Increasing frequency of gene copy number aberrations is associated with immunosuppression and predicts poor prognosis in gastric adenocarcinoma.

BACKGROUND: Patients with Epstein-Barr virus-positive gastric cancers or those with microsatellite instability appear to have a favourable prognosis. However, the prognostic value of the chromosomal status (chromosome-stable (CS) versus chromosomal instable (CIN)) remains unclear in gastric cancer. METHODS: Gene copy number aberrations (CNAs) were determined in 16 CIN-associated genes in a retrospective study including test and validation cohorts of patients with gastric cancer. Patients were stratified into CS (no CNA), CINlow (1-2 CNAs) or CINhigh (3 or more CNAs). The relationship between chromosomal status, clinicopathological variables, and overall survival (OS) was analysed. The relationship between chromosomal status, p53 expression, and tumour infiltrating immune cells was also assessed and validated externally. RESULTS: The test and validation cohorts included 206 and 748 patients, respectively. CINlow and CINhigh were seen in 35.0 and 15.0 per cent of patients, respectively, in the test cohort, and 48.5 and 20.7 per cent in the validation cohort. Patients with CINhigh gastric cancer had the poorest OS in the test and validation cohorts. In multivariable analysis, CINlow, CINhigh and pTNM stage III-IV (P < 0.001) were independently associated with poor OS. CIN was associated with high p53 expression and low immune cell infiltration. CONCLUSION: CIN may be a potential new prognostic biomarker independent of pTNM stage in gastric cancer. Patients with gastric cancer demonstrating CIN appear to be immunosuppressed, which might represent one of the underlying mechanisms explaining the poor survival and may help guide future therapeutic decisions.

KRAS status is related to histological phenotype in gastric cancer: results from a large multicentre study.

BACKGROUND: Gastric cancer (GC) is histologically a very heterogeneous disease, and the temporal development of different histological phenotypes remains unclear. Recent studies in lung and ovarian cancer suggest that KRAS activation (KRASact) can influence histological phenotype. KRASact likely results from KRAS mutation (KRASmut) or KRAS amplification (KRASamp). The aim of the study was to investigate whether KRASmut and/or KRASamp are related to the histological phenotype in GC. METHODS: Digitized haematoxylin/eosin-stained slides from 1282 GC resection specimens were classified according to Japanese Gastric Cancer Association (JGCA) and the Lauren classification by at least two observers. The relationship between KRAS status, predominant histological phenotype and clinicopathological variables was assessed. RESULTS: KRASmut and KRASamp were found in 68 (5%) and 47 (7%) GCs, respectively. Within the KRASmut and KRASamp cases, the most frequent GC histological phenotype was moderately differentiated tubular 2 (tub2) type (KRASmut: n = 27, 40%; KRASamp: n = 21, 46%) or intestinal type (KRASmut: n = 41, 61%; KRASamp: n = 23, 50%). Comparing individual histological subtypes, mucinous carcinoma displayed the highest frequency of KRASmut (JGCA: n = 6, 12%, p = 0.012; Lauren: n = 6, 12%, p = 0.013), and KRASamp was more frequently found in poorly differentiated solid type (n = 12, 10%, p = 0.267) or indeterminate type (n = 12, 10%, p = 0.480) GC. 724 GCs (57%) had intratumour morphological heterogeneity. CONCLUSIONS: This is the largest GC study investigating KRAS status and histological phenotype. We identified a relationship between KRASmut and mucinous phenotype. The high level of intratumour morphological heterogeneity could reflect KRASmut heterogeneity, which may explain the failure of anti-EGFR therapy in GC.

Correction to: KRAS status is related to histological phenotype in gastric cancer: results from a large multicentre study.

In the original publication of this article, Fig. 2 was published incorrectly. The correct Fig. 2 is given in this correction.

Frequent Coamplification of Receptor Tyrosine Kinase and Downstream Signaling Genes in Japanese Primary Gastric Cancer and Conversion in Matched Lymph Node Metastasis.

