Evaluation of the Impact of Magnetic Resonance Imaging with Susceptibility-weighted Imaging for Screening and Surveillance of Radiation-induced Cavernomas in Long-term Survivors of Malignancy.

AIMS: Radiation-induced cavernomas (RIC) are common late toxicities in long-term survivors of malignancy following cerebral irradiation. However, the natural history of RIC is poorly described. We report the first series of long-term surveillance of RIC using modern magnetic resonance imaging (MRI) including highly sensitive susceptibility-weighted imaging (SWI). The aims of this research were to better characterise the natural history of RIC and investigate the utility of MRI-SWI for screening and surveillance. MATERIALS AND METHODS: Eligibility required long-term survivors of malignancy with previous exposure to cerebral irradiation and RIC identified on MRI-SWI surveillance. The number and size of RIC were reported on Baseline MRI-SWI and last Follow-up MRI-SWI. RESULTS: In total, 113 long-term survivors with RIC underwent MRI-SWI surveillance; 109 (96%) were asymptomatic at the time of RIC diagnosis. The median age at cerebral irradiation was 9.3 years; the median radiotherapy dose was 50.4 Gy. The median time from cerebral irradiation to Baseline MRI-SWI was 17.9 years. On Baseline MRI-SWI, RIC multiplicity was present in 89% of patients; 34% had >10 RIC; 65% had RIC ≥4 mm. The median follow-up from Baseline MRI-SWI was 7.3 years. On Follow-up MRI-SWI, 96% of patients had multiple RIC; 62% had >10 RIC; 72% had RIC ≥4 mm. Of the 109 asymptomatic patients at RIC diagnosis, 96% remained free from RIC-related symptoms at 10 years. Only two required neurosurgical intervention for RIC; there was no RIC-related mortality. CONCLUSIONS: RIC are commonly multiple, asymptomatic and typically increase in size and number over time. Our findings suggest that MRI-SWI for screening of RIC is unlikely to influence longer term intervention in asymptomatic cancer survivors. In the absence of neurological symptoms, assessment or monitoring of RIC are insufficient indications for MRI-SWI surveillance for long-term survivors of malignancy with past exposure to cerebral irradiation.

In pursuit of equity: partnering to improve breast and prostate cancer outcomes among African Americans.

PURPOSE: Community-based participatory research (CBPR) is a collaborative partnership approach that leverages the strengths of academic-community groups to address local problems. CBPR emphasizes equity (e.g., co-learning, power-sharing, participatory decision-making) among groups to achieve goals and promote sustainability. This study examines group dynamics, and their influence on achieving shared goals, within a CBPR-guided partnership established to improve breast and prostate cancer outcomes among underserved African American communities in St. Louis, Missouri. METHODS: We conducted in-person, semi-structured interviews with key academic and community informants and surveyed via email community collaborators involved in outreach activities. Interviews were audiotaped, transcribed, and independently coded by two authors using an iterative, open-coding process to identify major themes. Surveys were summarized using similar coding criteria for open-ended responses and descriptive statistics for discrete responses. Using a grounded theory approach, we summarized and compared themes from each data source to identify similarities and differences and triangulated results to generate overarching thematic findings. RESULTS: Participants described benefits from the partnership (funding; clinical, public health and evaluation expertise; training and networking opportunities) and found beneficial ways to leverage the partners' strengths in collaborating Participants expressed long-term commitment to sustaining the partnership and building capacity to address cancer disparities, but faced challenges related to power-sharing and participatory decision-making. CONCLUSIONS: Using CBPR to address cancer disparities is an effective approach to capacity-building and achieving shared goals. By evaluating the structures and processes within CBPR collaborations through the lens of equity, partners may identify and address challenges that threaten long-term partnership sustainability.

Long-term Survival with 18-Fluorodeoxyglucose Positron Emission Tomography-directed Therapy in Non-small Cell Lung Cancer with Synchronous Solitary Brain Metastasis.

