An analysis of the relationship between metastases and cachexia in lung cancer patients.

Weight loss and hematogenous metastases are poor prognosis factors in lung cancer patients that can but do not necessarily co-occur. We retrospectively investigated the clinical association between cachexia, tumor characteristics (such as metastatic burden and mutational status), and treatment in lung cancer patients. The medical records of 394 lung cancer patients from two institutions (Columbia University, USA and Tohoku University, Japan) were reviewed. Information collected included the presence of cachexia, histologic subtype, tumor stage, number of metastases, mutation status, treatment, and survival. Descriptive statistics were performed. Only stage IV patients exhibited >5% weight loss (0.8%, 2.2%, 3.6%, and 5.1%, for stages I to IV; P = 0.0001). Patients with metastases developed cachexia more often than patients without metastases independent of treatment (6.0% and 7.1% weight loss in patients with metastases vs. 2.5% and 2.0% in patients without metastases, before [P = 0.0001] and after [P < 0.0001] treatment, respectively). The change in number of metastatic sites over time correlated with increasing weight loss (5.2%, 10.6%, 13.4%, and 13.4%, for an increase of 0, 1, 2, and ≥3 metastatic sites, from initial diagnosis to the endpoint; P < 0.0001). Patients with cachexia had worse survival than patients without cachexia (hazard ratio, 2.94; 95% confidence interval, 2.08-4.16; P < 0.0001). Tumors with mutated KRAS were associated with an increased risk of weight loss (11.4% weight loss in patients with mutated KRAS vs. 6.0% in patients with wild-type KRAS; P = 0.0011). Our findings suggest that the capabilities of lung cancer to metastasize and cause cachexia might be linked intrinsically and are independent of treatments administered. KRAS-mutated tumors were more commonly associated with cachexia.

Current situation regarding central venous port implantation procedures and complications: a questionnaire-based survey of 11,693 implantations in Japan.

BACKGROUND: We conducted a nationwide questionnaire-based survey to understand the current situation regarding central venous port implantation in order to identify the ideal procedure. METHODS: Questionnaire sheets concerning the number of implantation procedures and the incidence of complications for all procedures completed in 2012 were sent to 397 nationwide designated cancer care hospitals in Japan in June 2013. Venipuncture sites were categorized as chest, neck, upper arm, forearm, and others. Methods were categorized as landmark, cut-down, ultrasound-mark, real-time ultrasound guided, venography, and other groups. RESULTS: We received 374 responses (11,693 procedures) from 153 centers (38.5 %). The overall complication rates were 7.4 % for the chest (598/8,097 cases); 6.8 % for the neck (157/2325); 5.2 % for the upper arm (54/1,033); 7.3 % for the forearm (9/124); and 6.1 % for the other groups (7/114). Compared to the chest group, only the upper arm group showed a significantly lower incidence of complications (P = 0.010), and multivariate logistic regression (odds ratio 0.69; 95 % confidence interval 0.51-0.91; P = 0.008) also showed similar findings. Real-time ultrasound-guided puncture was most commonly used in the upper arm group (83.8 %), followed by the neck (69.8 %), forearm (53.2 %), chest (41.8 %), and other groups (34.2 %). CONCLUSION: Upper arm venipuncture with ultrasound guidance seems the most promising technique to prevent complications of central venous port implantation.

Transgenic expression of the N525S-tuberin variant in Tsc2 mutant (Eker) rats causes dominant embryonic lethality.

The Tsc2 product, tuberin, negatively regulates the mTOR pathway. We have exploited the Eker (Tsc2-mutant) rat system to analyse various Tsc2 mutations. Here, we focus on the N525S-Tsc2 variant (NSM), which is known to cause distinct symptoms in patients even though normal suppression of mTOR is observed. Unexpectedly, we were repeatedly unable to generate viable rats carrying the NSM transgene. Genotypic analysis revealed that most of the embryos carrying the transgene died around embryonic day after 14.5-similar to the stage of lethality observed for Eker homozygotes. Thus, the NSM transgene appeared to have a dominant lethal effect in our rat model. Further, no significant differences were observed for various signal transduction molecules in transiently expressed NSM cells compared to WT. These results indicate that a non-mTOR pathway, critical for embryogenesis, is being regulated by tuberin, providing a link between tuberin expression and the severity of Tsc2 mutation-related pathogenesis.

