Introduction

Cystinosis is a rare metabolic genetic disorder caused by a mutation in the cystinosin lysosomal cystine transporter gene. Clinically, it is characterized by systemic accumulation of cystine crystals in tissues causing end-organ dysfunction in the kidney, eyes, muscles, and other organs in the body. In very rare cases, it can also involve the bone marrow and the resulting cystine crystal deposition can cause myelosuppression leading to pancytopenia.

Case presentation

Here we report the case of a 26-year-old white woman with cystinosis and other complex medical comorbidities who developed pancytopenia. She was worked up extensively and ruled out for common causes of pancytopenia (infectious disorders, vitamin deficiencies secondary to gastrointestinal malabsorption, rheumatologic, and hematologic disorders). On bone marrow biopsy she was found to have extensive deposits of cystine crystals, which was thought to be the cause of her myelosuppression leading to her pancytopenia. As a result, by treating her underlying cystinosis more aggressively we were able to observe an improvement in her pancytopenia a few months afterwards.

Conclusions

Pancytopenia secondary to myelosuppression from cystine crystal deposition in the bone marrow is a very rare complication that has been reported in only a handful of case reports. This case illustrates the importance of keeping a broad differential diagnosis and systematically ruling out common causes of pancytopenia. It also demonstrates the importance of bone marrow biopsies in the evaluation of unexplained pancytopenia.

Composite lymphoma (CL) is a rare disease with 2 distinct lymphomas concurrently arising in a single patient with an estimated incidence of 1-4.7% of newly diagnosed lymphomas per year. CL most commonly involves 2 B-cell non-Hodgkin lymphomas (NHL) or a B-cell NHL with a Hodgkin lymphoma. Our case is unique in that it was a bilineage CL with both a T-cell and B-cell NHL, which has only been reported in a few case reports. A 49-year-old woman presented with several months of progressive cough, weight loss, dyspnea, and supraclavicular lymphadenopathy. Computed tomographic imaging done upon admission to the hospital found that she had extensive anterior and middle mediastinal lymphadenopathy as well as bilateral supraclavicular lymphadenopathy. The patient underwent an excisional biopsy on the supraclavicular lymph node and was found to have a composite lymphoma involving both a T-cell and B-cell NHL. Her final pathological diagnosis was peripheral T-cell lymphoma and lymphoplasmacytic lymphoma. The patient was found to have stage IIIB disease. Her HIV, hepatitis panel, and tuberculosis tests were all negative. She then underwent chemotherapy with dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab). The patient showed a complete response and was then referred to a bone marrow transplant center for an autologous hematopoietic stem cell transplant. CL is a rare disease composed of at least 2 distinct lymphomas concurrently arising in a single patient. Due to the complexity in having to treat multiple types of lymphoma simultaneously CL presents challenges with treatment and assessing prognosis.

Disseminated microinfarctions are uncommonly encountered in clinical practice. Here we describe a patient with long-standing cerebral microbleeds who developed acute cognitive decline in the setting of acute hypotension. Magnetic resonance imaging showed acute disseminated microinfarctions, with no change in microbleeds. This case emphasizes the important relationship between ischemic and hemorrhagic microvascular disease of the brain, especially in the setting of acute blood pressure changes compounding preexisting microvascular injury.

Breast cancer is the second leading cause of cancer-related deaths in women in the United States. Of these women, 5-10% have an inherited form of breast cancer with a mutation in a major gene, such as the breast cancer susceptibility genes 1 or 2 (BRCA1 or BRCA2). Triple negative (the most common subtype of BRCA1-associated breast cancers) and Her2-positive breast cancer patients have more frequently been observed to develop central nervous system (CNS) metastases compared to other molecular subtypes of breast cancers. However, it remains an open question if BRCA2-associated breast cancers also have a higher propensity to develop CNS metastases. Here we report a rare case of recurrent BRCA2-associated breast cancer which manifested as orbital metastases. At the time of this publication, this is one of the first cases of BRCA2-associated breast cancer to present with orbital metastases. In this article, we discuss the diagnostic challenges and review the literature regarding this rare presentation.

In the last couple of decades, breast conservation therapy, which utilizes a combination of surgery, radiotherapy, and endocrine or chemotherapy, has become the standard of care for treating early-stage breast cancer. This practice has been greatly beneficial in the improvement of the patient's quality of life but has also led to the increased use of radiotherapy and associated soft-tissue sarcomas, with angiosarcoma being the most common malignancy. Radiation-associated angiosarcoma (RAS) of the breast is a rare phenomenon, which has been reported to occur in approximately 0.9 out of 1,000 cases, with a reported onset as late as 23 years following radiotherapy. Here we report 2 cases of RAS that occurred within 6 and 13 years following radiotherapy of their primary breast lesion. We discuss the diagnostic and therapeutic challenges regarding this disease and review the current literature. This case report serves as cautionary lessons on the importance of considering RAS of the breast in the differential diagnosis during evaluation for recurrent breast neoplasms. Ongoing clinical trials using combinations of vascular endothelial growth factor inhibitors and chemotherapy may provide future avenues of treatment for this difficult-to-treat disease.

