Association between skin toxicity and efficacy of necitumumab in squamous non-small-cell lung cancer: a pooled analysis of two randomized clinical trials-SQUIRE and JFCM.

BACKGROUND: Efficacy of necitumumab [recombinant human monoclonal antibody that blocks the ligand binding epidermal growth factor receptor (EGFR)] in patients with squamous (SQ) non-small-cell lung cancer (NSCLC) has been confirmed in two randomized clinical trials (SQUIRE and JFCM). This study evaluated the association between efficacy and initial skin toxicity with necitumumab treatment by analyzing pooled data from two clinical trials (SQUIRE and JFCM). MATERIALS AND METHODS: Data of 635 patients with SQ-NSCLC (intent-to-treat population) treated with necitumumab plus gemcitabine and cisplatin (N + GC) were pooled from two clinical trials (SQUIRE and JFCM). The relationship between skin toxicities developed by the end of the second cycle and efficacy was evaluated. Efficacy endpoints included overall survival (OS), progression-free survival (PFS), and objective response rate (ORR). Univariate and multivariate analyses were carried out for these endpoints. RESULTS: OS and ORR were associated with skin toxicity, whereas PFS was not. Patients with grade ≥2 or grade 1 skin toxicity had significantly longer OS compared to patients without skin toxicity (grade 0) in the N + GC group [median = 15.0 (grade ≥2); 12.7 (grade 1); 9.4 (grade 0) months; hazard ratio (HR) = 0.51 (grade ≥2 to grade 0); 95% confidence interval (CI) 0.40-0.64, P < 0.001 and HR = 0.64 (grade 1 to grade 0); 95% CI 0.52-0.80, P < 0.001]. In multivariate analysis, OS was significantly associated with skin toxicity. CONCLUSIONS: A significant association was found between necitumumab-induced skin toxicity and efficacy. These results are consistent with the previously reported association between other EGFR inhibitors-induced skin toxicity and efficacy.

Artifact reduction in low and ultra-low dose chest computed tomography for patients with pacemaker: A phantom study.

INTRODUCTION: Implanted pacemakers (PM) would decrease the detection of lung nodules in chest computed tomography (CT) due to the metal artifact. This study aimed to explore the computer-aided diagnosis (CAD) detectability of pulmonary nodules for the patients implanted with PMs in low- and ultra-low-dose chest CT screening. METHODS: Four different sizes of artificial nodules were placed in an anthropomorphic chest phantom with two alternative diameters utilized. A commercially available PM was placed on the surface of the left chest wall of the phantom. The image acquisitions were performed with 120 kV and 150 kV with a dedicated selective photon shield made of tin filter (Sn150 kV) at low- and ultra-low- radiation doses (1.0 and 0.5 mGy of volume CT dose index), and reconstructed with and without Iterative Metal Artifact Reduction (iMAR, Siemens Healthineers, Erlangen, Germany). The relative artifact index (AIr) was calculated as an index of metal artifacts, and the nodule detectability was evaluated with a CAD system. RESULTS: Sn150 kV reduced AIr in all acquisitions when comparing 120 kV and Sn150 kV. Although PM reduced the detectability of nodules, Sn150 kV showed higher detectability compared to 120 kV. The use of iMAR showed inconsistent results in nodule detectability. CONCLUSION: Sn150 kV reduced PM-induced metal artifacts and improved nodule detectability with CAD compared to 120 kV acquisition in many conditions including low and ultra-low doses and large phantoms, but iMAR did not improve the detectability. IMPLICATIONS FOR PRACTICE: Based on the results of the current phantom study, low and ultra-low dose with Sn150 kV acquisition reduced PM-induced metal artifacts and improved nodule detectability.

Impact of the lateral skeletal stability following bilateral sagittal split ramus osteotomy for mandibular asymmetry.

