Genomic profiling of Acute lymphoblastic leukemia in ataxia telangiectasia patients reveals tight link between ATM mutations and chromothripsis.

Recent developments in sequencing technologies led to the discovery of a novel form of genomic instability, termed chromothripsis. This catastrophic genomic event, involved in tumorigenesis, is characterized by tens to hundreds of simultaneously acquired locally clustered rearrangements on one chromosome. We hypothesized that leukemias developing in individuals with Ataxia Telangiectasia, who are born with two mutated copies of the ATM gene, an essential guardian of genome stability, would show a higher prevalence of chromothripsis due to the associated defect in DNA double-strand break repair. Using whole-genome sequencing, fluorescence in situ hybridization and RNA sequencing, we characterized the genomic landscape of Acute Lymphoblastic Leukemia (ALL) arising in patients with Ataxia Telangiectasia. We detected a high frequency of chromothriptic events in these tumors, specifically on acrocentric chromosomes, as compared with tumors from individuals with other types of DNA repair syndromes (27 cases total, 10 with Ataxia Telangiectasia). Our data suggest that the genomic landscape of Ataxia Telangiectasia ALL is clearly distinct from that of sporadic ALL. Mechanistically, short telomeres and compromised DNA damage response in cells of Ataxia Telangiectasia patients may be linked with frequent chromothripsis. Furthermore, we show that ATM loss is associated with increased chromothripsis prevalence in additional tumor entities.

Leaf gas exchange characteristics differ among Sonoran Desert riparian tree species.

We investigated leaf gas exchange responses to leaf temperature, leaf-to-air vapor pressure deficit (VPD), and predawn and midday shoot water potential (psipd and psimd, respectively) of two native Sonoran Desert riparian tree species, Fremont cottonwood (Populus fremontii S. Wats.) and Goodding willow (Salix gooddingii Ball), and one exotic riparian tree species, saltcedar (Tamarix chinensis Lour. and related species). Measurements were made at two sites over 2 years that differed climatically. Because multiple linear regression models explained less than 29% of the variation in stomatal conductance (gs) and less than 48% of the variation in net photosynthetic rate (Pn) of all species, we used boundary-line analysis to compare gas exchange responses among species. Gas exchange rates were high in all species. The hyperbolic relationship between Pn and gs suggested that initial reductions in gs at high gs did not inhibit Pn. Reductions in gs of cottonwood and willow occurred at psimd values at or below previously reported xylem cavitation thresholds (-1.6 and -1.4 MPa, respectively), indicating tight stomatal regulation of water loss and a narrow cavitation safety margin. In contrast, reductions in gs of saltcedar occurred at psimd values well above the cavitation threshold (-7.0 MPa), but at much lower psimd values than in cottonwood and willow, suggesting a wider cavitation safety margin and less tight regulation of water loss in saltcedar. High VPD had a smaller effect on leaf gas exchange in willow than in cottonwood. In contrast, willow had a less negative psipd threshold for stomatal closure than cottonwood. Compared with cottonwood and willow, leaf gas exchange of saltcedar was more tolerant of high VPD and low psipd. These physiological characteristics of saltcedar explain its widespread success as an invader of riparian ecosystems containing native Fremont cottonwood and Goodding willow in the Sonoran Desert.

Foliar injury, leaf gas exchange and biomass responses of black cherry (Prunus serotina Ehrh.) half-sibling families to ozone exposure.

Open pollinated families of black cherry seedlings were studied to determine genotypic differences in foliar ozone injury and leaf gas exchange in 1994 and growth response following three growing seasons. An O(3)-sensitive half-sibling family (R-12) and an O(3)-tolerant half-sibling family (MO-7) planted in natural soil were studied along with generic nursery stock (NS) seedlings. Ozone exposure treatments were provided through open top chambers and consisted of 50, 75, and 97% of ambient ozone, and open plots from May 9 to August 26, 1994. Ambient ozone concentrations reached an hourly peak of 88 ppb with 7-hour averages ranging from 39 to 46 ppb. Seedlings in the 50 and 75% of ambient chambers were never exposed to greater than 80 ppb O(3). Visible foliar ozone injury (stipple) was significantly higher for R-12 seedlings than MO-7 seedlings and increased with increasing ozone exposures. For the chamber treatments averaged over all families, there was no significant difference in stomatal conductance and net photosynthetic rates, but there was a significant decrease in root biomass, and a significant decrease in root/shoot ratio between the 50 and 97% of ambient chambers. Stomatal conductance and net photosynthetic rates were significantly different between families with R-12 seedlings generally greater than MO-7 seedlings. The R-12 seedlings had a 7.5 mmol m(-2) increase in ozone uptake compared to MO-7, and at the same cumulative O(3) exposure R-12 exhibited 40.9% stippled leaf area, whereas MO-7 had 9.2% stippled leaf area. Significant differences were observed in stem volume growth and total final biomass between the open-top chambers and open plots. Although R-12 had the most severe foliar ozone injury, this family had significantly greater stem volume growth and total final biomass than MO-7 and NS seedlings. Root:shoot ratio was not significantly different between MO-7 and R-12 seedlings.