Upper arm central venous port implantation: a 6-year single institutional retrospective analysis and pictorial essay of procedures for insertion.

BACKGROUND: The requirement of central venous (CV) port implantation is increasing with the increase in the number of cancer patients and advancement in chemotherapy. In our division, medical oncologists have implanted all CV ports to save time and consultation costs to other departments. Recently, upper arm implantation has become the first choice as a safe and comfortable method in our unit. Here we report our experience and discuss the procedure and its potential advantages. METHODS: All CV port implantations (n = 599) performed in our unit from January 2006 to December 2011 were analyzed. Procedural success and complication rates between subclavian and upper arm groups were compared. RESULTS: Both groups had similar patient characteristics. Upper arm CV port and subclavian implantations were equivalently successful and safe. Although we only retrospectively analyzed data from a single center, the upper arm group had a significantly lower overall postprocedural complication rate than the subclavian group. No pneumothorax risk, less risk of arterial puncture by ultrasound, feasibility of stopping potential arterial bleeding, and prevention of accidental arterial cannulation by targeting the characteristic solitary basilic vein were the identified advantages of upper arm CV port implantation. In addition to the aforementioned advantages, there is no risk of "pinch-off syndrome," possibly less patient fear of manipulation, no scars on the neck and chest, easier accessibility, and compatibility with the "peripherally inserted central catheter" technique. CONCLUSIONS: Upper arm implantation may benefit clinicians and patients with respect to safety and comfort. We also introduce our methods for upper arm CV port implantation with the videos.

[Infusion reaction and anaphylaxis].

Infusion reactions and allergic reactions are common side effects of anti-cancer drugs, and are known as hypersensitivity reactions. Patients with these severe reactions require close attention because these reactions sometimes lead to critical conditions. Infusion reactions are caused by cytokine release, although the precise mechanisms involved are still obscure. Infusion reactions are often caused by rituximab, an anti-CD20 antibody, and other monoclonal antibodies. Allergic reactions, mediated by IgE, are observed with a variety of chemotherapeutic drugs, especially platinum compounds and taxanes. An acute severe allergic reaction is called anaphylaxis, and is often fatal unless treated appropriately. In this review, we describe the prevention of hypersensitivity reactions and their treatment based on our clinical experience.

Serine 62 is a phosphorylation site in folliculin, the Birt-Hogg-Dubé gene product.

Recently, it was reported that the product of Birt-Hogg-Dubé syndrome gene (folliculin, FLCN) is directly phosphorylated by 5'-AMP-activated protein kinase (AMPK). In this study, we identified serine 62 (Ser62) as a phosphorylation site in FLCN and generated an anti-phospho-Ser62-FLCN antibody. Our analysis suggests that Ser62 phosphorylation is indirectly up-regulated by AMPK and that another residue is directly phosphorylated by AMPK. By binding with FLCN-interacting proteins (FNIP1 and FNIP2/FNIPL), Ser62 phosphorylation is increased. A phospho-mimic mutation at Ser62 enhanced the formation of the FLCN-AMPK complex. These results suggest that function(s) of FLCN-AMPK-FNIP complex is regulated by Ser62 phosphorylation.

Regulation of folliculin (the BHD gene product) phosphorylation by Tsc2-mTOR pathway.

The Birt-Hogg-Dubé gene (BHD) encodes the tumor suppressor protein folliculin (FLCN). The function of FLCN has recently been implicated in the regulation of rapamycin-sensitive mTOR complex (mTORC1). Reciprocally, the mTORC1-dependent phosphorylation of FLCN was reported. However, precise mechanism of FLCN phosphorylation and functional interaction of FLCN with tuberin, the product of tuberous sclerosis 2 gene (TSC2) which is a negative regulator of mTORC1, are unclear. Here we report that multiple phosphorylation in FLCN are evoked by downregulation of tuberin as well as by Rheb expression. We found that phosphorylation at Ser62 and Ser302 are differently regulated by mTORC1-dependent pathway. Some unknown kinases downstream of tuberin-mTORC1 are thought to directly phosphorylate FLCN. Interestingly, our results also suggest that the complex formation of FLCN with AMPK is modulated by FLCN phosphorylation. These results suggest that FLCN is involved in a novel mechanism of signal transduction downstream of tuberin.