This study evaluated the stability of bilateral sagittal split ramus osteotomy (BSSRO) associated with positional plagiocephaly and temporal and masseter muscles using posteroanterior cephalogram analysis and three-dimensional computed tomography (3D-CT). This retrospective cohort study included 31 patients who underwent BSSRO for mandibular asymmetry. The cranial vault asymmetry index (CVAI) and the cephalic index were used as indicators of positional plagiocephaly. The distance from the vertical reference line to the menton (Me) was measured on posteroanterior cephalograms immediately and 1 year after surgery, and postoperative stability was assessed. Temporal and masseter muscles were constructed from 3D-CT data and their volumes were measured. Simple regression analysis showed a significant correlation between postoperative changes in the vertical reference line to the Me and the CVAI (R = 0.56, p = 0.001), the amount of surgical movement in the vertical reference line to the Me (R = 0.41, p = 0.023), and the variable temporal muscle volume (R = 0.27, p = 0.028). There was no significant correlation between postoperative changes in the vertical reference line to the Me and the cephalic index (R = 0.093, p = 0.62) and variable masseter muscle volume (R = 0.16, p = 0.38). According to multivariate analysis, CVAI (p = 0.003) and amount of surgical movement in the vertical reference line to the Me (p = 0.014) were significant predictors of postoperative change in the vertical reference line to the Me. Positional plagiocephaly and amount of surgical movement influence lateral skeletal stability following BSSRO for mandibular asymmetry.

The effect of Daikenchuto on blood flow of the superior mesenteric artery and portal vein in ELBW: A prospective study.

BACKGROUND: Focal intestinal perforation (FIP) is a devastating complication of premature birth, and extremely low birth weight (ELBW) infants are at highest risk. This study aimed to evaluate the relationship of the superior mesenteric artery (SMA) and portal vein (PV) blood flow velocities to investigate the association between intestinal blood flow and FIP. In addition, the herbal formula Daikenchuto (TJ-100) is expected to improve intestinal blood flow disorders; therefore, we evaluated its effect. METHODS: We conducted a prospective cohort study of 15 ELBW infants from January 2020 to August 2021. Measured variables included birth weight, 5-minute Apgar score, time of oral feeding initiation, ductus arteriosus (PDA) closure (percent), diastolic and systolic blood pressure, SMA and PV blood flow velocity, and FIP onset data. Fifteen infants were divided into three groups: a non-surgery group (Group I; 6), a surgery group with FIP (Group II; 4), and a TJ-100 administration group (Group III; 5). The main outcome parameters included SMA and PV blood flow velocities with TJ-100. RESULTS: SMA and PV blood flow differed significantly for the SMA of Group I and the SMA and PV of Group III (P < 0.01, P = 0.01, and P = 0.04, respectively). There was a correlation between SMA and PV in Group III (P = 0.03). CONCLUSION: TJ-100 may increase SMA and PV blood flow and improve intestinal blood flow in ELBW infants at risk of FIP. Therefore, the effects of TJ-100 should undergo further study.

Final overall survival analysis from the phase III J-ALEX study of alectinib versus crizotinib in ALK inhibitor-naïve Japanese patients with ALK-positive non-small-cell lung cancer.

BACKGROUND: Mature progression-free survival (PFS) data from the phase III J-ALEX study showed superiority for alectinib versus crizotinib [hazard ratio (HR) 0.37, 95% confidence interval (CI) 0.26-0.52; median PFS 34.1 versus 10.2 months, respectively] in advanced ALK (anaplastic lymphoma kinase)-positive non-small-cell lung cancer (NSCLC). Overall survival (OS) data were immature (HR 0.80, 99.8799% CI 0.35-1.82) at the time of data cut-off (30 June 2018). We report final OS data after ≥5 years of follow-up. PATIENTS AND METHODS: ALK inhibitor naive Japanese patients who were chemotherapy naive or had received one prior chemotherapy regimen were enrolled. Patients were randomized to receive alectinib 300 mg (n = 103) or crizotinib 250 mg (n = 104) twice daily until progressive disease, unacceptable toxicity, death, or withdrawal. The primary endpoint was independent review facility-assessed PFS, with OS (not fully powered) as a secondary endpoint. RESULTS: Median duration of OS follow-up was 68.6 months with alectinib and 68.0 months with crizotinib. Treatment with alectinib did not prolong OS relative to crizotinib (HR 1.03, 95.0405% CI 0.67-1.58; P = 0.9105). Five-year OS rates were 60.9% (95% CI 51.4-70.3) with alectinib and 64.1% (95% CI 54.9-73.4) with crizotinib. In total, 91.3% (n = 95/104) of crizotinib-treated patients and 46.6% (n = 48/103) of alectinib-treated patients received at least one subsequent anticancer therapy. After study drug discontinuation, 78.8% of patients in the crizotinib arm switched to alectinib, while 10.7% of patients in the alectinib arm switched to crizotinib as a first subsequent anticancer therapy. Patients randomized to crizotinib tended to switch treatment earlier than those randomized to alectinib. CONCLUSION: Final OS analysis from J-ALEX did not show superiority of alectinib to crizotinib; this result was most likely confounded by treatment crossover. Alectinib remains a standard of care for the treatment of patients with advanced ALK-positive NSCLC.

