Search

BackgroundTo evaluate the midterm results of percutaneous cryoablation for medically inoperable stage I non-small cell lung cancer.Methodology/principal findingsBetween January 2004 and June 2010, 160 patients underwent computer tomography guided percutaneous cryoablation for lung tumors at our institution. Of these patients, histologically proven stage I lung cancer patients with more than one year of follow-up, were retrospectively reviewed. All of these patients were considered to be medically inoperable with Charlson comorbidity index of 3 or greater. Follow-up was based primarily on computed tomography. There were 22 patients with 34 tumors who underwent 25 sessions of cryoablation treatment. Complications were pneumothoraces in 7 treatments (28%, chest tube required in one treatment), and pleural effusions in 8 treatments (31%). The observation period ranged from 12-68 months, average 29±19 months, median 23 months. Local tumor progression was observed in one tumor (3%). Mean local tumor progression-free interval was 69±2 months. One patient died of lung cancer progression at 68 months. Two patients died of acute exacerbations of idiopathic pulmonary fibrosis which were not considered to be directly associated with cryoablation, at 12 and 18 months, respectively. The overall 2- and 3-year survivals were 88% and 88%, respectively. Mean overall survival was 62±4 months. Median overall survival was 68 months. The disease-free 2- and 3-year survivals were 78% and 67%, respectively. Mean disease-free survival was 46±6 months. Pulmonary function tests were done in 16 patients (18 treatments) before and after cryoablation. Percentage of predicted vital capacity, and percentage of predicted forced expiratory volume in 1 second, did not differ significantly before and after cryoablation (93±23 versus 90±21, and 70±11 versus 70±12, respectively).Conclusions/significanceAlthough further accumulation of data is necessary regarding efficacy, cryoablation may be a feasible option in medically inoperable stage I lung cancer patients.

OBJECTIVE: A risk of tumor seeding after percutaneous needle biopsy has been reported in various organs, including the lung. This study retrospectively evaluated the proportion of ipsilateral pleural recurrence after computed tomography-guided needle biopsy (CTNB) in p-stage I lung cancer patients. METHODS: Of the 321 patients diagnosed with p-stage I lung cancer, 124 underwent CTNB before surgery, while 197 underwent non-CTNB procedures, including bronchoscopic biopsy in 188 patients and thoracoscopic wedge resection in 9. These patients were retrospectively analyzed. RESULTS: While the tumor size was significantly larger in the non-CTNB group (25 ± 9 mm) in comparison to the CTNB group (19 ± 9 mm) (p

OBJECTIVE: To evaluate the safety and efficacy of cryoablation for metastatic lung tumors from colorectal cancer. METHODS: The procedures were performed on 24 patients (36-82 years of age, with a median age of 62; 17 male patients, 7 female patients) for 55 metastatic tumors in the lung, during 30 sessions. The procedural safety, local progression free interval, and overall survival were assessed by follow-up computed tomographic scanning performed every 3-4 months. RESULTS: The major complications were pneumothorax, 19 sessions (63%), pleural effusion, 21 sessions (70%), transient and self-limiting hemoptysis, 13 sessions (43%) and tract seeding, 1 session (3%). The 1- and 3-year local progression free intervals were 90.8% and 59%, respectively. The 3-years local progression free intervals of tumors ≤15 mm in diameter was 79.8% and that of tumors >15 mm was 28.6% (p = 0.001; log-rank test). The 1- and 3-year overall survival rates were 91% and 59.6%, respectively. CONCLUSION: The results indicated that percutaneous cryoablation is a feasible treatment option. The local progression free interval was satisfactory at least for tumors that were ≤15 mm in diameter.

Background: Historically, local control of recurrent sarcomas has been limited to radiotherapy when surgical re-resection is not feasible. For metastatic carcinomas to the bone or soft tissue, radiotherapy and some interventional radiology treatment along with other systemic therapies have been widely advocated due to the possibility of disseminated disease. These techniques are effective in alleviating pain and achieving local control for some tumor types, but it has not been effective for prolonged local control of most tumors. Recently, cryoablation has been reported to have satisfactory results in lung and liver carcinoma treatment. In this study, we analyzed the clinical outcome of CT-guided cryoablation for malignant bone and soft tissue tumors to elucidate potential problems associated with this procedure. Methods: Since 2011, 11 CT-guided cryoablations in 9 patients were performed for locally recurrent or metastatic bone and soft tissue tumors (7 males and 2 females) at our institute. The patients' average age was 74.8 years (range 61-86) and the median follow up period was 24.1 months (range 5-48). Histological diagnosis included renal cell carcinoma (n = 4), dedifferentiated liposarcoma (n = 2), myxofibrosarcoma (n = 2), chordoma (n = 1), hepatocellular carcinoma (n = 1), and thyroid carcinoma (n = 1). Cryoablation methods, clinical outcomes, complications, and oncological outcomes were analyzed. Results: There were 5 recurrent tumors and 6 metastatic tumors, and all cases had contraindication to either surgery, chemotherapy or radiotherapy. Two and 3 cycles of cryoablation were performed for bone and soft tissue tumors, respectively. The average length of the procedure was 101.1 min (range 63-187), and the average number of probes was 2.4 (range 2-3). Complications included 1 case of urinary retention in a patient with sacral chordoma who underwent prior carbon ion radiotherapy, 1 transient femoral nerve palsy, and 1 minor wound complication. At the final follow up, 4 patients showed no evidence of disease, 2 were alive with disease, and 3 died of disease. Conclusions: Reports regarding CT-guided cryoablation for musculoskeletal tumors are rare and the clinical outcomes have not been extensively studied. In our case series, CT-guided cryoablation had analgesic efficacy and there were no cases of local recurrence post procedure during the follow-up period. Although collection of further data regarding use of this technique is necessary, our data suggest that cryoablation is a promising option in medically inoperable musculoskeletal tumors. [ABSTRACT FROM AUTHOR]