Differences in leaf gas exchange and water relations among species and tree sizes in an Arizona pine-oak forest.

We compared leaf gas exchange and water potential among the dominant tree species and major size classes of trees in an upland, pine-oak forest in northern Arizona. The study included old-growth Gambel oak (Quercus gambelii Nutt.), and sapling, pole, and old-growth ponderosa pines (Pinus ponderosa var. scopulorum Dougl. ex Laws.). Old-growth oak had higher predawn leaf water potential (Psi(leaf)) than old-growth pine, indicating greater avoidance of soil water stress by oak. Old-growth oak had higher stomatal conductance (G(w)), net photosynthetic rate (P(n)), and leaf nitrogen concentration, and lower daytime Psi(leaf) than old-growth pine. Stomatal closure started at a daytime Psi(leaf) of about -1.9 MPa for pine, whereas old-growth oak showed no obvious reduction in G(w) at Psi(leaf) values greater than -2.5 MPa. In ponderosa pine, P(n) and G(w) were highly sensitive to seasonal and diurnal variations in vapor pressure deficit (VPD), with similar sensitivity for sapling, pole, and old-growth trees. In contrast, P(n) and G(w) were less sensitive to VPD in Gambel oak than in ponderosa pine, suggesting greater tolerance of oak to atmospheric water stress. Compared with sapling pine, old-growth pine had lower morning and afternoon P(n) and G(w), predawn Psi(leaf), daytime Psi(leaf), and soil-to-leaf hydraulic conductance (K(l)), and higher foliar nitrogen concentration. Pole pine values were intermediate between sapling and old-growth pine values for morning G(w) and daytime Psi(leaf), similar to sapling pine for predawn Psi(leaf), and similar to old-growth pine for morning and afternoon P(n), afternoon G(w), K(l), and foliar nitrogen concentration. For the pines, low predawn Psi(leaf), daytime Psi(leaf), and K(l) were associated with low P(n) and G(w). Our data suggest that hydraulic limitations are important in reducing P(n) in old-growth ponderosa pine in northern Arizona, and indicate greater avoidance of soil water stress and greater tolerance of atmospheric water stress by old-growth Gambel oak than by old-growth ponderosa pine.

Occult cancer in women with dense breasts: detection with screening US--diagnostic yield and tumor characteristics.

PURPOSE: To evaluate bilateral screening ultrasound (US) in the detection of otherwise occult masses and cancer in women with dense breasts and normal mammographic and physical examination findings. MATERIALS AND METHODS: Of 11,220 consecutive patients prospectively examined, all 3,626 women with dense breasts and normal mammographic and physical examination findings underwent physician-performed screening US. The size and stage of cancers detected with US alone were compared with those of cancers detected on mammograms, at physical examination, or both, in the remainder of the patients. RESULTS: In the group of 3,626 women, 11 surgically proved cancers in 11 women (prevalence, 0.30%) were identified with US alone. These cancers were not statistically significantly different in mean surgical size and stage from those of 61 nonpalpable, mammographically detected cancers and were smaller and lower in stage than 64 palpable cancers (P < .01) that were diagnosed in the remainder of the population. In the women with dense breasts, overall cancer detection increased by 17% (from 63 to 74 tumors), and the number of tumors detected only with imaging increased by 37% (from 30 to 41 tumors). CONCLUSION: Screening US can depict small, early-stage, otherwise occult cancers similar in size and stage to mammographically identified nonpalpable cancers and smaller and lower in stage than palpable cancers in dense breasts.

Ophthalmoplegia and facial numbness following treated squamous carcinoma of the forehead.

A 62-year-old man presented with progressive diplopia, left ptosis, proptosis, complete ophthalmoplegia, facial numbness, and headache of 2 1/2 months' duration. The symptoms started 1 month after surgical resection of a squamous cell carcinoma in the left side of the forehead. Imaging studies helped localize the lesion, correlating with clinical features. The differential diagnosis is discussed. The final diagnosis was confirmed by autopsy.

Estimation of myocardial water content using transverse relaxation time from dual spin-echo magnetic resonance imaging.

