In this study, we examined the efficacy and toxicity of S-1 with cisplatin as a second-line palliative chemotherapy for gemcitabine-refractory pancreatic cancer patients. Patients who had been previously treated with gemcitabine-based chemotherapy as palliative first-line chemotherapy received S-1/cisplatin [body surface area (BSA) <1.25 m2, S-1 40 mg/day; BSA ≤1.25 to <1.5 m2, 50 mg/day; BSA ≥1.5 m2 60 mg/day, orally, bid, daily on days 1–14 followed by a 7-day washout and cisplatin 60 mg/m2/day intravenously on day 1] every three weeks. The enrollment of 32 patients was planned, but the study was terminated early, prior to the first stage, following the enrollment of 11 patients. The median age of the patients was 56 (range, 42–74) years. Nine patients had a performance status (PS) of one. In total, there were 21 chemotherapy cycles and the median treatment duration was 21 (range, 7–96) days. Of the 11 patients, five could not be evaluated due to discontinuation prior to the response evaluation. One of the six evaluable patients achieved stable disease (9.1% in intention to treat analysis and 16.7% in per-protocol analysis), while five had progressive disease. Grade 3–4 hematological toxicities were anemia in one, neutropenia in one and thrombocytopenia in one cycle. Grade 3–4 nonhematological toxicities were fatigue in three, nausea in four, anorexia in two, diarrhea in one and peripheral neuropathy in two cycles. With a median follow-up period of 8.9 (range, 3.2–11.3) months, the median time to progression was 44 days [95% confidence interval (CI) 25.4–62.6] and the median overall survival was 81 days (95% CI 9.3–152.7). Combination chemotherapy with S-1 and cisplatin as applied in this study did not result in promising antitumor activity, a high degree of toxicity and poor compliance.
pancreatic cancer; S-1; cisplatin; gemcitabine-refractory
A test of within-channel detection of acoustic temporal fine structure (aTFS) cues is presented. Eight cochlear implant listeners (CI) were asked to discriminate between two Schroeder-phase (SP) complexes using a two-alternative, forced-choice task. Because differences between the acoustic stimuli are primarily constrained to their aTFS, successful discrimination reflects a combination of the subjects’ perception of and the strategy’s ability to deliver aTFS cues.
Subjects were mapped with single-channel Continuous Interleaved Sampling (CIS) and Simultaneous Analog Stimulation (SAS) strategies. To compare within- and across- channel delivery of aTFS cues, a 16-channel clinical HiRes strategy was also fitted. Throughout testing, SAS consistently outperformed the CIS strategy (p ≤ 0.002). For SP stimuli with F0 =50 Hz, the highest discrimination scores were achieved with the HiRes encoding, followed by scores with the SAS and the CIS strategies, respectively. At 200 Hz, single-channel SAS performed better than HiRes (p = 0.022), demonstrating that under a more challenging testing condition, discrimination performance with a single-channel analog encoding can exceed that of a 16-channel pulsatile strategy.
To better understand the intermediate steps of discrimination, a biophysical model was used to examine the neural discharges evoked by the SP stimuli. Discrimination estimates calculated from simulated neural responses successfully tracked the behavioral performance trends of single-channel CI listeners.
Leukemic promyelocytes have the unique ability to undergo differentiation after exposure to retinoic acid and both differentiation and apoptosis after exposure to arsenic trioxide (ATO). Recent studies have shown that inhibition of Src family kinases (SFKs) resulted in enhancement of retinoic acid-induced myeloid differentiation.
Materials and Methods
In this study, we investigated the question of whether the SFK inhibitor PP2 enhanced the differentiation of NB4 cells when combined with ATO as well as when combined with all-trans-retinoic acid (ATRA). In addition, we attempted to determine the difference in retinoic acid-induced gene expression between cells treated with PP2 in combination with ATRA and in combination with ATO.
SFK inhibitor PP2 induced significant enhancement of ATRA- or ATO-induced differentiation of NB4 cells. A significantly stronger synergistic effect was observed when PP2 was combined with ATRA than when combined with ATO. Flow cytometric analysis demonstrated a significant increase in CD11b-positive granulocytes up to 60.73% and 31.58%, respectively. These results were confirmed by nitroblue tetrazolium staining. These effects were not related to apoptosis. Results of Annexin-V-fluorescein staining revealed that PP2 combined with ATRA or PP2 combined with ATO did not induce apoptosis in NB4 cells. Retinoic acid-induced gene expression was different in both groups. Intercellular adhesion molecule-1 expression showed a significant increase in cells treated with PP2 in combination with ATRA, whereas cathepsin D expression showed a significant increase in cells treated with PP2 in combination with ATO.
