Intratumor heterogeneity and branched evolution revealed by multiregion sequencing.

BACKGROUND: Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples. METHODS: To examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy profiling on multiple spatially separated samples obtained from primary renal carcinomas and associated metastatic sites. We characterized the consequences of intratumor heterogeneity using immunohistochemical analysis, mutation functional analysis, and profiling of messenger RNA expression. RESULTS: Phylogenetic reconstruction revealed branched evolutionary tumor growth, with 63 to 69% of all somatic mutations not detectable across every tumor region. Intratumor heterogeneity was observed for a mutation within an autoinhibitory domain of the mammalian target of rapamycin (mTOR) kinase, correlating with S6 and 4EBP phosphorylation in vivo and constitutive activation of mTOR kinase activity in vitro. Mutational intratumor heterogeneity was seen for multiple tumor-suppressor genes converging on loss of function; SETD2, PTEN, and KDM5C underwent multiple distinct and spatially separated inactivating mutations within a single tumor, suggesting convergent phenotypic evolution. Gene-expression signatures of good and poor prognosis were detected in different regions of the same tumor. Allelic composition and ploidy profiling analysis revealed extensive intratumor heterogeneity, with 26 of 30 tumor samples from four tumors harboring divergent allelic-imbalance profiles and with ploidy heterogeneity in two of four tumors. CONCLUSIONS: Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through Darwinian selection. (Funded by the Medical Research Council and others.).

Prevention of secondary lymphedema.

After some preliminary remarks upon pathophysiologic and anatomo-surgical aspects, the main complications of axillary lymph-nodal dissection for breast cancer treatment are reported. The role of surgical technique is particularly underlined and also the importance of proper management of wound and surgical drainage post-operatively are pointed out. Author describes, finally, the necessity of an adequate knowledge of lymphatic drainage not only of mammary region, but also of surrounding area, in order to prevent lesions to lymphatic pathways, particularly to those draining upper arm at the same site of breast cancer.

A population-based study of the use and outcome of radical radiotherapy for invasive bladder cancer.

PURPOSE: The objective of this study is to describe the use and outcome of radical radiotherapy for bladder cancer in the province of Ontario, Canada, between 1982 and 1994. METHODS: Electronic records of invasive bladder cancer (ICD code 188) from the Ontario Cancer Registry were linked to surgical records from all Ontario hospitals and radiotherapy (RT) records from all Ontario cancer centers. We identified cases receiving radical RT by selecting RT records containing "bladder" or "pelvis" anatomic region codes and a radical or curative intent code (or dose >39.5 Gy if intent missing). We identified cases receiving salvage total cystectomy by selecting total cystectomy procedure codes occurring at any time beyond 4 months from the start of radical RT. We used life table methods to compute the following: the time from diagnosis to radical RT, the time from radical RT to salvage cystectomy, overall and cause-specific survival from radical radiotherapy to death, and overall and cause-specific survival from salvage cystectomy to death. We modeled the factors associated with time to death, time to cystectomy conditional on survival, and time to cystectomy or death, whichever came first, using Cox proportional hazards regression. RESULTS: From the 20,906 new cases of bladder cancer diagnosed in Ontario from 1982 to 1994, we identified 1,372 cases treated by radical radiotherapy (78% male, 22% female; mean age 69.8 years). The median interval to start of radical RT from diagnosis was 13.4 weeks. Ninety-three percent of patients were treated on high-energy linacs, and the most common dose/fractionation scheme was 60 Gy/30 (31% of cases). Five-year survival rates were as follows: bladder cancer cause-specific, 41%; overall, 28%; cystectomy-free, 25%; bladder cancer cause-specific following salvage cystectomy, 36%; overall following salvage cystectomy, 28%. Factors associated with a higher risk of death and a poorer cystectomy-free survival were histology (squamous or nonpapillary transitional cell carcinoma [TCC]) and advanced age. CONCLUSION: This population-based study confirms previous institutional studies and clinical trials and shows that radical RT has a curative role in the management of invasive bladder cancer and allows about one-quarter of patients receiving radiotherapy to survive 5 years while retaining the bladder. Salvage cystectomy following RT provides a chance of cure at the time of bladder relapse.

Long-term outcome of radical radiation therapy for prostatic carcinoma: 1967-1987.

