ABSTRACT
An older patient with stage II bladder carcinoma presented with 1 week of fatigue and 2 days of dyspnea on exertion. He was receiving carboplatin/gemcitabine with 6 mg of pegylated G-CSF chemotherapy; his white blood cell count was elevated, hemoglobin low, and ferritin notably increased. What is the diagnosis and what would you do next?
Subject(s)
Antineoplastic Agents , Antineoplastic Combined Chemotherapy Protocols , Granulocyte Colony-Stimulating Factor , Leukopoiesis , Urinary Bladder Neoplasms , Humans , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Gemcitabine/administration & dosage , Gemcitabine/adverse effects , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/pathology , Carboplatin/administration & dosage , Carboplatin/adverse effects , Granulocyte Colony-Stimulating Factor/administration & dosage , Granulocyte Colony-Stimulating Factor/adverse effects , Leukopoiesis/drug effectsABSTRACT
CASE PRESENTATION: A 46-year-old previously healthy woman presented with dyspnea, fatigue, and diarrhea. She had been experiencing these symptoms for > 1 year, but they had worsened in the few weeks prior to presentation. She had become progressively dyspneic on exertion and at rest and had increased the number of pillows she was sleeping on at night. She reported having episodes of nonbloody, watery diarrhea five to six times a day. The episodes were not associated with abdominal pain or recent travel and occurred even with fasting. Review of systems was positive for intermittent hot flashes, heart palpitations, and myalgias. She was premenopausal. She denied fever, weight loss, cough, hemoptysis, chest pain, or new edema. She had a pertinent medical history of gastritis, a nonspecific murmur since childhood, current tobacco use with a five pack-year history, and a family history of non-first-degree relatives having lung, breast, and colon cancer. She had not received medical care since moving from Brazil to the United States 4 years earlier.
Subject(s)
Dyspnea , Thorax , Female , Humans , Child , Middle Aged , Dyspnea/diagnosis , Dyspnea/etiology , Cough/diagnosis , Hemoptysis/diagnosis , Diarrhea/diagnosis , Diarrhea/etiology , Diagnosis, DifferentialABSTRACT
Perturbing redox homeostasis potentially constitutes a selective cancer-killing strategy. An engineered human enzyme, cyst(e)inase that degrades extracellular cysteine (l-Cys) and cystine (CSSC) leading to depletion of intracellular l-Cys and glutathione (GSH) was evaluated for its effects on pancreatic cancer cell lines. Cyst(e)inase caused oxidative stress and apoptosis in only Panc1 cells, whereas MIA-PaCa2 and BxPC3 cells demonstrated survival under conditions of cyst(e)inase-mediated l-Cys depletion through maintenance of mitochondrial metabolism and lower levels of reactive oxygen species (ROS). A correlation was also observed between thioredoxin 1 protein levels and resistance to cyst(e)inase treatment. Notably, cyst(e)inase in combination with auranofin, a thioredoxin reductase inhibitor, caused a synergistic increase in mitochondrial ROS and apoptosis and inhibition of mitophagy in the more resistant cells. In addition, auranofin treatment sensitized the more resistant pancreatic cancer xenografts to cyst(e)inase without systemic toxicity. These data provide strong rationale to further investigate therapeutic strategies that target multiple antioxidant pathways for treatment of pancreatic ductal adenocarcinoma.
