A year-long dietary intervention was effective at reducing caloric intake in pediatric ALL patients receiving steroid-based chemotherapy, indicating that this is a modality that can be built upon for obesity prevention and management.

The presence of the Philadelphia chromosome in patients with acute lymphoblastic leukemia (Ph+ALL) is a negative prognostic indicator. Tyrosine kinase inhibitors (TKI) that target BCR/ABL, such as imatinib, have improved treatment of Ph+ALL and are generally incorporated into induction regimens. This approach has improved clinical responses, but molecular remissions are seen in less than 50% of patients leaving few treatment options in the event of relapse. Thus, identification of additional targets for therapeutic intervention has potential to improve outcomes for Ph+ALL. The human epidermal growth factor receptor 2 (ErbB2) is expressed in ∼30% of B-ALLs, and numerous small molecule inhibitors are available to prevent its activation. We analyzed a cohort of 129 ALL patient samples using reverse phase protein array (RPPA) with ErbB2 and phospho-ErbB2 antibodies and found that activity of ErbB2 was elevated in 56% of Ph+ALL as compared to just 4.8% of Ph−ALL. In two human Ph+ALL cell lines, inhibition of ErbB kinase activity with canertinib resulted in a dose-dependent decrease in the phosphorylation of an ErbB kinase signaling target p70S6-kinase T389 (by 60% in Z119 and 39% in Z181 cells at 3 µM). Downstream, phosphorylation of S6-kinase was also diminished in both cell lines in a dose-dependent manner (by 91% in both cell lines at 3 µM). Canertinib treatment increased expression of the pro-apoptotic protein Bim by as much as 144% in Z119 cells and 49% in Z181 cells, and further produced caspase-3 activation and consequent apoptotic cell death. Both canertinib and the FDA-approved ErbB1/2-directed TKI lapatinib abrogated proliferation and increased sensitivity to BCR/ABL-directed TKIs at clinically relevant doses. Our results suggest that ErbB signaling is an additional molecular target in Ph+ALL and encourage the development of clinical strategies combining ErbB and BCR/ABL kinase inhibitors for this subset of ALL patients.

Over and under nutrition are associated with worse outcomes for children with leukemia and lymphoma; however, the molecular basis for this clinical observation is not well understood. Many chemotherapeutics used for leukemia treatment are known to generate oxidative stress in vitro; therefore, we evaluated redox status and diet in pediatric leukemia patients during therapy in order to ascertain relationships between nutrition and oxidative stress. Dietary intake and redox measures in peripheral blood mononuclear cells from 32 pediatric leukemia and lymphoma patients were collected over six months during treatment. Baseline measures when patients were off chemotherapy and subsequent assessments were collected after one, two and six months. Oxidative stress increased over time in all patients, consistent with chemotherapy-induced redox effects. Older and younger children showed significantly different baseline levels of reactive oxygen species, which increased over time in all age ranges. Diet was assessed at points proximal to oxidative stress measurements and revealed a novel association with consumption of animal protein, vegetable protein, and total protein intake. Our findings demonstrate that chemotherapy increases oxidative stress in pediatric leukemia patients, and raises the possibility that dietary protein or altered protein metabolism could contribute to clinical outcomes.

Diffuse large B-cell lymphoma (DLBCL) represents around one quarter of non-Hodgkin lymphomas in both the United States and globally. The activated B-cell (ABC) subtype of DLBCL is associated with higher relapse rates and a worse prognosis when treated with standard regimens in comparison to other subtypes of DLBCL. Recent studies have demonstrated a potential benefit with combination of dose-adjusted rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-REPOCH) in comparison to standard combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in ABC DLBCL patients. We aimed to see if there was any benefit on progression-free survival (PFS) and overall survival (OS) in a pooled patient population from a community oncology practice with the use of DA-REPOCH in ABC DLBCL. Our study did not reveal a statistically significant advantage in either PFS or OS with DA-REPOCH; however, a smaller percentage or patients progressed or relapsed when treated with DA-REPOCH. While the toxicity profile was similar, a higher percentage of patients receiving R-CHOP experienced grade 3 or higher toxicities. A prospective trial of R-CHOP versus DA-REPOCH in patients with the ABC subtype of DLBCL is warranted to further determine a potential benefit to DA-REPOCH in this patient population.

