Prognostic implication of metastasis limited to segmental (level 13) and/or subsegmental (level 14) lymph nodes in patients with surgically resected nonsmall cell lung carcinoma and pathologic N1 lymph node status

BACKGROUND:

In patients with nonsmall cell lung carcinoma (NSCLC) who have with pathologic N1 (pN1) lymph node status, the prognostic significance of segmental lymph node (level 13) metastasis and/or subsegmental lymph node (level 14) metastasis is unknown.

METHODS:

Lymph node metastasis patterns were analyzed in 230 patients with NSCLC who had pN1 status. Clinical outcomes were examined for 230 patients with pN1 status and 700 patients with pN0 status. The pN1 group was stratified into 4 subgroups according to the highest level of lymph node involvement.

RESULTS:

The 5‐year disease‐free survival (5DFS) rates for pN1 and pN0 patients were 50.1% and 90.5%, respectively. The highest level of lymph node involvement was a significant prognostic indicator; the 5DFS rates for patients with pN1 status who had level 13/14, lobar (level 12), interlobar (level 11), and hilar (level 10) lymph node metastasis were 69.4%, 46.4%, 46.7%, and 37%, respectively. Patient outcomes were significantly worse for those with pN1 status who had only level 13/14 lymph node metastasis than for patients with pN0 status (P = .0034), and outcomes were significantly worse for patients with pN1 status who had level 11/12 lymph node metastasis than for patients who had only level 13/14 lymph node metastasis (P = .021). The median number of level 13/14 lymph nodes examined was 3 (range, 0‐22 level 13/14 lymph nodes), and metastases to these lymph nodes were detected in 61% of patients who had pN1 status. A single lymph node pN1 disease, single‐level pN1 status, and squamous cell carcinoma histopathology also were indicators of a better patient outcome.

CONCLUSIONS:

The current results indicated that the highest level of lymph node involvement may be used to stratify the outcome of patients who have NSCLC with pN1 status. Patients with pN1 status who had only level 13/14 lymph node metastasis had an intermediate 5DFS rate between that of patients with pN0 status and other patients with pN1 status. Routine examination of level 13/14 lymph nodes is important for accurate pathologic staging and for the predicting clinical outcome of patients with NSCLC. Cancer 2012. © 2012 American Cancer Society.     

A case of sinonasal teratocarcinosarcoma treated with surgery and post-operative intensity-modulated radiotherapy (IMRT)

Sinonasal teratocarcinosarcoma (SNTCS) is a rare and aggressive malignant neoplasm, which has poor prognosis. SNTCS is histologically characterized by the combination of one or more epithelial elements and mesenchymal components. We report a 59-year-old man with SNTCS involving right maxillary and ethmoid sinuses. He complained of numbness of the right cheek for 1 month. Computed tomography and magnetic resonance imaging revealed soft tissue filling the right maxillary and ethmoid sinuses, protruding into the nasal cavity. Tumor was removed with Denker rhinotomy, and post-operative intensity-modulated radiation therapy (IMRT: 64Gy in 32 fractions) was performed. Follow-up examination for 2 years after the IMRT has shown no evidence of recurrence or metastasis. IMRT is a new type of conformal radiotherapy that is based on the use of non-uniform radiation beam intensities. IMRT can achieve optimal dose distributions and may improve the clinical outcomes dramatically with minimal complications. This report describes this patient's clinical course, etiology, diagnosis and management of SNTCS, and the advantage of IMRT in the treatment of SNTCS.     

Tumor-infiltrating lymphocytes are correlated with response to neoadjuvant chemotherapy in triple-negative breast cancer