Our data showed that SFK inhibitor PP2 enhanced acute promyelocytic leukemia cell differentiation when combined with either ATRA or ATO with difference in activation of retinoic acid-induced genes.
Acute promyelocytic leukemia; All-trans-retinoic acid; Arsenic trioxide; Src kinase; Cell differentiation
The number of pediatric cochlear implant (CI) recipients has increased substantially over the past 10 years, and it has become more important to understand the underlying mechanisms of the variable outcomes in this population. In this study, psychoacoustic measures of spectral-ripple and Schroeder-phase discrimination, the Clinical Assessment of Music Perception, and consonant-nucleus-consonant (CNC) word recognition in quiet and spondee reception threshold (SRT) in noise tests have been presented to 11 prelingually deafened CI users, aged 8–16 years with at least 5 years of CI experience. The children's performance was compared to the previously reported results of postlingually deafened adult CI users. The average spectral-ripple threshold (n = 10) was 2.08 ripples/octave. The average Schroeder-phase discrimination was 67.3% for 50 Hz and 56.5% for 200 Hz (n = 9). The Clinical Assessment of Music Perception test showed that the average complex pitch direction discrimination was 2.98 semitones. The mean melody score was at a chance level, and the mean timbre score was 34.1% correct. The mean CNC word recognition score was 68.6%, and the mean SRT in steady noise was −8.5 dB SNR. The children's spectral-ripple resolution, CNC word recognition, and SRT in noise performances were, within statistical bounds, the same as in a population of postlingually deafened adult CI users. However, Schroeder-phase discrimination and music perception were generally poorer than in the adults. It is possible then that this poorer performance seen in the children might be partly accounted for by the delayed maturation in their temporal processing ability, and because of this, the children's performance may have been driven more by their spectral sensitivity.
Cochlear implant; Prelingual hearing loss; Psychophysics; Music; Speech perception
Previous work showed that the Fidelity120 processing strategy provides better spectral sensitivity, while the HiResolution processing strategy can deliver more detailed temporal information for Advanced Bionics cochlear implant users. The goal of this study was to develop a new sound processing strategy by maximizing the spectral benefit of Fidelity120 and the temporal benefit of HiResolution to improve both aspects of hearing. Using acoustic simulations of Fidelity120 and HiResolution strategies, a dual-processing strategy was created by combining Fidelity120 in the low frequency channels and HiResolution in the high frequency channels. Compared to Fidelity120, the dual processing provided an improvement in performance for Schroeder-phase discrimination at 200-Hz and temporal modulation detection at 200-Hz with the cost of a slightly decreased performance for spectral-ripple discrimination relative to Fidelity120. Spectral-ripple discrimination was better with the dual processing than with HiResolution. However, no benefit for speech perception in noise was found for the dual processing strategy over Fidelity 120 or HiResolution in our preliminary tests. Some other more optimal combination of Fidelity120 and HiResolution may be required to maximize the spectral and temporal benefits to yield improved speech perception.
cochlear implant; spectral and temporal sensitivity; sound processing strategy
Previous work showed that the Fidelity120 processing strategy provides better spectral sensitivity, while the HiResolution processing strategy can deliver more detailed temporal information for Advanced Bionics cochlear implant users. The goal of this study was to develop a new sound processing strategy by maximizing the spectral benefit of Fidelity120 and the temporal benefit of HiResolution to improve both aspects of hearing. Using acoustic simulations of Fidelity120 and HiResolution strategies, a dual-processing strategy was created by combining Fidelity120 in the low frequency channels and HiResolution in the high frequency channels. Compared to Fidelity120, the dual processing provided an improvement in performance for Schroeder-phase discrimination at 200 Hz and temporal modulation detection at 200 Hz with the cost of a slightly decreased performance for spectral-ripple discrimination relative to Fidelity120. Spectral-ripple discrimination was better with the dual processing than with HiResolution. However, no benefit for speech perception in noise was found for the dual-processing strategy over Fidelity 120 or HiResolution in our preliminary tests. Some other more optimal combination of Fidelity120 and HiResolution may be required to maximize the spectral and temporal benefits to yield improved speech perception.
cochlear implant; spectral and temporal sensitivity; sound processing strategy
The objectives were to evaluate the relationships among music perception, appraisal, and experience in cochlear implant users in multiple clinical settings and to examine the viability of two assessments designed for clinical use.
