POH1/Rpn11/PSMD14: a journey from basic research in fission yeast to a prognostic marker and a druggable target in cancer cells.

POH1/Rpn11/PSMD14 is a highly conserved protein in eukaryotes from unicellular organisms to human and has a crucial role in cellular homoeostasis. It is a subunit of the regulatory particle of the proteasome, where it acts as an intrinsic deubiquitinase removing polyubiquitin chains from substrate proteins. This function is not only coupled to the translocation of substrates into the core of the proteasome and their subsequent degradation but also, in some instances, to the stabilisation of ubiquitinated proteins through their deubiquitination. POH1 was initially discovered as a functional homologue of the fission yeast gene pad1+, which confers drug resistance when overexpressed. In translational studies, expression of POH1 has been found to be increased in several tumour types relative to normal adjacent tissue and to correlate with tumour progression, higher tumour grade, decreased sensitivity to cytotoxic drugs and poor prognosis. Proteasome inhibitors targeting the core particle of the proteasome are highly active in the treatment of myeloma, and recently developed POH1 inhibitors, such as capzimin and thiolutin, have shown promising anticancer activity in cell lines of solid tumours and leukaemia. Here we give an overview of POH1 function in the cell, of its potential role in oncogenesis and of recent progress in developing POH1-targeting drugs.

Biopsy Ratio of Suspected to Confirmed Sarcoma Diagnosis.

The ratio of malignancy in suspicious soft tissue and bone neoplasms (RMST) has not been often addressed in the literature. However, this value is important to understand whether biopsies are performed too often, or not often enough, and may therefore serve as a quality indicator of work-up for a multidisciplinary team (MDT). A prerequisite for the RMST of an MDT is the assessment of absolute real-world data to avoid bias and to allow comparison among other MDTs. Analyzing 950 consecutive biopsies for sarcoma-suspected lesions over a 3.2-year period, 55% sarcomas were confirmed; 28% turned out to be benign mesenchymal tumors, and 17% non-mesenchymal tumors, respectively. Of these, 3.5% were metastases from other solid malignancies, 1.5% hematologic tumors and 13% sarcoma simulators, which most often were degenerative or inflammatory processes. The RMST for biopsied lipomatous lesions was 39%. The ratio of unplanned resections was 10% in this series. Reorganizing sarcoma work-up into integrating practice units (IPU) allows the assessment of real-world data with absolute values over the geography, thereby enabling the definition of quality indicators and addressing cost efficiency aspects of sarcoma care.

Activity of Afatinib in Heavily Pretreated Patients With ERBB2 Mutation-Positive Advanced NSCLC: Findings From a Global Named Patient Use Program.

INTRODUCTION: Approximately 1% to 4% of NSCLC tumors harbor erb-b2 receptor tyrosine kinase 2 (ERBB2) mutation; there is no approved targeted treatment for this subgroup. METHODS: Patients with stage IV NSCLC that progressed after clinical benefit on erlotinib/gefitinib and/or had activating EGFR or ERBB2 mutations, had exhausted other treatments, and were ineligible for afatinib trials were enrolled in a named patient use program, receiving afatinib 30 to 50 mg/d on a compassionate basis within routine clinical practice. Efficacy and safety were retrospectively assessed in the subgroup with ERBB2 mutation-positive NSCLC. RESULTS: Twenty-eight heavily pretreated patients in the named patient use program had a documented ERBB2 mutation by local testing. Median time-to-treatment failure (TTF; time from treatment initiation to discontinuation for any reason) was 2.9 months; eight patients (29%) had TTF greater than 1 year. Objective response rate was 19% (3 of 16 patients with response data achieved partial response) and disease control rate (DCR) was 69% (11 of 16). Among 12 patients for whom type of ERBB2 mutation was specified, 10 had a p.A775_G776insYVMA insertion in exon 20, four of whom (40%) remained on afatinib for more than 1 year. This subgroup had median TTF of 9.6 months, objective response rate of 33% (two of six), and disease control rate of 100% (six of six). CONCLUSIONS: This analysis of patients treated in clinical practice provides further evidence of the activity of afatinib in ERBB2 mutation-positive NSCLC, and suggests that identification of specific subgroups with certain mutations, such as p.A775_G776ins/YVMA insertion in exon 20, could help optimize outcomes with ErbB2-targeted treatment.