Cutaneous ischemia-reperfusion injury is exacerbated by IL-36 receptor antagonist deficiency.

BACKGROUND: Loss-of-function homozygous or compound heterozygous mutations in IL36RN, which encodes interleukin-36 receptor antagonist (IL-36Ra), has been implicated in the pathogenesis of skin disorders. However, the pathogenic role of IL-36Ra in cutaneous ischemia-reperfusion (I/R) injury remains unclear. OBJECTIVES: We investigated the role of IL36Ra in cutaneous I/R injury. METHODS: We examined I/R injury in Il36rn-/- mice. The area of wounds, numbers of infiltrated cells, apoptotic cells and neutrophil extracellular trap (NET) formation were assessed. The expression levels of various genes were analysed using real-time RT-PCR. The expression of high mobility group box 1 (HMGB1), an endogenous toll-like receptor (TLR) 4 ligand, was confirmed using immunohistology, and serum HMGB1 levels were measured by ELISA. Cytokine production by stimulated cultured J774A.1 and HaCaT cells was examined. RESULTS: IL-36Ra deficiency resulted in significantly delayed wound healing and increased neutrophil and macrophage infiltration into the wound tissues. Il36rn-/- mice had increased mRNA expression levels of CXCL1, CXCL2, CCL4, TNF-α, TGF-ß, IL-1ß, IL-6 and IL-36γ relative to wild-type mice. Apoptosis was identified in keratinocytes by TUNEL assay. HMGB1 expression in the I/R site was decreased in both keratinocytes and adnexal cells, while serum HMGB1 levels were significantly elevated after reperfusion. The mRNA levels of various cytokines, including IL-1ß, were elevated in J774A.1 cells through TLR4 signalling by HMGB1 stimulation. In addition, HaCaT cells stimulated with IL-1ß showed significantly increased CXCL1, TNF-α, IL-6, IL-36ß and IL-36γ mRNA expression. Furthermore, NET formation was increased by IL-36Ra deficiency. Finally, either the blockade of TLR4 signalling by TAK-242 or inhibition of NET formation by Cl-amidine normalized exacerbated I/R injury in Il36rn-/- mice. CONCLUSIONS: This study indicated that IL-36Ra deficiency exacerbates cutaneous I/R injury due to excessive inflammatory cell recruitment, NET formation, and excessive cytokine and chemokine production via the TLR4 pathway by HMGB1 released from epidermal apoptotic cells.

A collagen hydrolysate/milk protein-blend stimulates muscle anabolism equivalently to an isoenergetic milk protein-blend containing a greater quantity of essential amino acids in older men.

