93 mm, P = 0.001), and the displacement of zygomaticosphenoid suture was smaller (0 vs 0.9 mm, P = 0.009). Patients in the navigation group underwent surgery via the single buccal-gingival approach without the need for longer operation time. There were no significant differences in the length of hospital stay, maximal mouth opening, or cheek numbness. All patients recovered without major complications and were comparatively satisfied with their final appearance. CONCLUSIONS: The navigation system has been demonstrated to be a useful tool for improving the symmetry in delayed or secondary reconstruction of zygomatic fractures. This study showed its effectiveness and safety in cases of early treatment as well, achieving a more accurate correction in a less invasive manner.

Surgical treatment of isolated zygomatic fracture: Outcome comparison between titanium plate and bioabsorbable plate.

BACKGROUND: Zygoma fracture is of clinical importance because malar prominence plays an essential role in facial appearance. Traditionally, most maxillofacial surgeons perform osteosynthesis with titanium plates and screws for rigid fixation. However, this procedure has certain disadvantages that include the possibility of implant exposure, palpability or loosening of the screws, painful irritation, temperature sensitization, and radiographic artifacts. In this study, we compared the function and satisfaction outcome between Bonamates® bioabsorbable implant and Leibinger titanium implant. METHOD: Consecutively 53 patients with isolated unilateral zygomatic fracture that were treated with the Bonamates® bioabsorbable plate system, n = 53 were compared to patients with the titanium plate system, n = 55 in the period between 2009 and 2013. All patients were followed-up at least 6 months. Preoperative and postoperative facial computed tomography (CT) scans were performed and scored from 0 to 2 in the 5 areas of zygoma. A score of 2 indicated the most severely displaced fracture in one of the areas. A visual analogue scale ranging from 0 to 10 was used to assess the postoperative aesthetic and functional satisfactions. RESULT: The mean ages of the patients in the bioabsorbable and titanium plate groups were 33 years and 30 years, respectively. The male to female ratios were 1.2:1 (bioabsorbable plate group) and 1.1:1 (titanium plate group). The average preoperative CT scan scores of the bioabsorbable and titanium plate groups were 5.7 and 5.1, respectively. The postoperative CT scan scores of the bioabsorbable and titanium plate groups were 1.3 and 1.1, respectively. The implant cost of the bioabsorbable group was approximately 6-fold higher than that of the titanium plate group. The complication rate was similar in both groups and included complications such as palpable implant, skin irritation, and hypersensitive cheek. The patients in both groups attained similar mouth-opening function and a satisfactory score at 6 months after operation. CONCLUSION: This study revealed that the bioabsorbable plate outcome was similar to the titanium plate outcome for patients with isolated unilateral zygomatic fracture. The bioabsorbable implant system provides another option for internal fixation devices in the treatment of zygomatic fractures and avoids implant removal surgery; however, the implant cost of bioabsorbable plates is higher than that of titanium plates in Taiwan.

Clinical outcomes for minimally invasive primary and secondary orbital reconstruction using an advanced synergistic combination of navigation and endoscopy.