Background questionnaires (IMBQ) were administered by audiologists in 14 clinics in the United States and Canada. The CAMP included tests of pitch-direction discrimination, and melody and timbre recognition. The IMBQ queried users on prior musical involvement, music listening habits pre and post implant, and music appraisals.
One-hundred forty-five users of Advanced Bionics and Cochlear Ltd cochlear implants.
Performance on pitch direction discrimination, melody recognition, and timbre recognition tests were consistent with previous studies with smaller cohorts, as well as with more extensive protocols conducted in other centers. Relationships between perceptual accuracy and music enjoyment were weak, suggesting that perception and appraisal are relatively independent for CI users.
Perceptual abilities as measured by the CAMP had little to no relationship with music appraisals and little relationship with musical experience. The CAMP and IMBQ are feasible for routine clinical use, providing results consistent with previous thorough laboratory-based investigations.
Music; music perception; cochlear implant; music appraisal; hearing impairment
This study was designed to determine what acoustic elements are associated with musical perception ability in cochlear implant (CI) users; and to understand how acoustic elements, which are important to good speech perception, contribute to music perception in CI users. It was hypothesized that the variability in the performance of music and speech perception may be related to differences in the sensitivity to specific acoustic features such as spectral changes or temporal modulations, or both.
A battery of hearing tasks was administered to forty-two CI listeners. The Clinical Assessment of Music Perception (CAMP) was used, which evaluates complex-tone pitch-direction discrimination, melody recognition, and timbre recognition. To investigate spectral and temporal processing, spectral-ripple discrimination and Schroeder-phase discrimination abilities were evaluated. Speech perception ability in quiet and noise was also evaluated. Relationships between CAMP subtest scores, spectral-ripple discrimination thresholds, Schroeder-phase discrimination scores, and speech recognition scores were assessed.
Spectral-ripple discrimination was shown to correlate with all three aspects of music perception studied. Schroeder-phase discrimination was generally not predictive of music perception outcomes. Music perception ability was significantly correlated with speech perception ability. Nearly half of the variance in melody and timbre recognition was predicted jointly by spectral-ripple and pitch-direction discrimination thresholds. Similar results were observed on speech recognition as well.
The current study suggests that spectral-ripple discrimination is significantly associated with music perception in CI users. A previous report showed that spectral-ripple discrimination is significantly correlated with speech recognition in quiet and in noise (Won et al., 2007). The present study also showed that speech recognition and music perception are also related to one another. Spectral-ripple discrimination ability seems to reflect a wide range of hearing abilities in CI users. The results suggest that materially improving spectral resolution could provide significant benefits in music and speech perception outcomes in CI users.
cochlear implants; psychophysical abilities; music perception; speech perception
The prognosis of gastric cancer patients with bone marrow metastases is extremely poor. The current study was conducted to evaluate the clinical outcomes of advanced gastric cancer patients with bone marrow metastases.
Materials and Methods
We retrospectively reviewed the medical records of 26 advanced gastric cancer patients with bone marrow metastases who were treated at Soonchunhyang University Hospital between September 1986 and February 2009.
The median age was 46 years (range, 24 to 61 years). All patients had poorly differentiated adenocarcinoma, including 17 signet ring cell carcinomas. The majority of the patients had thrombocytopenia, anemia, and elevated lactate dehydrogenase levels. Sixteen patients (61.5%) received palliative chemotherapy (median, 4 cycles; range, 1 to 13 cycles). The median overall survival after detection of bone marrow metastases for the cohort of patients was 37 days (95% confidence interval, 12.5 to 61.5 days). The median overall survival after detection of bone marrow involvement was 11 days in the best supportive care group (range, 2 to 34 days) and 121 days (range, 3 to 383 days) in the palliative chemotherapy group (p<0.001). The causes of death were tumor progression (11 patients, 45%), brain hemorrhage (6 patients, 25%), infection (5 patients, 21%), and disseminated intravascular coagulation (1 patient, 4%). There were no chemotherapy-related deaths.