AIMS: At diagnosis, <1% of patients with non-small cell lung cancer (NSCLC) have synchronous solitary brain metastasis (SSBM). In prior cohorts without 18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) staging, definitive treatment to intracranial and intrathoracic disease showed a 5-year overall survival (OS) of 11-21%. We investigated the long-term survival outcomes for patients with SSBM NSCLC, diagnosed in the FDG-PET/CT era and treated definitively with local therapies to both intracranial and intrathoracic sites of disease. MATERIALS AND METHODS: This retrospective study assessed patients staged with FDG-PET/CT who received definitive lung and SSBM treatment from February 1999 to December 2017. A lung-molecular graded prognostic assessment (lung-molGPA) score was assigned for each patient using age, performance status score, and, where carried out, molecular status. Overall survival and progression-free survival (PFS) were calculated using Kaplan-Meier methods. Cox proportional hazard models determined OS and PFS prognostic factors. RESULTS: Forty-nine patients newly diagnosed with NSCLC and SSBM had a median age of 63 years (range 34-76). The median follow-up of all patients was 3.9 years. Thirty-three patients (67%) had ≥T2 disease, 23 (47%) had ≥N2. At 2 years, 45% of first failures were intracranial only (95% confidence interval 30-59). At 3 and 5 years, OS was 45% (95% confidence interval 32-63) and 30% (95% confidence interval 18-51), respectively. In ≥N1 disease, 5-year OS was 34% (95% confidence interval 18-63). The 3- and 5-year PFS was 8% (95% confidence interval 3-22) and 0%, respectively. Higher lung-molGPA was associated with longer OS (hazard ratio 0.26, 95% confidence interval 0.11-0.61, P = 0.002). Higher lung-molGPA (hazard ratio 0.33, 95% confidence interval 0.15-0.71, P = 0.005) and lower N-stage (hazard ratio 1.56, 95% confidence interval 1.13-2.15, P = 0.007) were associated with longer PFS. CONCLUSIONS: Definitive treatment of patients with NSCLC and SSBM staged with FDG-PET/CT can result in 5-year survivors, including those with ≥N1 disease.

Incidence of transformation to aggressive lymphoma in limited-stage follicular lymphoma treated with radiotherapy.

BACKGROUND: The established treatment of limited-stage follicular lymphoma is radiotherapy (RT). There is an inherent risk of transformation of follicular lymphoma to aggressive lymphoma; however, the frequency and impact on the outcome are unknown in limited-stage patients. MATERIALS AND METHODS: We identified 237 patients with limited-stage follicular lymphoma treated with curative intent RT. Cases were reviewed to determine the frequency of transformation and subsequent survival. RESULTS: With a median follow-up of 7.4 years, the 10-year risk of transformation was 18.5%. With a median follow-up after transformation of 4.7 years, the 3-year post-transformation progression-free survival (PFS) and overall survival (OS) were 42% and 44%, respectively. The addition of rituximab improved the 3-year post-transformation PFS and OS compared with combination chemotherapy alone (78% versus 15%, P < 0.00001) and (87% versus 38.5%, P < 0.00001), respectively. In multivariate analysis, only rituximab was associated with OS [HR 0.07 (95% CI 0.015-0.312, P = 0.001)] and PFS [HR 0.19 (95% CI 0.55-0.626, P = 0.007)] following transformation. CONCLUSIONS: There is a moderate risk of transformation in limited-stage follicular lymphoma treated with curative intent RT, and it substantially impacts outcome in these patients. Treatment with rituximab at the time of transformation appears to improve survival in this otherwise poor-risk population.

Minimising critical organ irradiation in limited stage Hodgkin lymphoma: a dosimetric study of the benefit of involved node radiotherapy.

BACKGROUND: Chemotherapy plus radiotherapy is the standard of care for patients with limited stage Hodgkin lymphoma (HL). Radiotherapy is evolving from involved field radiotherapy (IFRT) to involved node radiotherapy (INRT) to decrease radiotherapy-related morbidity. In the absence of long-term toxicity data, dose-volume metrics of organs at risk (OAR) provide a surrogate measure of toxicity risk. PATIENTS AND METHODS: Ten female patients with stage I-IIA supradiaphragmatic HL were randomly selected. All patients had pre-chemotherapy computerised tomography (CT) and CT-positron emission tomography staging. Using CT planning, three radiotherapy plans were produced per patient: (i) IFRT, (ii) INRT using parallel-opposed beams and (iii) INRT using volumetric modulated arc therapy (VMAT). Radiotherapy dose was 30.6 Gy in 1.8 Gy fractions. OAR evaluated were lungs, breasts, thyroid, heart and coronary arteries. RESULTS: Compared with IFRT, INRT significantly reduced mean doses to lungs (P < 0.01), breasts (P < 0.01), thyroid (P < 0.01) and heart (P < 0.01), on Wilcoxon testing. Compared with conventional INRT, VMAT improved dose conformality but increased low-dose radiation exposure to lungs and breasts. VMAT reduced the heart volume receiving 30 Gy (V30) by 85%. CONCLUSIONS: Reduction from IFRT to INRT decreased the volumes of lungs, breasts and thyroid receiving high-dose radiation, suggesting the potential to reduce long-term second malignancy risks. VMAT may be useful for patients with pre-existing heart disease by minimising further cardiac toxicity risks.