PURPOSE: This study was done to review long-term results of radical radiotherapy for prostate cancer. METHODS AND MATERIALS: The records of 674 patients with Stage T1a, T1b, T2a, T2b, T3, and any T,N1,M0 disease, treated with external beam radiotherapy between January 1, 1967 and December 1987, were reviewed. These patients were treated to an average total dose of 66 Gy, with an average fractional dose of 2.05 Gy, using megavoltage. The duration of follow-up for surviving patients ranged from a minimum of 7 years to more than 20 years. RESULTS: The survival for 151 Stage T1a,T1b patients was 98.5% at 5 years, 93.6% at 10 years, and 75.2% at 15 years. Survival for 346 Stage T2a,b patients was 94.4% at 5 years, 67.9% at 10 years, and 41.5% at 15 years. Survival for 92 Stage T3 patients was 87.3% at 5 years, 54% at 10 years, and 26.6% at 15 years. The survival for 85 any T,N1,M0 patients was 73.9% at 5 years, 34.4% at 10 years, and 8.5% at 15 years. At 15 years, 75.2% of Stage T1a,b patients, 41.5% of Stage T2a,b patients, 21.7% of Stage T3 patients, and 8.5% of Stage T,N1,M0 patients remained free of local recurrence and distant metastases. The elevation of prostatic acid phosphatase prior to radiotherapy was an unfavorable prognostic factor, with impact on both loco-regional recurrences and survival. CONCLUSIONS: The external beam radiotherapy for localized carcinoma of the prostate produced a good loco-regional control, NED, and overall survival. Patients with smaller tumors and low grade fared better than the ones with more aggressive and/or bulky tumors. The weakness of this study is the absence of serial prostate-specific measurements, which were not available during the period under study. The complication rate requiring surgical intervention was low, i.e. 0.4%.

Low frequency of endoscopic esophagitis in Asian patients.

The aim of this study was to determine the frequency of endoscopic esophagitis in patients seen for upper gastrointestinal complaints in an Asian center. We studied a consecutive series of 11,943 patients undergoing diagnostic esophagogastroduodenoscopy at our unit over a 10-year period. Three hundred and eighty-nine patients (3.3%) had endoscopic esophagitis with no other significant lesion (primary esophagitis), whereas 143 (1.2%) had esophagitis associated with peptic ulcer or gastric or duodenal malignancy (secondary esophagitis). In contrast, peptic ulcer was diagnosed in 2,787 patients (23.3%) and gastric carcinoma in 286 (2.4%). The reported frequency of endoscopic esophagitis among patients undergoing endoscopy in Western countries varied from 9 to 23%. Our data therefore show that endoscopic esophagitis is much less common in Singaporean patients.

The diagnostic yield of upper gastrointestinal endoscopy in the investigation of anaemia.

Computer records of patients endoscoped over a 34-month period were studied to assess the diagnostic yield of gastrointestinal endoscopy in patients with anaemia. Patients with obvious gastrointestinal bleeding and known gastrointestinal pathology were excluded. On hundred and thirty-six patients were endoscoped for anaemia. Eighty-three of them (61%) had iron deficiency anaemia and 53 (39%) had other types of anaemia. The ages of the patients with iron deficiency anaemia (mean 56 years) were significantly lower than those of other anaemias (means 65 years), (p less than 0.003). Patient characteristics were otherwise comparable. There were significant endoscopic findings (ulcers, carcinoma and haemorrhagic or erosive gastritis) in 26 of 83 patients (31%) with iron deficiency anaemia, in 11 of 53 patients with other anaemias (21%) and 37 of 136 patients (27%) combined. Significant endoscopic findings were found in 506 of 2224 patients (23%) endoscoped during this period who were not anaemic, did not have obvious gastrointestinal haemorrhage and were not known to have gastrointestinal diseases. The diagnostic yield for iron deficiency anaemia was significantly higher than for the non anaemic group (p less than 0.05). There was no difference between the diagnostic yields of iron deficiency and other anaemias, other anaemias and the non anaemic group, or total anaemias and the non anaemic group. Gastrointestinal symptoms and history of analgesic or steroid usage did not appear to increase the incidence of gastrointestinal lesions in either iron deficiency anaemia or other anaemias. Twenty-three of 41 patients (56%) who had no cause for anaemia found at the end of all investigations were colonscoped.(ABSTRACT TRUNCATED AT 250 WORDS)

The site of recurrent duodenal ulcer.