BACKGROUND: Sequelae of inadequate orbital reconstruction include enophthalmos, hypoglobus, and diplopia. Accuracy of orbital reconstruction is largely subjective and especially difficult to achieve because of anatomic distortion in secondary or late reconstruction and in extensive injury. We combined computer navigation and endoscopy to perform accurate, aesthetic, and safe minimal-access primary and secondary orbital reconstruction. METHODS: From 2013 to 2014, 24 patients underwent unilateral primary and secondary or late minimally invasive orbital reconstruction with mainly Medpor and/or titanium mesh by navigation and endoscopic assistance through transantral, transconjunctival, or upper blepharoplasty approaches. Mean follow-up was 13.8 months (range, 6.2 months to 2.8 years). RESULTS: All orbital fractures were successfully reduced. Average enophthalmos among patients who underwent early reconstruction, late reconstruction, and multiorbital wall repair improved (p < .001) to 0.2 mm from 1.6, 2.6, and 2.6 mm, respectively. Hypoglobus and diplopia resolved in all. In early reconstruction patients, mean interorbital volume difference improved from 1.72 ± 0.87 to 0.53 ± 0.83 ml (P = .03). For late reconstruction patients, this difference improved from 3.41 ± 1.23 to 0.56 ± 0.96 ml (p < .001). There were no major complications during follow-up, and all were satisfied with their final appearance and function. CONCLUSION: Navigation sharpens reconstructive accuracy and avoids injury to vital structures. Combined with endoscopic assistance for minimal-access reconstruction of wide-ranging orbital defects from primary to secondary or late cases and to extensive multiwall fractures, navigation facilitates minimal cosmetic incision and synergistic endoscope use and clearly optimizes aesthetic and functional outcomes, all with enhanced safety and unparalleled intraoperative visualization.

The role of preliminary hospitals in the management of a mass burn casualty disaster.

PURPOSE: The Formosa Fun Coast explosion is an internationally-known event that occurred in Taiwan on June 27th, 2015. The blast involved 495 casualties in total, with 253 patients receiving 2nd degree or deeper burns on greater than 40% of the total body surface area (TBSA). Questions were raised regarding whether these victims were sent to the appropriate hospitals or not. Therefore, we analyzed the effect of the initial admission destination in this study. MATERIAL AND METHODS: We retrospectively reviewed all of the victims from the explosion who were sent to the emergency department of Linkou and Keelung Chang Gung Memorial Hospitals. Patients were divided by direct admission and received via transfer. The basic demographics, the efficacy of the initial resuscitation and the clinical outcomes were analyzed. RESULTS: In total, forty-six patients were included. Thirty-five of them were primarily admitted, and eleven of them were received via transfer. Between the two groups, there was no significant difference in the resuscitation outcome. The ratio of delaying intubation was similar (14.3% vs 27.3%, p=0.322). The rate of delayed-detected ischemic events was significantly increased in the referral group (0% vs 27.3%, p=0.001). However, there was no amputation event in either group. No difference in mortality was observed between groups (5.7% vs 9.1%, p=0.692). CONCLUSION: Our preliminary findings suggest that local hospitals are capable of providing high-quality acute care to mass casualty burn victims. Our results suggest that patients with suspected limb ischemia should be rapidly transferred to a regional burn center to ensure optimal care. Systemic pre-planning such as employing telemedicine and personnel collaboration, should be considered by the administration to maximize the function of preliminary hospitals in burn care.

Vorinostat enhances the cisplatin-mediated anticancer effects in small cell lung cancer cells.

BACKGROUND: Vorinostat, a histone deacetylase (HDAC) inhibitor, is a promising agent for cancer therapy. Combining vorinostat with cisplatin may relax the chromatin structure and facilitate the accessibility of cisplatin, thus enhancing its cytotoxicity. Studies have not yet investigated the effects of the combination of vorinostat and cisplatin on small cell lung cancer (SCLC). METHODS: We first assessed the efficacy of vorinostat with etoposide/cisplatin (EP; triple combination) and then investigated the effects of cotreatment with vorinostat and cisplatin on H209 and H146 SCLC cell lines. The anticancer effects of various combinations were determined in terms of cell viability, apoptosis, cell cycle distribution, and vorinostat-regulated proteins. We also evaluated the efficacy of vorinostat/cisplatin combination in H209 xenograft nude mice. RESULTS: Our data revealed that the triple combination engendered a significant reduction of cell viability and high apoptotic cell death. In addition, vorinostat combined with cisplatin enhanced cell growth inhibition, induced apoptosis, and promoted cell cycle arrest. We observed that the acetylation levels of histone H3 and α-tubulin were higher in combination treatments than in vorinostat treatment alone. Moreover, vorinostat reduced the expression of thymidylate synthase (TS), and TS remained inhibited after cotreament with cisplatin. Furthermore, an in vivo study revealed that the combination of vorinostat and cisplatin significantly inhibited tumor growth in xenograft nude mice (tumor growth inhibition T/C% = 20.5 %). CONCLUSIONS: Combined treatments with vorinostat promote the cytotoxicity of cisplatin and induce the expression of vorinostat-regulated acetyl proteins, eventually enhancing antitumor effects in SCLC cell lines. Triple combinations with a low dosage of cisplatin demonstrate similar therapeutic effects. Such triple combinations, if applied clinically, may reduce the undesired adverse effects of cisplatin. The effects of the combination of vorinostat and cisplatin should be evaluated further before conducting clinical trials for SCLC treatment.