Palliative chemotherapy could be considered in advanced gastric cancer patients with bone marrow metastases as a treatment option.
Stomach neoplasms; Bone marrow; Neoplasm metastasis; Drug therapy
We investigated the effects of mesenchymal stem cells (MSCs) on wound healing using a three-dimensional (3D) collagen gel scaffold. Three circular full-thickness skin defects were created on the back of Sprague-Dawley rats. One site was covered with a 3D collagen gel containing 2 × 106 MSCs (MSCs+/3D collagen+). Another site was replaced with a 3D collagen gel without MSCs and the third site was left empty. The wound size was significantly reduced in the MSCs+/3D collagen+ sites. MSCs+/3D collagen+ sites exhibited the most neovascularization. FISH showed that Y-chromosome possessing cells were found within the dermis of MSCs+/3D collagen+ sites. Gelatin zymography revealed that the most intense expression of MMP-9 was detected early in the MSCs+/3D collagen+ sites. Our results indicate that MSCs upregulate the early expression of MMP-9 which induces the early mobilization of VEGF. Thus, MSCs appear to accelerate significantly wound healing via early activation of MMP-9 and VEGF.
Mesenchymal Stem Cells; Wound Healing
Although worldwide experience with umbilical cord blood (UCB) transplantation is still relatively limited, clinical experience with UCB transplantation is encouraging. The use of UCB for hematopoietic stem cell transplantation (HSCT) has advantages and disadvantages. Among the advantages are rapid availability, ability to more rapidly schedule the transplant as the UCB units are stored and ready for use, the apparent reduced need for an exact human leukocyte antigen (HLA) match, and induction of a less severe graft versus host disease (GVHD) compared with bone marrow. The major limitation of reduced numbers of hematopoietic stem cells (HSC) in UCB is being addressed by basic research. It is promising that potential improvements in engraftment efficiency without increased stem cell numbers or actual increased stem cell numbers through dual UCB transplant or ex-vivo expansion might lead to improved treatment approaches. However, its therapeutic potential extends beyond the hematopoietic component suggesting regenerative potential in solid organs as well. Many different stem and progenitor cell populations have been postulated with potential ranging from embryonic like to lineage-committed progenitor cells. UCB derived MSCs have the differentiation capacity and also the therapeutic potential with regard to regenerative medicine, stromal support, immune modulation and gene therapy. Therefore, further advances are eagerly anticipated.
Umbilical cord blood cells; Transplantation; Therapeutic potential
Choriocarcinoma in the testis is very rare, and it represents less than 1% (0.3%) of all the testicular germ cell tumors. It is a particularly aggressive variant of non-seminoma tumor, which is characterized by a high serum β-HCG level and multiple lung metastases. The optimal management for this disease remains undefined. We report here on a case of choriocarcinoma with multiple lung metastases, and the patient has achieved continuous remission for 2 years after combination chemotherapy of BEP (bleomycin, etoposide and cisplatin) and sequential high-dose chemotherapy with autologous peripheral stem cell rescue.
Neoplasms; Germ cell and embryonal; Testicular choriocarcinoma; High-dose chemotherapy
This study evaluated the maximal attainable performance of speech enhancement strategies based on coherent modulation filtering. An optimal adaptive coherent modulation filtering algorithm was designed to enhance known signals from a target talker in two-talker babble noise. The algorithm was evaluated in a closed-set, speech-recognition-in-noise task. The speech reception threshold (SRT) was measured using a one-down, one-up adaptive procedure. Five hearing-impaired subjects and five cochlear implant users were tested in three processing conditions: (1) original sounds; (2) fixed coherent modulation filtered sounds; and (3) optimal coherent modulation filtered sounds. Six normal-hearing subjects were tested with a 6-channel cochlear implant simulation of sounds processed in the same three conditions. Significant improvements in SRTs were observed when the signal was processed with the optimal coherent modulation filtering algorithm. There was no benefit when the signal was processed with the fixed modulation filter. The current study suggested that coherent modulation filtering might be a promising method for front-end processing in hearing aids and cochlear implants. An approach such as hidden Markov models could be used to generalize the optimal coherent modulation filtering algorithm to unknown utterances and to extend it to open-set speech.