The aim of this retrospective study was to determine the site of recurrent duodenal ulcer in relation to the site of the index ulcer. One hundred and thirty-five patients who had recurrent duodenal ulcer after documented healing of an index ulcer were studied. The recurrent ulcer was more likely to occur in the anterior bulb if the index ulcer was anterior (35 of 58 = 60%) than if the index ulcer was not anterior (29 of 77 = 38%, p less than 0.01). However, the likelihood of a recurrent ulcer on the posterior wall of the bulb was not significantly different whether the index ulcer was posterior (11 of 36 = 31%) or not (22 of 99 = 22%, p less than 0.24). Three of 20 patients (15%) who initially presented with bleeding bled again with their recurrent ulcers, compared with eight of 115 patients (7%) who first presented with dyspepsia only (p = 0.39). Thirteen patients were assessed independently by two endoscopists to determine ulcer site. Their assessments concurred for 12 (92%).

Helicobacter pylori and gastritis in patients with peptic ulcer and non-ulcer dyspepsia: ethnic differences in Singapore.

Peptic ulcer occurs with different frequencies in the three main racial groups in Singapore. This study aimed firstly to determine the prevalence of Helicobacter pylori in peptic ulcer and non-ulcer dyspepsia patients of the different races and secondly, to assess the relation between H pylori, histological gastritis, patient diagnosis, and race. Gastric antral biopsy specimens from 1502 patients undergoing gastroduodenoscopy were studied and 892 (59%) were positive for H pylori. H pylori was strongly associated with gastritis: 873 of 1197 (73%) patients with gastritis were positive compared with 19 of 305 (6%) without gastritis (p less than 0.0001). The prevalences of H pylori and gastritis were similar in peptic ulcer patients of different races. Malay patients with non-ulcer dyspepsia, however, were less likely to be positive for H pylori (10 of 46 (22%] or to have antral gastritis (17 of 46 (37%] than Chinese (292 of 605 (48%) were positive for H pylori and 421 of 605 (70%) had gastritis) and Indians (35 of 61 (57%) were H pylori positive and 42 of 61 (69%) had gastritis). Patients with duodenal ulcer were more likely to be positive for H pylori than those with non-ulcer dyspepsia, even when subjects with gastritis were considered separately. While our results do not help to explain the observed racial differences in peptic ulcer frequency it may be that the pathophysiology of non-ulcer dyspepsia is different in the different races in Singapore.

Effect of colloidal bismuth subcitrate on symptoms and gastric histology in non-ulcer dyspepsia. A double blind placebo controlled study.

The aim of this study was to determine the effect of colloidal bismuth subcitrate (De Nol) on symptoms and gastric histology in patients with non-ulcer dyspepsia. In a single centre trial, patients with food related upper abdominal pain not caused by ulcer disease were randomised to receive one tablet of colloidal bismuth subcitrate or matching placebo four times daily for eight weeks. Seventy three patients were entered and 51 completed the trial: 28 patients in the colloidal bismuth subcitrate group and 23 in the placebo group. Overall there was no difference between the two groups in terms of symptom relief. Among patients with histological gastritis (n = 23), however, those who took colloidal bismuth subcitrate used fewer antacid tablets (for three of four fortnightly periods) and were more likely to become asymptomatic (eight of 11 v three of 12, p less than 0.05); their gastritis was more likely to resolve (five of 10 v 0 of 12, p less than 0.025) and their gastric biopsies more likely to become negative for Helicobacter like organisms (eight of nine v 0 of 12, p less than 0.001) when compared with patients taking placebo. In contrast, patients who did not have gastritis in their index biopsies (n = 28) fared similarly whether they received colloidal bismuth subcitrate or placebo. Our results indicate that the administration of colloidal bismuth subcitrate benefited non-ulcer dyspepsia patients with gastritis but had no effect on those without.

Acid induced duodenal ulcer pain: the influence of symptom status and the effect of an antispasmodic.

The aims of this study were to determine whether the development of acid induced duodenal ulcer pain was influenced by the symptomatic status of the patient and whether the administration of an antispasmodic could abolish pain. One hundred millilitres of 0.1 N hydrochloric acid was infused onto the ulcer craters or scars of 143 duodenal ulcer patients on 168 occasions. Symptomatic patients were randomised to receive 40 mg of hyoscine intravenously before acid infusion, or to a control group. Typical ulcer pain developed in seven of 55 (13%) instances for non-symptomatic patients, 24/57 (42%) of control symptomatic patients, and 20/56 (36%) of symptomatic patients given hyoscine. (Asymptomatic group v control symptomatic group, p less than 0.005; control symptomatic group v hyoscine group, NS - 95% confidence limits 12% in favour of the control and 24% in favour of the hyoscine group). The results suggest that acid infusion seldom reproduces ulcer pain in non-symptomatic duodenal ulcer patients and that the pathogenesis of acid induced duodenal ulcer pain probably involves a mechanism other than spasm, as pain was not prevented by an anticholinergic.