Dual spin-echo magnetic resonance imaging may be used for calculation of transverse myocardial relaxation time from the signal intensity of the echoes considered. In this study, the ability of myocardial transverse relaxation time (T2) to quantitate myocardial edema of the right ventricle (RV) and left ventricle (LV) was tested. Dual spin-echo magnetic resonance images of the entire hearts were obtained and T2 of the RV and LV myocardium calculated from the signal intensities within multiple regions of interest distributed over the myocardium. Six hearts were intermittently perfused through an aortic cannula with three perfusates of decreasing osmolality. Biopsies were obtained for water content (WC) analysis both before and after imaging the hearts at baseline and post-perfusion. A seventh (control) heart was not perfused; instead dual spin-echo imaging was performed at the same time intervals as in the perfused hearts. Prior to any intervention, there was no significant difference between baseline RV (79.49 +/- 2.10%) and LV (77.99 +/- 2.44%, p = .2) myocardial water content; RV myocardial T2 (59.9 +/- 5.8 msec) was slightly but not significantly longer than that of the LV (54.6 +/- 5.7 msec, p = .1). After induction of edema, strong correlation was found between right ventricular myocardial water content measurements and right ventricular T2 (RV WC = 68.5 + 0.19 x RV T2; N = 27, R = 0.92, p < .0001, SEE = 1.56%). Similarly, strong correlation was found between left ventricular myocardial water content and T2 (LV WC = 62.1 + 0.29 x LV T2; N = 27, R = 0.92, p < .0001, SEE = 1.80%).(ABSTRACT TRUNCATED AT 250 WORDS)

CHOP-VP16 chemotherapy and involved field irradiation for high grade non-Hodgkin's lymphomas: a phase II multicentre study.

Sixty previously untreated patients with high grade non-Hodgkin's lymphomas stages II-IV received cyclophosphamide 750 mg m2 i.v., doxorubicin 50 mg m2 i.v., and vincristine 2 mg i.v. on day 1, prednisolone 100 mg p.o. on days 1-5 and etoposide 100 mg m2 i.v. on days 3-5 (CHOP-VP16). After four courses an involved field irradiation with a total dose of 25 Gy was employed and followed by two additional courses of CHOP-VP16. The overall response rate was 93%, with 49 patients (82%) achieving a complete remission (CR). Seven patients had a partial response and four patients showed no response. During a median follow-up period of 55 months, 22 of the 49 patients with CR relapsed, seven of them achieving a second complete remission with the same drug regimen. A maintained complete remission of up to 68 months was seen in 55% of all patients initially achieving CR. The median survival is 43 months. Mean side-effects of this drug regimen were alopecia (89%), nausea/vomiting (76%) and leukopenia (61%). No therapy-related deaths were seen. The results of this study demonstrate that this combined modality treatment produces high complete remission rates and that more than half of these patients achieve long-term disease-free survival.

[Multicenter study of the treatment of highly malignant non-Hodgkin's lymphomas with polychemotherapy (CHOPV) and irradiation]. / Multizentrische Studie zur Behandlung hochmaligner Non-Hodgkin-Lymphome mit Polychemotherapie (CHOPV) und Bestrahlung.

In a multicenter study 46 untreated patients with highly-malignant non-Hodgkin's lymphomas stage II-IV received 6 courses of the following drug combination: cyclophosphamide 750 mg/m2 i.v. day 1, adriamycin 50 mg/m2 i.v. day 1, vincristine 2 mg i.v. day 1, prednisolone 100 mg p.o. days 1-5, and etoposide 100 mg/m2 i.v. days 3-5. Between courses 4 and 5 an involved field irradiation with a total dose of 25 Gy was employed. The overall response rate was 91%, with 38 patients achieving a complete remission (82%), 4 patients achieving a partial remission (9%), and 4 patients showing no response (9%). During a median follow-up period of 34 months 16 out of 38 patients relapsed, 4 of them achieving a second complete remission with the same drug regimen. A maintained complete remission up to 52 months was seen in 51% of all patients initially achieving CR. The overall survival curve shows a plateau at 60% at 30 months, while disease-free survival shows a plateau at 51% at 36 months. Mean side effects of this drug regimen were alopecia (89%), nausea/vomiting (76%), and leukopenia (61%). No therapy-related deaths were reported. The results of this study demonstrate that this treatment produces high complete remission rates and that the majority of these patients achieves long-term disease-free survival.

Cystosarcoma phyllodes metastatic to a brenner tumor of the ovary.

A patient had cytosarcoma phyllodes that developed metastases to bone and to a Brenner tumor of the ovary. The original breast tumor was reported as benign, but the patient died of metastases four months following mastectomy. The rapid growth in the ovary may have been due to estrogenic stroma in the Brenner tumor. This is the first report, to our knowledge, of cystosarcoma phyllodes metastasizing to another tumor.