Chromosomal alterations in oligodendroglial tumours over multiple surgeries: is tumour progression associated with change in 1p/19q status?

BACKGROUND: Oligodendroglial neoplasms have morphologic and genotypic heterogeneity. Loss of heterozygosity (LOH) of 1p and/or 19q is associated with increased treatment responsiveness and overall survival. However, the pathogenesis of treatment-resistance is unknown. We sought to determine if tumour progression is due to a proliferating sub-population of tumour cells with intact 1p, or if recurrent tumours retain 1p/19q LOH. METHODS: 24 patients with oligodendroglial neoplasms, possessing biopsy samples taken at diagnosis and at progression, were identified. 53 tumour specimens were available for LOH analysis of 1p and 19q, using PCR amplification of multiple microsatellite markers. 40 were also tested for 9p and 10q. RESULTS: At diagnosis, the median age was 34 (24-66) years, 14 were male. 19 tumours were WHO Grade II, and 5 were high grade. The most common genomic status was 19q LOH (70%). 13 (54%) tumours were 1p LOH at diagnosis: of these, 12 were 19q LOH, and 1 was 19q uninformative. All 12 patients with 1p/19q LOH primary tumours had persistent co-deletion at progression. 9 (38%) tumours were 1p intact at diagnosis, and 8 remained 1p intact in the progressed tumours. There was little heterogeneity of 9p and 10q between tumours at diagnosis and progression. CONCLUSION: 100% of oligodendroglial tumours with 1p/19q LOH, demonstrated persistent 1p/19q LOH in the progressed tumour. Therefore, progression of these tumours is not due to a proliferating sub-population of treatment-resistant, 1p intact tumour cells. We propose that additional mutations contribute to this aggressive phenotype, however, 9p LOH or 10q LOH are unlikely to be involved.

Reduction in gingival overgrowth associated with conversion from cyclosporin A to tacrolimus.

BACKGROUND: Unsightly gingival overgrowth affects many individuals immunosuppressed with cyclosporin A (CsA). Current management involves repeated periodontal surgery and intensive hygienist support. Tacrolimus is an effective alternative immunosuppressive agent for renal transplantation which does not appear to produce gingival enlargement. AIMS: The purpose of the present study was to monitor the gingival response of 4 renal transplant patients (RTPs), with clinically significant CsA-induced gingival overgrowth, after their immunosuppressive therapy was switched to tacrolimus. METHODS: Intra-oral photographs and alginate impressions were taken both prior to the drug conversion and again, 6 to 9 months later. Gingival overgrowth scores were determined, from plaster models on both these occasions. RESULTS: All of the RTPs experienced significant resolution of their gingival enlargement within the time period studied; however, only one had complete regression. CONCLUSION: It is concluded that conversion of RTPs with gingival overgrowth from CsA to tacrolimus may provide an effective management strategy for this clinical problem.

Megaloblastic anemia in pregnancy.

Megaloblastic anemia is one of the acquired nutritional anemias that may complicate pregnancy. It is most often secondary to folic acid deficiency because folate requirements are increased during gestation. When the diagnosis of megaloblastic anemia is confirmed, appropriate therapy will initiate a rapid reversal of the anemia process. Because of the association between neural tube defects and folate deficiency, it is recommended that women of reproductive age take folic acid supplementation.

Pre-preparation of the sterile instrument table for emergency cesarean section.

Cesarean section instrument tables are often not prepared in advance because of concern of contamination risk. The Association of Operating Room Nurses Standards decries the use of pre-preparation of surgical instrument tables because of this risk, although there are no scientific data to support this claim. We evaluated the contamination risk of pre-preparation of surgical instrument tables, prolonged table coverage and table uncovering using a specific technique referred to as the "sardine can roll." Colony counts were positive in only seven of 180 cultures (< or = 15 colonies per plate in each instance) from six tables evaluated after prolonged coverage or uncovering, or both. These data suggest that contamination risk is slight for the uncovering technique described herein and advance table preparation (24 hours or less, never recovered) is a reasonable clinical option in units in which table preparation reduces response time in emergent clinical situations, such as cesarean section for acute fetal distress.

Perinatal ovarian cyst: a nonsurgical approach.

A case of an ovarian cyst diagnosed antenatally by ultrasound and showing spontaneous resolution within 5 months after birth is presented. On the basis of this case and others reported in the literature, we recommend expectant follow-up of such lesions with operation recommended only for cysts with solid or complex components or cysts causing symptoms from large size or torsion.