The highly conserved Wnt signalling pathway plays an important role in embryonic development and disease pathogenesis, most notably cancer. The 'canonical' or β-catenin-dependent Wnt signal initiates at the cell plasma membrane with the binding of Wnt proteins to Frizzled:LRP5/LRP6 receptor complexes and is mediated by the translocation of the transcription co-activator protein, β-catenin, into the nucleus. β-Catenin then forms a complex with T-cell factor (TCF)/lymphoid enhancer binding factor (LEF) transcription factors to regulate multiple gene programmes. These programmes play roles in cell proliferation, migration, vasculogenesis, survival and metabolism. Mutations in Wnt signalling pathway components lead to constitutively active Wnt signalling that drives aberrant expression of these programmes and development of cancer. It has been a longstanding and challenging goal to develop therapies that can interfere with the TCF/LEF-β-catenin transcriptional complex. This review will focus on the (i) structural considerations for targeting the TCF/LEF-β-catenin and co-regulatory complexes in the nucleus, (ii) current molecules that directly target TCF/LEF-β-catenin activity and (iii) ideas for targeting newly discovered components of the TCF/LEF-β-catenin complex and/or downstream gene programmes regulated by these complexes.

Linked articles

This article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc.

Background

There is increasing evidence that oncogenic Wnt signaling directs metabolic reprogramming of cancer cells to favor aerobic glycolysis or Warburg metabolism. In colon cancer, this reprogramming is due to direct regulation of pyruvate dehydrogenase kinase 1 (PDK1) gene transcription. Additional metabolism genes are sensitive to Wnt signaling and exhibit correlative expression with PDK1. Whether these genes are also regulated at the transcriptional level, and therefore a part of a core metabolic gene program targeted by oncogenic WNT signaling, is not known.

Results

Here, we identify monocarboxylate transporter 1 (MCT-1; encoded by SLC16A1) as a direct target gene supporting Wnt-driven Warburg metabolism. We identify and validate Wnt response elements (WREs) in the proximal SLC16A1 promoter and show that they mediate sensitivity to Wnt inhibition via dominant-negative LEF-1 (dnLEF-1) expression and the small molecule Wnt inhibitor XAV939. We also show that WREs function in an independent and additive manner with c-Myc, the only other known oncogenic regulator of SLC16A1 transcription. MCT-1 can export lactate, the byproduct of Warburg metabolism, and it is the essential transporter of pyruvate as well as a glycolysis-targeting cancer drug, 3-bromopyruvate (3-BP). Using sulforhodamine B (SRB) assays to follow cell proliferation, we tested a panel of colon cancer cell lines for sensitivity to 3-BP. We observe that all cell lines are highly sensitive and that reduction of Wnt signaling by XAV939 treatment does not synergize with 3-BP, but instead is protective and promotes rapid recovery.

Conclusions

We conclude that MCT-1 is part of a core Wnt signaling gene program for glycolysis in colon cancer and that modulation of this program could play an important role in shaping sensitivity to drugs that target cancer metabolism.

The recent classification of colon cancer into molecular subtypes revealed that patients with the poorest prognosis harbor tumors with the lowest levels of Wnt signaling. This is contrary to the general understanding that overactive Wnt signaling promotes tumor progression from early initiation stages through to the later stages including invasion and metastasis. Here, we directly test this assumption by reducing the activity of ß-catenin-dependent Wnt signaling in colon cancer cell lines at either an upstream or downstream step in the pathway. We determine that Wnt-reduced cancer cells exhibit a more aggressive disease phenotype, including increased mobility in vitro and disruptive invasion into mucosa and smooth muscle in an orthotopic mouse model. RNA sequencing reveals that interference with Wnt signaling leads to an upregulation of gene programs that favor cell migration and invasion and a downregulation of inflammation signatures in the tumor microenvironment. We identify a set of upregulated genes common among the Wnt perturbations that are predictive of poor patient outcomes in early-invasive colon cancer. Our findings suggest that while targeting Wnt signaling may reduce tumor burden, an inadvertent side effect is the emergence of invasive cancer.

Implications

Decreased Wnt signaling in colon tumors leads to a more aggressive disease phenotype due to an upregulation of gene programs favoring cell migration in the tumor and downregulation of inflammation programs in the tumor microenvironment; these impacts must be carefully considered in developing Wnt-targeting therapies.