BACKGROUND & AIMS: Nutritional composition is key for skeletal muscle maintenance into older age. Yet the acute effects of collagen protein blended with other protein sources, in relation to skeletal muscle anabolism, are ill-defined. We investigated human muscle protein synthesis (MPS) responses to a 20 g blend of collagen protein hydrolysate + milk protein (CP+MP, 125 ml) oral nutritional supplement (ONS) vs. 20 g non-blended milk protein source (MP, 200 ml) ONS, in older adults. METHODS: Healthy older men (N = 8, 71±1 y, BMI: 27±1 kg·m-2) underwent a randomized trial of 20 g protein, from either a CP+MP blend (Fresubin®3.2 kcal DRINK), or a kcal-matched (higher in essential amino acids (EAA) ONS of MP alone. Vastus lateralis (VL) MPS and plasma AA were determined using stable isotope-tracer mass spectrometry; anabolic signaling was quantified via immuno-blotting in VL biopsies taken at baseline and 2/4 h after ONS feeding. Plasma insulin was measured via enzyme-linked immunosorbent assay (ELISA). Measures were taken at rest, after the feed (FED) and after the feed + exercise (FED-EX) conditions (unilateral leg exercise, 6 × 8, 75% 1-RM). RESULTS: MP resulted in a greater increase in plasma leucine (MP mean: 152 ± 6 µM, CP+MP mean: 113 ± 4 µM (Feed P < 0.001) and EAA (MP mean: 917 ± 25 µM, CP+MP mean: 786 ± 15 µM (Feed P < 0.01) than CP+MP. CP + MP increased plasma glycine (peak 385 ± 57 µM (P < 0.05)), proline (peak 323 ± 29 µM (P < 0.01)) and non-essential amino acids (NEAA) (peak 1621 ± 107 µM (P < 0.01)) with MP showing no increase. Plasma insulin increased in both trials (CP+MP: 58 ± 10 mU/mL (P < 0.01), MP: 42 ± 6 mU/mL (P < 0.01), with peak insulin greater with CP+MP vs. MP (P < 0.01). MPS demonstrated equivalent increases in response to CP+MP and MP under both FED (MP: 0.039 ± 0.005%/h to 0.081 ± 0.014%/h (P < 0.05), CP+MP: 0.042 ± 0.004%/h to 0.085 ± 0.007%/h (P < 0.05)) and FED-EX (MP: 0.039 ± 0.005%/h to 0.093 ± 0.013%/h (P < 0.01), CP+MP: 0.042 ± 0.004%/h to 0.105 ± 0.015%/h, (P < 0.01)) conditions. FED muscle p-mTOR fold-change from baseline increased to a greater extent with CP+MP vs. MP (P < 0.05), whilst FED-EX muscle p-eEF2 fold-change from baseline decreased to a greater extent with CP+MP vs. MP (P < 0.05); otherwise anabolic signaling responses were indistinguishable. CONCLUSION: Fresubin®3.2 kcal DRINK, which contains a 20 g mixed blend of CP+MP, resulted in equivalent MPS responses to MP alone. Fresubin® 3.2 Kcal DRINK may provide a suitable alternative to MP for use in older adults and a convenient way to supplement calories and protein to improve patient adherence and mitigate muscle mass loss.

A case of neonate effectively treated with everolimus for giant hepatic hemangioma complicated with congenital duodenal atresia and Kasabach-Merritt syndrome.

BACKGROUND: Disseminated intravascular coagulation (DIC) with Kasabach-Merrit syndrome from a large hepatic hemangioma is life-threatening. We report a case of giant hepatic hemangioma of the newborn with KMS. RESULTS: The patient was born at 37 gestational weeks and 2 days via cesarean section; weight at birth was 2952 g. Congenital duodenal atresia was noted during the fetal period. DIC developed after delivery and a giant liver hemangioma was diagnosed via abdominal CT. The cause of DIC was Kasabach-Merritt syndrome owing to a giant hepatic hemangioma. First, combination therapy of 2 mg/kg/day of prednisolone and 0.2 mg/kg/day of propranolol was initiated form enterostomy. However, the size of the hepatic hemangioma did not alter, as observed via image evaluation. Therefore, 0.3 mg/kg/day of everolimus was administered frorm enterostomy. Subsequently, the size of the hepatic hemangioma was assessed via image evaluation. Although it did not alter, blood flow to the hepatic hemangioma decreased and thrombocytopenia was also suppressed. We performed hepatic lateral segmentectomy, radical operation for duodenal atresia. The pathological diagnosis of the removed tumor was infantile hemangioma. CONCLUSION: We report everolimus may be useful when PSL and propranolol are ineffective.

Relationship between nutritional status and esophageal fistula formation after radiotherapy for esophageal cancer.

PURPOSE: Chemoradiotherapy and radiotherapy for esophageal cancer sometimes cause esophageal fistulas. Esophageal fistulas often require additional procedures and are associated with a high mortality rate. The present study was conducted to determine the risk factors associated with esophageal fistulas in patients with esophageal cancer. PATIENTS AND METHODS: We reviewed the cases of 206 patients who were treated with definitive radiotherapy for esophageal cancer. The planning dose, which ranged from 44 to 64.8Gy (median: 59.4Gy), was delivered to the primary lesion and regional lymph nodes. Descriptive statistics were calculated, and time-to-event analyses were performed using Cox proportional hazards regression analysis. RESULTS: None of the 68 patients with T1 or T2 esophageal cancer developed esophageal fistulas. Among the 138 patients with T3 or T4 esophageal cancer, esophageal fistulas were detected in 20 (14.5%) patients. Multivariate analysis of the 138 patients with T3 or T4 esophageal cancer revealed low body mass index (BMI) to be an independent risk factor for esophageal fistula formation (P=0.0055). The optimal BMI cut-off value for predicting esophageal fistula formation was 20 kg/m2 (P=0.0121, odds ratio=4.130). CONCLUSION: In patients with esophageal cancer treated with definitive radiotherapy, a BMI below20kg/m2 is a risk factor for esophageal fistula formation. A well-designed randomized controlled trial comparing the incidence of esophageal fistulas between patients with esophageal cancer who do and do not receive nutritional support before radiotherapy is required.