Genetic analysis of the enhancer requirements for polyomavirus DNA replication in mice.

In this report, we describe the first systematic analysis of the genetic requirements for polyomavirus (Py) enhancer-activated viral DNA replication during the acute phase of infection in mice. Four mutants were made which substituted XhoI sites for conserved enhancer consensus sequences (adenovirus type 5 E1A, c-fos, simian virus 40, and a glucocorticoidlike consensus sequence). Viral DNA replication in infected mouse organs was measured by DNA blot analysis. Only the loss of the glucocorticoidlike consensus sequence element significantly reduced Py DNA replication in the kidneys, the primary target organ for viral replication. The loss of the c-fos, adenovirus type 5 E1A, or simian virus 40 consensus sequences, however, expanded organ-specific viral DNA replication, relative to wild-type Py, by allowing high-level replication in the pancreas or heart or both. Analysis of Py variants selected for replication in undifferentiated embryonal carcinoma cell lines (PyF441, PyF111) showed that there was little change in levels of viral DNA replication in kidneys and other organs as compared with those in the wild-type virus. If the entire B enhancer is deleted, only low overall levels of viral replication are observed. Wild-type levels of replication in the kidneys can be reconstituted by addition of a single domain from within the A enhancer (nucleotides 5094 to 5132) to the B enhancer deletion virus, suggesting that a single domain from the A enhancer can functionally substitute for the entire B enhancer. This also indicates that the determinants for kidney-specific replication are not found in the B enhancer.

Functional analysis of the individual enhancer core sequences of polyomavirus: cell-specific uncoupling of DNA replication from transcription.

Polyomavirus (Py) enhancer core elements were compared for their ability to activate Py early transcription and DNA replication in mouse 3T6 cells, lymphoid cell lines, and undifferentiated embryonal carcinoma cells. By examining the pattern of genetic change in a number of cell-specific Py variants, we identified subenhancer sequences that may be functionally important for virus replication. Four such distinct enhancer consensus sequences were synthesized and designated as the A core (homologous with adenovirus 5 E1A enhancer), B core (homologous to the simian virus 40 A enhancer core), C core (containing an inverted repeat within the Py B enhancer), and BPV core (homologous to the bovine papillomavirus enhancer). When used to replace the complete Py B enhancer, single copies of all but the BPV element were able to fully activate Py DNA replication after transfection, but this activation was usually cell type specific. In the PCC4 embryonal carcinoma cells, only the A-core sequence was able to activate transcription and DNA replication. The BPV core sequence containing the Py F441 point change was unable to activate DNA replication in the F9 embryonal carcinoma or any other cell line. No single insertion element was dominant nor did these elements display the wild-type enhancer pattern of cell-specific activation of DNA replication. In addition, differential effects were often observed on the activation of transcription versus DNA replication. In 3T6 cells, transcription could be highly activated by the A core without a corresponding activation of DNA replication. In murine T lymphoid cell lines, the B core activated DNA replication without a corresponding increase in transcription. Furthermore, both DNA replication and, to a lesser degree, transcription often showed a strong tissue-specific dependence on the polarity of the inserted core element for activation.

Tissue specific phenotypes of polyomavirus A and B enhancer transpositions and duplications: positional and nonpositional effects on replication in lymphoid cells.

We have extended our studies using the mouse lymphoid cell system to determine if polyomavirus (Py) cell type specificity is a consequence of the simple presence of either the A and B enhancers, or if specificity results from specific combinations or arrangements of the individual enhancer elements. Mouse fibroblasts and several T lymphoid cell lines were transfected with wild-type DNA or genomes containing either a deletion of the B enhancer, a transposition of the A and B enhancers relative to their normal positions, or a tandem duplication of either the A or B enhancers. In some cells activation of DNA replication was dependent on the simple presence of the B enhancer and not upon its position, as all genomes containing a B enhancer replicated efficiently. In other cells, deletion or transposition of the B enhancer abolished DNA replication which suggested that activation depended upon the position of this element. The A enhancer core duplication replicated well in lymphoid cell lines, but duplication of the B enhancer did not yield a generally efficient configuration. We have interpreted these results to suggest that individual enhancer components can interact via specific combinational principles to yield cell type specific effects upon Py DNA replication.

A pancreas specificity results from the combination of polyomavirus and Moloney murine leukemia virus enhancer.