The purpose of the present study was to identify histological surrogate predictive markers of pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC). Among 474 patients who received NAC and subsequent surgical therapy for stage II?CIII invasive breast carcinoma between 1999 and 2007, 102 (22%) had TNBC, and 92 core needle biopsy (CNB) specimens obtained before NAC were available. As controls, CNB specimens from 42 tumors of the hormone receptor-negative and HER2-positive (HR?/HER2+) subtype and 46 tumors of the hormone receptor-positive and HER2-negative (HR+/HER2?) subtype were also included. Histopathological examination including tumor-infiltrating lymphocytes (TIL) and tumor cell apoptosis, and immunohistochemical studies for basal markers were performed, and the correlation of these data with pathological therapeutic effect was analyzed. The rates of pCR at the primary site were higher for TNBC (32%) and the HR?/HER2+ subtype (21%) than for the HR+/HER2? subtype (7%) (P?=?0.006). Expression of basal markers and p53, histological grade 3, high TIL scores, and apoptosis were more frequent in TNBC and the HR?/HER2+ subtype than in the HR+/HER2? subtype (P?=?0.002 for TIL and P?<?0.001 for others). In TNBC, the pCR rates of tumors showing a high TIL score and of those showing a high apoptosis score were 37 and 47%, respectively, and significantly higher or tended to be higher than those of the tumors showing a low TIL score and of the tumors showing a low apoptosis score (16 and 27%, respectively, P?=?0.05 and 0.10). In a total of 180 breast cancers, the pCR rates of the tumors showing a high TIL score (34%) and of those showing a high apoptosis score (35%) were significantly higher than those of the tumors showing a low TIL score (10%) and those of the tumors showing a low apoptosis score (19%) (P?=?0.0001 and 0.04, respectively). Histological grade and basal marker expression were not correlated with pCR. Although the whole analysis was exploratory, the degree of TIL correlated with immune response appear to play a substantial role in the response to NAC in TNBC.     

TAp73 regulates the spindle assembly checkpoint by modulating BubR1 activity

The role of various p73 isoforms in tumorigenesis has been controversial. However, as we have recently shown, the generation of TAp73-deficient (TAp73^−/−) mice reveals that TAp73 isoforms exert tumor-suppressive functions, indicating an emerging role for Trp-73 in the maintenance of genomic stability. Unlike mice lacking all p73 isoforms, TAp73^−/− mice show a high incidence of spontaneous tumors. Moreover, TAp73^−/− mice are infertile and produce oocytes exhibiting spindle abnormalities. These data suggest a link between TAp73 activities and the common molecular machinery underlying meiosis and mitosis. Previous studies have indicated that the spindle assembly checkpoint (SAC) complex, whose activation leads to mitotic arrest, also regulates meiosis. In this study, we demonstrate in murine and human cells that TAp73 is able to interact directly with several partners of the SAC complex (Bub1, Bub3, and BubR1). We also show that TAp73 is involved in SAC protein localization and activities. Moreover, we show that decreased TAp73 expression correlates with increases of SAC protein expression in patients with lung cancer. Our results establish TAp73 as a regulator of SAC responses and indicate that TAp73 loss can lead to mitotic arrest defects. Our data suggest that SAC impairment in the absence of functional TAp73 could explain the genomic instability and increased aneuploidy observed in TAp73-deficient cells.     

Characterization of endoplasmic reticulum-associated degradation of a protein S mutant identified in a family of quantitative protein S deficiency

INTRODUCTION: Misfolded and unassembled glycoproteins are eliminated from the endoplasmic reticulum (ER) lumen by the ER-associated degradation (ERAD).We previously identified a Tyr595Cys (Y595C) mutation of protein S (PS) in a family of a quantitative PS deficiency. The mutation causes intracellular degradation and decreased secretion of the Y595C mutant PS. The aim of the present study was to further characterize the molecular basis of the intracellular degradation of the mutant. MATERIALS AND METHODS: We stably expressed the mutant in mammalian cells, and analyzed the intracellular localization of the protein. The intracellular degradation pathway was determined by pulse-chase analyses in the presence of various inhibitors of ERAD. RESULTS AND CONCLUSIONS: Endoglycosidase H digestion and immunofluorescence staining revealed the mutant being retained in the ER. Epoxomicin, a potent and specific proteasome inhibitor, and Ala-Ala-Phe-CH(2)Cl (AAF), an inhibitor of tripeptidyl peptidase II (TPPII), suppressed the intracellular degradation of the mutant by about 65% and 50%, respectively. When epoxomicin was combined with AAF, the inhibitory effect was substantially enhanced. Although castanospermine, an inhibitor of glucosidases I and II, did not affect the degradation, kifunensine, an inhibitor of ER mannosidase I, suppressed it. Thus, it appears that the Y595C mutant is degraded through more than one pathway of ERAD, including the proteasome-dependent pathway and an alternate proteasome-independent pathway where proteases such as TPPII may be involved. Production of the critical B isoform of Man(8)GlcNAc(2) targets the mutant for ERAD, however, the interaction with calnexin/calreticulin through monoglucosylated oligosaccharides may not be required for the degradation of the mutant.