Coherent modulation filter; speech enhancement; hearing aids; cochlear implants
Extramedullary plasmacytoma of the liver is a very rare tumor. Although a few cases of extramedullary plasmacytoma of the liver have been reported, we could not find any report on truly localized extramedullary plasmacytoma of the liver in the literature. The patient was a 63-yr-old man who exhibited a solitary liver mass on dynamic computed tomography and magnetic resonance imaging. Histologically, the tumor was composed of mature plasma cells with mild atypia. Immunohistochemistry demonstrated monoclonal IgG and Kappa light chain expression. Bone marrow examination revealed no abnormalities. There was no evidence of a monoclonal protein in the serum and urine, lytic bone lesions, anemia, renal insufficiency, and hypercalcemia. The patient was treated with 5,000 cGy of radiotherapy, and the tumor disappeared 6 months after treatment.
Plasmacytoma; Liver; Monoclonal Gammopathies; Radiotherapy
Mesenchymal stem cells (MSCs) have recently been identified and characterized in humans. Moreover, MSC secrete cytokines that can support hematopoietic progenitor growth. In the present study, we evaluated whether the efficacy of hematopoietic stem cell transplantation is improved by their co-transplantation with MSC, and whether this is positively correlated with the dose of infused MSCs. Accordingly, irradiated NOD/SCID mice were transplanted with 1×105 human CD34+ cells in the presence or absence of culture expanded MSCs (1×106 or 5×106). We evaluated human hematopoietic cell engraftment by flow cytometry and assessed MSC tissue distributions by fluorescence in situ hybridization. We found that CD45+ and CD34+ cell levels were significantly elevated in a dose-dependent manner in cotransplanted mice 4 weeks after transplantation. The engraftments of CD33+ and CD19+ cells also increased dose-dependently. However, the engraftment of CD3+ cells did not increase after co-transplantation with MSCs. Human Y chromosome+ cells were observed in multiple tissues and were more frequently observed in mice co-transplanted with 5×106 rather than 1×106 MSCs. These results suggest that MSCs are capable of enhancing hematopoietic cell engraftment and distribution in multiple organs in a dose-dependent fashion.
Mesenchymal Stem Cells; Hematopoietic Stem Cells; Transplantation
We investigated the clinical features and treatment outcomes of patients with mantle cell lymphoma (MCL) in Korea.
We retrospectively analyzed the clinical characteristics and prognosis of 131 patients diagnosed with MCL between January 2004 and December 2009 at 15 medical centers in Korea; all patients received at least 1 chemotherapeutic regimen for MCL.
The median age for the patients was 63 years (range, 26-78 years), and 77.9% were men. A total of 105 patients (80.1%) had stage III or IV MCL at diagnosis. Fifty-two patients (39.7%) were categorized with high- or high-intermediate risk MCL according to the International Prognostic Index (IPI). Eighteen patients (13.7%) were in the high-risk group according to the simplified MCL-IPI (MIPI). The overall incidence of extranodal involvement was 69.5%. The overall incidence of bone marrow and gastrointestinal involvements at diagnosis was 41.2% and 35.1%, respectively. Cyclophosphamide, doxorubicin, vincristine, prednisolone, and rituximab were used frequently as the first-line treatment (41.2%). With a median follow-up duration of 20.0 months (range, 0.2-77.0 months), the overall survival (OS) at 2 years was 64.7%, while the event-free survival (EFS) was 39.7%. Multivariate analysis showed that the simplified MIPI was significantly associated with OS. However, the use of a rituximab-containing regimen was not associated with OS and EFS.
Similar to results from Western countries, the current study found that simplified MIPI was an important prognostic factor in Korean patients with MCL.
Mantle cell lymphoma; Epidemiology; Trend; Survival; Chemotherapy; Rituximab
The gastrointestinal (GI) tract is one of the most common extranasal sites in extranodal NK/T-cell lymphoma (ENKTL). However, data regarding ENKTL involving the GI tract are relatively scarce. Thus, we performed a multicenter, multinational retrospective study to analyze clinical features and treatment outcomes of ENKTL involving the GI tract.
Patients and methods
Patients with ENKTL involving the GI tract diagnosed in twelve participating centers between 1991 and 2012 were retrospectively analyzed from five Asian countries.