Opportunity is the greatest barrier to providing palliative care to advanced colorectal cancer patients: a survey of oncology clinicians.

Palliative care (pc) is part of the recommended standard of care for patients with advanced cancer. Nevertheless, delivery of pc is inconsistent. Patients who could benefit from pc services are often referred late-or not at all. In planning for improvements to oncology pc practice in our health care system, we sought to identify barriers to the provision of earlier pc, as perceived by health care providers managing patients with metastatic colorectal cancer (mcrc). We used the Michie Theoretical Domains Framework (tdf) and Behaviour Change Wheel (bcw), together with knowledge of previously identified barriers, to develop a 31-question survey. The survey was distributed by e-mail to mcrc health care providers, including physicians, nurses, and allied staff. Responses were obtained from 57 providers (40% response rate). The most frequently cited barriers were opportunity-related-specifically, lack of time, of clinic space for consultations, and of access to specialist pc staff or services. Qualitative responses revealed that resource limitations varied by cancer centre location. In urban centres, time and space were key barriers. In rural areas, access to specialist pc was the main limiter. Self-perceived capability to manage pc needs was a barrier for 40% of physicians and 30% of nurses. Motivation was the greatest facilitator, with 89% of clinicians perceiving that patients benefit from pc. Based on the Michie tdf and bcw model, interventions that best address the identified barriers are enablement and environmental restructuring. Those findings are informing the development of an intervention plan to improve oncology pc practices in a publicly funded health care system.

Effects of assisted reproductive technologies in neonates with indications for surgery (2007-2016).

PURPOSE: Recently, the number of births using assisted reproductive technologies (ART) has increased. An associated increase in the incidence of congenital malformations in babies conceived using this technology has also been reported. Therefore, we aimed to investigate the rate of malformations in babies with neonatal surgical diseases, who were conceived using ART. MATERIALS AND METHODS: Between January 2007 and December 2016, 1737 patients were admitted to our hospital. We analyzed the incidence of congenital cardiac diseases, genetic anomalies, and congenital anomalies of the kidney and urinary tract (CAKUT) in neonates conceived by ART. The χ2 test and logistic regression analysis were used to assess the odds ratios (ORs) for congenital malformations. A P-value < 0.05 indicated statistical significance. RESULTS: The OR for CAKUT was 16.94 for the first-birth neonates conceived using ART, [P < 0.05, AUC (area under the curve) = 0.86]. However, for non-surgery neonates, the OR for CAKUT was 5.99 (P = 0.15, AUC = 0.87), compared to 32.27 (P < 0.05, AUC = 0.93) for parallel conditions in surgery-neonates. CONCLUSION: Neonates conceived using ART are prone to develop CAKUT, which will need surgical treatment. Therefore, more management is necessary for associated malformations in these babies, particularly in cases with CAKUT.

Hypoxic volume evaluated by 18F-fluoromisonidazole positron emission tomography (FMISO-PET) may be a prognostic factor in patients with oral squamous cell carcinoma: preliminary analyses.

Tumour hypoxia can be detected by 18F-fluoromisonidazole positron emission tomography (FMISO-PET). Few studies have assessed the relationships of new PET parameters, including hypoxic volume (HV), metabolic tumour volume (MTV), and total lesion glycolysis (TLG), with 5-year survival of patients treated surgically for oral squamous cell carcinoma (OSCC). This study evaluated the relationships between these PET parameters and 5-year survival in OSCC patients. Twenty-three patients (age 42-84 years; 15 male, eight female) with OSCC underwent FMISO- and 18F-fluoro-2-deoxyglucose (FDG)-PET computed tomography before surgery. All of them underwent radical surgery and were followed up for more than 5 years. The FDG-PET maximum standardized uptake value (SUVmax), HV, MTV, and TLG were measured. The ability of PET parameters to predict disease-free survival (DFS) and loco-regional recurrence (LR) was evaluated using receiver operating characteristic curve analysis. During the follow-up period, five of the 23 patients (22%) died and six (26%) experienced LR. Although FDG-PET SUVmax was not significantly associated with DFS or LR, HV correlated significantly with both DFS and LR. TLG, but not MTV, was significantly associated with DFS; however neither MTV nor TLG was related significantly to LR. In conclusion, tumour HV may predict outcomes in patients with OSCC.