OBJECTIVE: To establish the gene copy number status of receptor tyrosine kinase (RTK) and downstream signaling (DSS) genes genes in primary gastric cancer (primGC) and matched lymph node metastases (LNmet). BACKGROUND: Evidence suggests that coamplification between RTKs and DSSs and conversion between primGC and LNmet are associated with resistance to targeted therapy. METHODS: DNA from 237 Japanese primGC and 103 matched LNmet was analyzed using a newly developed multiplex ligation-dependent probe amplification (MLPA) probemix to investigate RTK (EGFR, HER2, FGFR2, and MET) and DSS (PIK3CA, KRAS, MYC, and CCNE1) gene copy number status. Results were compared between primGC and LNmet and related to clinicopathological data including survival. RESULTS: A total of 150 (63%) primGC had either RTK or DSS amplification. DSS coamplification was more frequent than RTK coamplification in primGC and LNmets. Moreover, 70 (30%) GC showed a disconcordant RTK and/or DSS gene copy number status between primGC and LNmet, most common was negative conversion for DSS genes (n=40 GC). The presence of RTK amplification in primGC was related to poorer survival in univariate analysis (P=0.04). CONCLUSIONS: This is the first and most comprehensive study in gastric cancer investigating the concordance between gene copy number status of targetable RTKs and downstream signaling oncogenes in primGC and LNmets. Future studies need to establish whether the relative high frequency of RTK and DSS coamplification and/or the relative high rate of negative conversion in LNmet can potentially explain recent failures of RTK targeted therapy in gastric cancer patients.

Iliac Fossa Muscle Splitting Incision in Laparoscopic Donor Nephrectomy: A comparison With the Suprapubic Approach.

OBJECTIVE: To compare the outcomes of a transverse suprapubic incision with peritoneal access through the midline (SPM) and an iliac fossa muscle splitting (IFMS) incision for kidney retrieval during laparoscopic donor nephrectomy (LDN). MATERIAL AND METHODS: This observational retrospective comparative cohort study was performed using data from a prospectively maintained database to compare the outcomes of 2 different incisions (SPM n = 35 and IFMS n = 35) used for kidney retrieval during LDN. All incisions were infiltrated with local anesthesia at the time of closure. The primary outcome measure was postoperative analgesic requirements. Secondary outcome measures included donor complication rates and recipient outcomes. Selection bias was minimized by the study of 2 consecutive series of donors. RESULTS: Overall, 28 of the 70 (40%) of the total cohort were male. There was no difference between age (IFMS 49 ± 12 vs SPM 49 ± 11 years, P = .317), body mass index (IFMS 26.5 ± 3.9 vs SPM 25.9 ± 3.3 kg/m2, P = .493), and total postoperative opioid analgesic requirements (IFMS 213 ± 168 vs SPM 211 ± 168 mg, P = .807) between the 2 groups. The volume of local anesthetic infiltrated during wound closure was higher in the IFMS 0.470 ± 0.160 vs SPM 0.370 ± 0.234 mL/kg (P = .030) and associated with a reduction in postoperative opioid requirements (r = -0.511, P = .002). There were no major donor or recipient postoperative complications in either group and no difference in renal allograft function at 3-, 6-, 9-, or 12 months post-transplant. CONCLUSION: An iliac fossa muscle splitting incision is a straightforward and safe approach, providing a reasonable alternative to the more traditional and widely used suprapubic incision for kidney retrieval during LDN.

Dolichoectasia Presenting as Renal Artery Aneurysm in a Deceased Donor Kidney: A Case Report and Review of the Literature.

We describe a case of fusiform aneurysm of the renal artery on a background of dolichoectasia in a kidney recovered from a deceased donor. The donor, a 57-year-old female, had died of an extensive nonsurvivable subarachnoid hemorrhage. Fusiform aneurysms involving the main renal artery and its superior branch had extended into the hilum with insufficient accessible stump for safe reconstruction. Placement of a stent through an intraoperative radiologic intervention was not possible without compromising renal perfusion. Consequently, renal transplant did not proceed. Dolichoectasia is a condition associated with generalized weakness of the arterial vascular wall and may result in aneurysm formation. When the renal artery is involved, a safe reconstruction excising the aneurysmal segment may be considered before transplant of the kidney.