Metastatic carcinomatosis cirrhosis is a pattern of metastasis in which malignancy infiltrates the liver and provokes hepatic fibrosis. It is an especially rare complication of several malignancies, including breast cancer. We report a case of a 61-year-old woman with lobular carcinoma of the breast who presented with confusion and rising serum tumor markers without evidence of disease recurrence on imaging. She subsequently developed clinical evidence of hepatic dysfunction and a liver biopsy revealed diffuse infiltration of the liver by breast carcinoma with surrounding fibrous tissue deposition, consistent with metastatic carcinomatosis cirrhosis. This case highlights a rare and clinically significant pattern of metastasis and is the first to describe lobular carcinoma of the breast causing metastatic carcinomatosis cirrhosis.

Key Clinical Message We highlight a novel case of TAFRO syndrome with disseminated intravascular coagulation, neurologic changes, and non‐ischemic cardiomyopathy. Through this clinical vignette, we hope to raise awareness of TAFRO syndrome and encourage providers to maintain a high level of suspicion for it when evaluating patients who meet the diagnostic criteria.

Clinical observations suggest that poor nutrition worsens outcomes for pediatric leukemia patients undergoing therapy. However, the molecular basis for this observation is not well understood. Ample data indicates that increased cellular oxidative stress is an important mechanism of action of chemotherapeutic regimens used for pediatric acute leukemias. Reports also suggest that diet may modulate the balance of cellular pro- and antioxidants. Here, we propose that age appropriate adequate nutrition promotes endogenous metabolic sources of oxidative stress, which when combined with chemotherapy induced oxidative stress, provide better outcomes for these patients. Assessments of nutrition and oxidative stress were completed for each patient at regularly scheduled intervals over a six month period. Changes in nutrition and oxidative stress were monitored. Nutrition was quantified by conducting 24 hour dietary recalls. Data was entered into the Minnesota Nutrition Data System for Research (NDSR) dietary analysis program. Cellular oxidative stress in mononuclear cells isolated from peripheral blood was also quantified. Specifically, intracellular superoxide and hydrogen peroxide were measured with dihydroethidium (HE) and 2′,7α-dichlorofluorescin diacetate (DCF-DA) staining by flow cytometry, respectively. Glutathione (GSH), an antioxidant, was also measured by monochlorobimane staining. To date, analyses have been completed for 12 patients. An increase in superoxides was detected in 72.7% of patients (8 of 11). An increase in hydrogen peroxide was detected in 50% of patients (6 of 12). An increase was defined as a two-fold or greater elevation in ROS at any subsequent visit compared to the baseline visit. A decrease in GSH was seen in 50% of patients (6 of 12) and 33% (4 of 12) demonstrated a decrease in GSH coincident with an increase in both superoxides and hydrogen peroxide. This increase in ROS and decrease in GSH suggests that the majority of our patients experience oxidative stress during therapy. To investigate the impact of diet on oxidant status, NDSR software was used to compare the consumption of dietary antioxidants, such as vitamins A, B3, C, and E, selenium, and glutamic acid, to the corresponding amounts of ROS from the same visit. The strongest correlation was between vitamin C consumption and hydrogen peroxide levels. An inverse relationship between vitamin C consumption and hydrogen peroxide levels was apparent in 58.3% of patients (7 of 12). These data provide insight into the relationship between diet and oxidative stress in pediatric leukemia patients. Future work will support the design of dietary interventions that will modulate oxidant status to favor improved survival of children with leukemia. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5434. doi:1538-7445.AM2012-5434

Primary central nervous system lymphoma (PCNSL) is an extranodal non-Hodgkin's lymphoma confined to the brain, leptomeninges, spinal cord, or eyes without systemic involvement. Nearly half of patients with PCNSL who achieve complete remission, relapse within five years. The majority of patients who relapse have a local recurrence. Systemic relapse, however, is much rarer. Here, we report a rare case of a 70-year-old male diagnosed with PCNSL who relapsed systemically nearly 1.5 years after achieving complete remission. His treatment consisted of chemoimmunotherapy and targeted therapy followed by an autologous transplant. Currently, there is no standard of care for systemic relapse of PCNSL. This multiagent treatment modality may be one such option for salvage therapy.