CYFRA 21-1 as a tumor marker for squamous cell carcinoma of the esophagus.

This study assessed the clinical value of CYFRA 21-1 in comparison with squamous cell carcinoma antigen (SCC-Ag), carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA19-9) in patients with esophageal squamous cell carcinoma. In 112 primary cancer patients, the diagnostic sensitivity of CYFRA 21-1 (33.9%) was superior to SCC-Ag (28.6%), CEA (12.5%), and CA19-9 (6.3%). Levels of CYFRA 21-1 were closely correlated with TNM stage and were below the cutoff value in all 21 patients with stage I disease. All 38 patients with a CYFRA 21-1 level over the cutoff value among the 80 patients who underwent esophagectomy had lymph node metastases (pNl). A correlation was found between CYFRA 21-1 levels and clinical response in serial measurements of 21 patients who received chemotherapy or chemo radiotherapy. Our findings suggest that CYFRA 21-1 is not useful for diagnosis, but that it is valuable for monitoring the efficacy of therapy.

Case report of multiple pustules of the bilateral lower limbs caused by a granulocyte colony-stimulating factor-producing solid pseudopapillary tumour of the pancreas.

Here we report a rare case of neutrophilic dermatoses related to a granulocyte colony-stimulating factor (G-CSF)-producing solid pseudopapillary tumour (SPT). The patient was a 39-year-old woman presenting with scattered pustules and crusts of the palms, heels and thighs and plaques of the bilateral lower legs. The skin biopsy revealed dense neutrophil infiltration in the epidermis to the dermis. A pancreatic head tumour was detected using computed tomography. A pathological examination of the resected specimen suggested an SPT. As the skin eruption promptly disappeared after SPT resection, we hypothesized that SPT secretes growth factors including epidermal growth factor (EGF) and G-CSF. The SPT cells stained positive for both EGF and G-CSF tumour cells. The serum levels of interleukin (IL)-6 and IL-10 and tumour necrosis factor-α were within normal limits before and after the SPT resection. In contrast, the serum IL-8, EGF and G-CSF levels decreased after the SPT resection. This is a rare case of neutrophilic dermatoses related to a G-CSF-producing SPT. The present case suggests that physicians should be aware that a G-CSF-producing tumour is a differential diagnosis to consider in patients with unusual aseptic pustulosis.

An in vivo screening system to identify tumorigenic genes.

Screening for oncogenes has mostly been performed by in vitro transformation assays. However, some oncogenes might not exhibit their transforming activities in vitro unless putative essential factors from in vivo microenvironments are adequately supplied. Here, we have developed an in vivo screening system that evaluates the tumorigenicity of target genes. This system uses a retroviral high-efficiency gene transfer technique, a large collection of human cDNA clones corresponding to ~70% of human genes and a luciferase-expressing immortalized mouse mammary epithelial cell line (NMuMG-luc). From 845 genes that were highly expressed in human breast cancer cell lines, we focused on 205 genes encoding membrane proteins and/or kinases as that had the greater possibility of being oncogenes or drug targets. The 205 genes were divided into five subgroups, each containing 34-43 genes, and then introduced them into NMuMG-luc cells. These cells were subcutaneously injected into nude mice and monitored for tumor development by in vivo imaging. Tumors were observed in three subgroups. Using DNA microarray analyses and individual tumorigenic assays, we found that three genes, ADORA2B, PRKACB and LPAR3, were tumorigenic. ADORA2B and LPAR3 encode G-protein-coupled receptors and PRKACB encodes a protein kinase A catalytic subunit. Cells overexpressing ADORA2B, LPAR3 or PRKACB did not show transforming phenotypes in vitro, suggesting that transformation by these genes requires in vivo microenvironments. In addition, several clinical data sets, including one for breast cancer, showed that the expression of these genes correlated with lower overall survival rate.