Intractable Neck Pain in an Oncologic Palliative Care Setting: Is Cancer Always the Answer?

Refractory pain is a common manifestation in an oncologic palliative care setting and represents a major challenge for health care professionals involved in care provision. The underlying neoplasm and its dissemination are the foremost pathophysiologic mechanism for the development of pain in patients with advanced cancer. Nonetheless, other etiologies such as trauma and infections need to be considered by clinicians in this particular care setting. The authors present the case of a patient with a recent diagnosis of hepatocellular carcinoma, suffering from intractable neck pain, progressive worsening of her general conditions, and the onset of a generalized seizure. The clinical suspicion of a bacteremia with central nervous system involvement was confirmed by the performed work-up, and a Listeria monocytogenes meningoencephalitis was diagnosed. The purpose of this case report is to raise clinicians' awareness on infectious complications, which may increase the symptom burden in patients treated in an oncologic palliative care setting. Moreover, the manifestation of such complications may be misinterpreted as the consequence of the underlying neoplasm, further delaying the diagnostic and therapeutic management in this particular population.

Decreased immunoreactivity for p27 protein in patients with early-stage breast carcinoma is correlated with HER-2/neu overexpression and with benefit from one course of perioperative chemotherapy in patients with negative lymph node status: results from International Breast Cancer Study Group Trial V.

BACKGROUND: The objective of this study was to clarify the prognostic and predictive value of immunoreactivity for the cyclin-dependent kinase inhibitor p27(Kip1) in patients with early-stage breast carcinoma and to investigate its relation with clinicopathologic features and other markers. METHODS: Immunoreactivity for p27 protein was analyzed on tumor slides from 461 patients who were enrolled in the International Breast Cancer Study Group (IBCSG) Trial V (median follow-up, 13 years), including 198 patients with lymph node negative disease and 263 patients with lymph node positive disease. Tumors with < 50% immunoreactive neoplastic cells were considered low expressors. Immunoreactivity for p27 was correlated with several clinicopathologic characteristics. Disease free survival (DFS) and overall survival were analyzed according to p27 immunoreactivity and treatment group. RESULTS: In the lymph node negative population, decreased p27 immunoreactivity was associated with higher tumor grade (P = 0.001) and HER-2/neu overexpression (P = 0.04). In the lymph node positive population, low p27 expression was associated with higher tumor grade (P = 0.01), low expression of thymidylate synthase (P = 0.001), and higher Ki-67 expression (P = 0.007). DFS was not significantly different according to p27 status in either lymph node negative patients (10-year DFS: low p27 expression, 53% +/- 5%; high p27 expression, 55% +/- 5%) or in lymph node positive patients (10 year DFS: low p27 expression, 33% +/- 4%; high p27 expression, 32% +/- 4%). However, in the lymph node negative population, the benefit of one course of perioperative chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil was confined exclusively to patients with tumors that showed reduced p27 immunoreactivity (P = 0.03; test for interaction). CONCLUSIONS: This analysis indicates that p27 immunoreactivity has little if any prognostic value in patients with early-stage breast carcinoma. However, these findings suggest that, in patients with breast carcinoma who have negative lymph node status, reduced p27 immunoreactivity is associated with HER-2/neu overexpression and may be predictive of a benefit from the early administration of adjuvant chemotherapy.

The essential 26S proteasome subunit Rpn11 confers multidrug resistance to mammalian cells.

BACKGROUND: Identification of multidrug resistance (MDR) factors is crucial for designing chemotherapeutic strategies. Aberrant expression and dysfunction of proteasome subunits have been involved in malignant transformation and in cell resistance to various cytotoxic drugs. MATERIALS AND METHODS: We analyzed the expression levels of the proteasome subunit Rpn11 in a panel of cancer cell lines, and studied the effect of Rpn11 overexpression on the resistance of mammalian cells to cytotoxic drugs in clonogenic cytotoxicity assay. RESULTS: Rpn11 levels are highly variable in cancer cells; mammalian cells stably overexpressing Rpn11 display moderate resistance to vinblastine, cisplatin and doxorubicin, and also exhibit a slower proliferation rate when compared to the control cells. CONCLUSION: Rpn11-overexpression in mammalian cells affects cell proliferation and the response to cytotoxic drugs, both of which may promote tumor cell escape from chemotherapeutic agents, and may serve as a marker for MDR-cells.