An infectious recombinant polyomavirus was constructed in which a regulatory region of its genome, the B enhancer region (nucleotides 5128-5265) has been replaced with the 72- or 73-base-pair repeat enhancer from the Moloney murine leukemia virus genome. We show that this recombinant polyomavirus displays a strong tissue specificity for the pancreas of mice. This organ was not permissive for either the parental polyomavirus, which is predominantly kidney and salivary gland specific, or the Moloney murine leukemia virus, which is lymphotropic. This result indicated that tissue specificity can be achieved by a combination of apparently modular elements. Some of the implications of a modular mechanism of tissue specificity are considered.

Lymphoid and other tissue-specific phenotypes of polyomavirus enhancer recombinants: positive and negative combinational effects on enhancer specificity and activity.

Heterologous enhancer recombinants and deletions of the polyomavirus (Py) noncoding region were constructed and analyzed for tissue specificity of DNA replication and transcription in a number of lymphoid and other cell lines. The simian virus 40 72-base-pair repeat, mouse immunoglobulin heavy-chain enhancer, and Moloney murine leukemia virus enhancer were inserted into the PvuII-D locus (nucleotides 5128 through 5265) of Py. The ability of these recombinants and the parental PvuII-D deletion mutant to replicate in permissive 3T6 cells and MOP-6 cells as well as in nonpermissive mouse B lymphoid, T lymphoid, mastocyte, and embryonal carcinoma cells was determined. Wild-type Py DNA was not permissive for replication in most lymphoid cell lines, except one hybridoma line. Simply deleting the Py PvuII-D region, however, gave Py an expanded host range, allowing high-level replication in some T lymphoid and mastocytoma cell lines, indicating that this element can be a tissue-specific negative as well as positive element. Substitution of the murine leukemia virus enhancer for Py PvuII-D yielded a Py genome which retained the ability to replicate in 3T6 cells but also replicated well in B lymphoid cells. Substitution with the immunoglobulin heavy-chain enhancer allowed replication in B lymphoid cells but interfered with replication in 3T6 cells and mastocytomas. Surprisingly, substitution with the simian virus 40 72-base-pair enhancer repeat gave a recombinant which would not replicate in any cell line tried, including MOP-6 cells, even though other recombinants with this enhancer would replicate. Thus, we observed both cooperation and interference in these combinations between enhancer components and the Py genome and that these combined activities were cell specific. These results are presented as evidence that there may be a positional dependence, or syntax, for the recognition of genetic elements controlling Py tissue specificity.

Host species specificity of polyomavirus DNA replication is not altered by simian virus 40 72-base-pair repeats.

The simian virus 40 72-base-pair repeats substituted for the polyomavirus enhancer, allowing replication and transcription in mouse 3T6 but not monkey CV-1 cells. A polyomavirus genome containing the entire simian virus 40 control region replicated at low levels in 3T6 and CV-1 cells; however, transcripts were detected only in 3T6 cells. Our results suggest that the simian virus 40 72-base-pair repeats are unable to alter the host species specificity of the complete polyomavirus genome.

Direct transfection of viral and plasmid DNA into the liver or spleen of mice.

A method for the direct transfection of polyoma viral DNA and polyoma-plasmid recombinant DNA into the liver or spleen of newborn or adult mice was developed. Calcium phosphate-precipitated DNA was injected directly into mouse organs in combination with hyaluronidase and collagenase. Transfected DNA was shown to replicate at moderate efficiency, relative to direct infection of organs with virus. Transfection with viral DNA rapidly led to an acute infection. A polyoma-bacterial plasmid recombinant DNA also was shown to replicate when transfected into mice. With this plasmid, however, genomic-length polyoma DNA rapidly recombined away from the bacterial component and replicated as viral DNA. This method should allow the direct determination of the biological activity of a cloned DNA within a mouse organ.

Morphologic types of diffuse large-cell lymphoma.

One hundred eighty-seven patients with confirmed diffuse non-Hodgkin's lymphoma were selected from a consecutive series of 391 patients who were evaluated and treated at Stanford University Medical Center. Lymphomas with any degree of nodularity and diffuse lymphomas of "well-differentiated" and "poorly differentiated" lymphocytic type were excluded from this study. Each of four observers identified cases of diffuse large-cell lymphoma from the 187 cases and further subdivided these cases into six morphologic types in accordance with criteria proposed by Strauchen et al. Initial intraobserver and interobserver agreement was relatively low but was greatly enhanced when the initial six morphologic types were grouped as either follicular center-cell or nonfollicular center-cell types. When individual observer results were pooled, statistically significant differences were seen between survival of patients in these two groups, with the patients in the nonfollicular differences were seen between survival of patients in these two groups, with the patients in the nonfollicular center-cell group having a worse prognosis (P = 0.04). This effect of morphologic type appeared to be independent of pathologic stage. Mitotic counts did not correlate with survival.