The analysis of 81 patients with ENKTL involving the GI tract revealed that more than 60% of patients presented as advanced disease with B symptoms. 55 patients (68%) had GI manifestations including abdominal pain (n = 26, 32%), GI tract bleeding (n = 17, 21%) and bowel perforation (n = 12, 15%). The most common GI site was the small intestine, including the jejunum and ileum (n = 57, 70.3%). There were 34 patients (42%) who received systemic chemotherapy while 33 patients (41%) underwent surgery plus chemotherapy. However, 35 patients (43%) died due to disease progression, and treatment-related mortality including sepsis occurred in 17 patients (21%). Thus, the median overall survival was 7.8 months (95% Confidence interval: 3.9 – 11.7 months). Patients who could undergo surgery plus chemotherapy showed a trend of better survival than those treated with chemotherapy alone.
Overall, the data indicated that ENKTL involving the GI tract has a dismal prognosis despite active treatment including chemotherapy and surgery. Thus, more effective treatment strategies are required for this disease entity.
Extranodal NK/T-cell lymphoma; Gastrointestinal tract; Prognosis
This study aimed to survey the clinical spectrum of diffuse large B-cell lymphoma (DLBCL) in terms of epidemiology, pathologic subtypes, stage, and prognostic index as well as treatment outcomes.
In 2007-2008, 13 university hospitals evenly distributed in the Korean peninsula contributed to the online registry of DLBCL at www.lymphoma.or.kr and filed a total of 1,665 cases of DLBCL recorded since 1990.
Our analysis showed a higher prevalence of DLBCL in male than in female individuals (M:F=958:707), and extranodal disease was more common than primary nodular disease (53% vs. 47%). Among the 1,544 patients who had been treated with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) or rituximab-CHOP (R-CHOP) therapy with or without radiation, 993 (63.9%) were alive, with 80% free of disease, 417 were dead (26.8%), with 13% free of disease, and 144 (9.3%) were lost to follow-up, with 23% free of disease. Age below 60 years, stage at diagnosis, international prognostic index (IPI) score regardless of age, and addition of rituximab to CHOP therapy in low- and low-intermediate-risk groups according to IPI scores significantly increased survival duration.
The epidemiology, clinical spectrum, and biological behavior of DLBCL in Korea are similar to those observed in Western countries, and the advent of rituximab improved survival.
Diffuse large B-cell lymphoma; Epidemiology; Survival; Rituximab; CHOP regimen
Previous studies have found a significant correlation between spectral-ripple discrimination and speech and music perception in cochlear implant (CI) users. This relationship could be of use to clinicians and scientists who are interested in using spectral-ripple stimuli in the assessment and habilitation of CI users. However, previous psychoacoustic tasks used to assess spectral discrimination are not suitable for all populations, and it would be beneficial to develop methods that could be used to test all age ranges, including pediatric implant users. Additionally, it is important to understand how ripple stimuli are processed in the central auditory system and how their neural representation contributes to behavioral performance. For this reason, we developed a single-interval, yes/no paradigm that could potentially be used both behaviorally and electrophysiologically to estimate spectral-ripple threshold. In experiment 1, behavioral thresholds obtained using the single-interval method were compared to thresholds obtained using a previously established three-alternative forced-choice method. A significant correlation was found (r = 0.84, p = 0.0002) in 14 adult CI users. The spectral-ripple threshold obtained using the new method also correlated with speech perception in quiet and noise. In experiment 2, the effect of the number of vocoder-processing channels on the behavioral and physiological threshold in normal-hearing listeners was determined. Behavioral thresholds, using the new single-interval method, as well as cortical P1-N1-P2 responses changed as a function of the number of channels. Better behavioral and physiological performance (i.e., better discrimination ability at higher ripple densities) was observed as more channels added. In experiment 3, the relationship between behavioral and physiological data was examined. Amplitudes of the P1-N1-P2 “change” responses were significantly correlated with d′ values from the single-interval behavioral procedure. Results suggest that the single-interval procedure with spectral-ripple phase inversion in ongoing stimuli is a valid approach for measuring behavioral or physiological spectral resolution.
spectral-ripple discrimination; behavioral and physiological measure; cochlear implant; auditory change response; auditory cortex
Arsenic trioxide (As2O3) is a well-known and effective treatment that can result in clinical remission for patients diagnosed with acute promyelocytic leukemia (APL). The biologic efficacy of As2O3 in APL and solid tumor cells has been explained through its actions on anti-proliferation, anti-angiogenesis, and apoptotic signaling pathways. We theorize that As2O3 activates a pathway that disrupts microtubule dynamics forming abnormal, nonfunctioning mitotic spindles, thus preventing cellular division. In this study, we investigated how As2O3 induces apoptosis by causing microtubule dysfunction.