Summary: Ubiquitination is a major post-translational modification of ribosomal proteins. The role of ubiquitination in the regulation of ribosome functions is still being elucidated. However, the importance of ribosome deubiquitination remains unclear. Here, we show that the cycle of ubiquitination and deubiquitination of the 40S ribosome subunit eS7 is important for efficient translation. eS7 ubiquitination at lysine 83 is required for efficient protein translation. We identified Otu2 and Ubp3 as the deubiquitinating enzymes for eS7. An otu2Δubp3Δ mutation caused a defect in protein synthesis. Ubp3 inhibited polyubiquitination of eS7 in polysomes to keep eS7 in a mono-ubiquitinated form, whereas Otu2 was specifically bound to the free 40S ribosome and promoted the dissociation of mRNAs from 40S ribosomes in the recycling step. Our results provide clues for understanding the molecular mechanism of the translation system via a ubiquitination-deubiquitination cycle.

The proteasome is a large protein complex responsible for proteolysis in cells. Though the proteasome is widely conserved in all eukaryotes, vertebrates additionally possess tissue-specific proteasomes, termed immunoproteasomes and thymoproteasomes. These specialized proteasomes diverge from constitutive proteasomes in the makeup of their catalytic 20S core particle (CP), whereby the constitutive β1, β2, and β5 catalytic subunits are replaced by β1i, β2i, and β5i in immunoproteasomes, or β1i, β2i, and β5t in thymoproteasomes. However, as constitutive β1, β2, and β5 are also present in tissues and cells expressing immuno- and thymoproteasomes, the specialized proteasomes must be able to selectively incorporate their specific subunits. Here, we review the mechanisms governing the assembly of constitutive and specialized proteasomes elucidated thus far. Studies have revealed that β1i and β2i are added onto the α-ring of the CP prior to the other β subunits. Furthermore, β5i and β5t can be incorporated independent of β4, whereas constitutive β5 incorporation is dependent on β4. These mechanisms allow the immuno- and thymoproteasomes to integrate tissue-specific β-subunits without contamination from constitutive β1, β2, and β5. We end the review with a brief discussion on the diseases caused by mutations to the immunoproteasome and the proteins involved with its assembly.

The 26S proteasome has a highly complicated structure comprising the 20S core particle (CP) and the 19S regulatory particle (RP). Along with the standard CP in all eukaryotes, vertebrates have two more subtypes of CP called the immunoproteasome and the thymoproteasome. The immunoproteasome has catalytic subunits β1i, β2i, and β5i replacing β1, β2, and β5 and enhances production of major histocompatibility complex I ligands. The thymoproteasome contains thymus-specific subunit β5t in place of β5 or β5i and plays a pivotal role in positive selection of CD8+ T cells. Here we investigate the assembly pathways of the specialized CPs and show that β1i and β2i are incorporated ahead of all the other β-subunits and that both β5i and β5t can be incorporated immediately after the assembly of β3 in the absence of β4, distinct from the assembly of the standard CP in which β-subunits are incorporated in the order of β2, β3, β4, β5, β6, β1, and β7. The propeptide of β5t is a key factor for this earlier incorporation, whereas the body sequence seems to be important for the earlier incorporation of β5i. This unique feature of β5t and β5i may account for preferential assembly of the immunoproteasome and the thymoproteasome over the standard type even when both the standard and specialized subunits are co-expressed.

The 26S proteasome is a key player in the degradation of ubiquitinated proteins, comprising a 20S core particle (CP) and a 19S regulatory particle (RP). The RP is further divided into base and lid subcomplexes, which are assembled independently from each other. We have previously demonstrated the assembly pathway of the CP and the base by observing assembly intermediates resulting from knockdowns of each proteasome subunit and the assembly chaperones. In this study, we examine the assembly pathway of the mammalian lid, which remains to be elucidated. We show that the lid assembly pathway is conserved between humans and yeast. The final step is the incorporation of Rpn12 into the assembly intermediate consisting of two modular complexes, Rpn3-7-15 and Rpn5-6-8-9-11, in both humans and yeast. Furthermore, we dissect the assembly pathways of the two modular complexes by the knockdown of each lid subunit.

In response to proteasome dysfunction, mammalian cells upregulate proteasome gene expression by activating Nrf1. Nrf1 is an endoplasmic reticulum-resident transcription factor that is continually retrotranslocated and degraded by the proteasome. Upon proteasome inhibition, Nrf1 escapes degradation and is cleaved to become active. However, the processing enzyme for Nrf1 remains obscure. Here we show that the aspartyl protease DNA-damage inducible 1 homolog 2 (DDI2) is required to cleave and activate Nrf1. Deletion of DDI2 reduced the cleaved form of Nrf1 and increased the full-length cytosolic form of Nrf1, resulting in poor upregulation of proteasomes in response to proteasome inhibition. These defects were restored by adding back wild-type DDI2 but not protease-defective DDI2. Our results provide a clue for blocking compensatory proteasome synthesis to improve cancer therapies targeting proteasomes.