Surgical Timing and Fracture Type on the Outcome of Diplopia After Orbital Fracture Repair.

BACKGROUND: Orbital fractures and the concomitant soft tissue injuries within the bony orbit result in well-recognized complications such as diplopia and enophthalmos. Guidelines for timing and indications for surgery for achieving an optimal outcome remain elusive. This study examined the effects of timing and fracture type on the outcome of orbital fracture repair. MATERIAL AND METHODS: Data on 255 patients treated for orbital fractures were retrospectively reviewed to determine the effects of the facial bones involved in the fractures, the types of orbital wall fracture, the timing of surgical repair, and diplopia evident before and after corrective surgery on surgical outcomes. RESULTS: The incidence of posttraumatic diplopia increased with the number of orbital wall fractures (P < 0.001). The rate of diplopia resolution after corrective surgery was slow in the first 3 months irrespective of the severity of orbital wall fracture. The diplopia resolution rate for type I orbital wall fractures was significantly higher than that for type II and type III fractures. Patients treated within 2 weeks of sustaining an orbital fracture exhibited a higher diplopia resolution rate than did patients treated 2 to 4 weeks and more than 4 weeks after sustaining the fracture (58% vs 38.1%). CONCLUSIONS: A higher number of orbital wall fractures are associated with a higher incidence of diplopia and a poorer long-term result. The timing of surgical repair influences the diplopia outcome. Performing corrective surgery for orbital fractures with diplopia after 2 weeks tends to result in a slower complete recovery rate.

Depression and pain: an appraisal of cost effectiveness and cost utility of antidepressants.

BACKGROUND: Although depression and chronic pain frequently co-occur, there is a lack of clarity in the literature regarding the cost-effectiveness and cost-utility of antidepressants in the presence of these two conditions. From the perspective of healthcare provider, the current study aims to compare the cost-effectiveness and cost-utility of antidepressants in a national cohort of depressed patients with and without comorbid pain conditions. METHODS: Adult patients prescribed with antidepressants for depression were identified from the National Health Insurance Research Database in Taiwan (n=96,501). By using remission as effectiveness measure and quality-adjusted life years (QALYs) as utility measure, the cost-effectiveness and cost-utility were compared across selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs), as well as by the presence of comorbid painful physical symptoms (PPS). RESULTS: SSRIs dominated SNRIs in both the cost-effectiveness and cost-utility regardless of comorbid PPS. In comparison with TCAs, SSRIs were likely to be the cost-effective option for patients without PPS. In patients with PPS, the cost-utility advantage for SSRIs over TCAs varied with threshold willingness-to-pay levels. Comorbid PPS may be considered an effect modifier of the cost-utility comparisons between SSRIs and TCAs. CONCLUSIONS: For depressed patients without PPS, SSRIs are likely to be cost-effective in improving remission rates and QALYs compared to TCAs and SNRIs. However, to improve cost-utility in those with comorbid PPS, people need to choose between SSRIs and TCAs according to threshold willingness-to-pay levels. Future research is warranted to clarify the impacts of different pain conditions on the economic evaluations of pharmacological treatments in patients with depression.