Cultured NB4 cells were treated with As2O3, paclitaxel, and vincristine. Flow cytometric analysis was then performed. An MTT assay was used to determine drug-mediated cytotoxicity. For tubulin polymerization assay, each polymerized or soluble tubulin was measured. Microtubule assembly-disassembly was measured using a tubulin polymerization kit. Cellular microtubules were also observed with fluorescence microscopy.
As2O3 treatment disrupted tubulin assembly resulting in dysfunctional microtubules that cause death in APL cells. As2O3 markedly enhanced the amount of depolymerized microtubules. The number of microtubule posttranslational modifications on an individual tubulin decreased with As2O3 concentration. Immunocytochemistry revealed changes in the cellular microtubule network and formation of polymerized microtubules in As2O3-treated cells.
The microtubules alterations found with As2O3 treatment suggest that As2O3 increases the depolymerized forms of tubulin in cells and that this is potentially due to arsenite's negative effects on spindle dynamics.
Acute promyelocytic leukemia; Arsenic trioxide; Tubulin; Apoptosis; Antimitotic agents
Compare auditory performance of Hybrid and standard cochlear implant users with psychoacoustic measures of spectral and temporal sensitivity and correlate with measures of clinical benefit.
Tertiary academic medical center.
Hybrid cochlear implant users between 12 and 33 months post implantation. Hybrid recipients all had preservation of low-frequency hearing.
Administration of psychoacoustic, music perception, and speech reception in noise tests.
Main outcome measures
Performance on spectral-ripple discrimination, temporal modulation detection, Schroeder-phase discrimination, Clinical Assessment of Music Perception (CAMP), and speech reception in steady-state noise tests.
CAMP pitch performance at 262 Hz was significantly better in Hybrid users compared to standard implant controls. There was a near significant difference on speech reception in steady-state noise. Surprisingly, neither Schroeder-phase discrimination at two frequencies nor temporal modulation detection thresholds across a range of frequencies revealed any advantage in Hybrid users. This contrasts with spectral-ripple measures that were significantly better in the Hybrid group. The spectral-ripple advantage was preserved even when using only residual hearing.
These preliminary data confirm existing data demonstrating that residual low-frequency acoustic hearing is advantageous for pitch perception. Results also suggest that clinical benefits enjoyed by Hybrid recipients are due to improved spectral discrimination provided by the residual hearing. No evidence indicated that residual hearing provided temporal information beyond that provided by electrical stimulation.
electroacoustic; Hybrid cochlear implant; spectral; temporal
We investigated the role of fasting hormones and pro-inflammatory cytokines in cancer patients. Hormones (ghrelin, adiponectin, and leptin) and cytokines (TNF-α, IFN-γ, and IL-6) were measured by ELISA or RIA in lung cancer and colorectal cancer patients before the administration of cancer therapy, and measurements were repeated every 2 months for 6 months. From June 2006 to August 2008, 42 patients (19 with colorectal cancer and 23 with lung cancer) were enrolled. In total, 21 patients were included in the cachexia group and the others served as a comparison group. No significant difference in the initial adiponectin, ghrelin, TNF-α, IFN-γ, or IL-6 level was observed between groups, although leptin was significantly lower in cachectic patients than in the comparison group (15.3 ± 19.5 vs 80.9 ± 99.0 pg/mL, P = 0.007). During the follow-up, the patients who showed a > 5% weight gain had higher ghrelin levels after 6 months. Patients exhibiting elevated IL-6 levels typically showed a weight loss > 5% after 6 months. A blunted adiponectin or ghrelin response to weight loss may contribute to cancer cachexia and IL-6 may be responsible for inducing and maintaining cancer cachexia.
Adiponectin; Cachexia; Cytokines; Ghrelin; Leptin