Recurrent chylous ascites in patient with previous retroperitoneal radiation treatment.

Chylous ascites is the accumulation of lymphatic fluid in the peritoneal cavity due to disruption of lymphatic drainage caused due to obstruction or trauma. We report a man in his 60s who was previously treated for diffuse large B cell lymphoma with radiation to bulky abdominal/mesenteric lymphadenopathy. He was later found to have recurrent chylous ascites several years later, requiring multiple paracentesis. Recurrent lymphoma was ruled out with negative cytology of peritoneal fluid as well as lymph node biopsy with no evidence of malignancy. We believe that the patient had obstruction of lymphatic drainage due to previous radiation therapy causing fibrosis. The patient underwent lymphangiography which did not visualise the central lymphatic duct within the abdomen raising suspicion for obstruction of the ducts secondary to previous radiation.

Myasthenia gravis induced or exacerbated by immune checkpoint inhibitors: a rising concern.

Immune checkpoint inhibitors can cause immune side effects, with myasthenia gravis (MG) being relatively rare. With this review, we present 66-year-old man with melanoma treated with pembrolizumab who developed MG. With immuno-oncology (IO) single agent usage, 42 cases reported new-onset MG and 9 cases reported exacerbation of pre-existing MG. Among the patients who had new-onset MG after administration of programmed cell death protein 1 (PD-1) inhibitors, 14 patients (38.8%) developed severe respiratory failure and required intubation and 10 patients (27.02%) died. Among the patients with exacerbation of pre-existing MG after receiving PD-1 inhibitors, 1 patient (11.1%) required intubation, and no death was reported. Combination IO therapy-induced MG was reported in seven cases, with at least two cases complicated by respiratory failure and one death. Our observations suggest a possible difference in the severity of the disease and outcome among different IO therapy options.

Delayed manifestation of extensive COVID-19-associated coagulopathy in high-risk patient.

COVID-19 is an infectious disease caused by the novel coronavirus. It presents as an acute respiratory illness, however, it also affects multiple other organ systems. One such unique manifestation is systemic coagulopathy involving arterial and venous systems. We present a 29-year-old woman with Hodgkin's lymphoma, who was diagnosed with COVID-19 infection prior to initiating chemotherapy. Two months after resolution of symptoms and testing negative for COVID-19, she presented with multiple acute thromboembolic complications of the infection, including bilateral jugular venous thrombosis, right atrial clot and arterial emboli in the brain resulting in cerebrovascular injury. These were thought to be delayed manifestations of the systemic coagulopathy secondary to infection. Also, some of these thromboembolic phenomena occurred while the patient was on anticoagulation, which emphasises the extensive hyperinflammatory state caused by the virus. This case highlights the importance of thromboprophylaxis especially in high-risk patients with this infection.

Anti-Lan Antibodies: A Rare Etiology of Severe Blood Transfusion Reaction.

Lan is a high prevalence red blood cell antigen present in the majority of the populations that belong to the Lan (Langereis) blood group system. Anti-Lan antibody is an immunoglobulin G (IgG) antibody that is known to cause delayed hemolytic transfusion reactions in adults as well as hemolytic disease in fetuses and newborns, however with variable clinical significance ranging from mild to severe. We present a 58-year-old woman with diffuse abdominal pain and a large gastric ulcer causing gastric outlet obstruction. She underwent antrectomy and Billroth I reconstruction surgery without complications. The patient's hemoglobin upon presentation was 10g/dL and dropped acutely post-operatively to 6.4 g/dL requiring blood transfusion. The patient developed acute respiratory distress within minutes of starting a packed red blood cell (pRBC) transfusion, requiring discontinuation. Laboratory testing demonstrated pan-reactivity with additional reference testing demonstrating an anti-Lan antibody. The rarity of Lan negative pRBC units is a challenge in managing such patients requiring blood transfusions. Autologous blood donation or donation by a compatible family member is another option to consider in these rare cases.

Overview of Cancer Survivorship Care for Primary Care Providers.

Survivorship care for a patient with cancer is often complex and requires a multidisciplinary approach. Cancer and its treatment can have late and long-term physical and psychosocial effects. After the acute and intense period of treatment and surveillance administered by oncology teams, cancer survivors slowly transition care to primary providers. Cancer survivors then enter into an extended phase of survivorship whether they are cancer-free, in remission, or living with cancer. In this phase, symptoms related to cancer and its treatment may vary over time. Developing a care plan can facilitate the transition of care between all providers taking care of cancer patients.

Long-time Response with Ado-trastuzumab Emtansine in a Recurrent Metastatic Breast Cancer.

Breast cancer is the most common cancer in a woman with a five-year survival of patients with metastatic disease is estimated at 23%. Ado-trastuzumab emtansine (T-DM1) is a HER2-antibody drug conjugate currently approved for the treatment of HER2-positive pre-treated metastatic breast cancer (BC). We report a case of recurrent metastatic breast cancer with unusually lengthy progression-free survival (PFS) on T-DM1 chemotherapy. She was diagnosed with Triple Positive Stage IIIC multifocal invasive ductal carcinoma of the left breast. After completing neoadjuvant chemotherapy, she underwent a bilateral mastectomy. Final pathology showed partial response. Postoperatively, she received adjuvant chemotherapy and radiation therapy. She was started on Q21 days trastuzumab following completion of adjuvant chemotherapy. Systemic imaging showed liver lesions and biopsy confirmed recurrence. She was started on T-DM1, endocrine therapy with anastrozole was continued. She is currently status post 45 cycles. T-DM1 was approved for the treatment (single-agent) of HER2-positive, metastatic BC based on phase III data from the EMILIA and TH3RESA study. Median PFS in the T-DM1 arm was 9.6 months. Herein, we present a case of a woman with recurrent triple positive metastatic BC with a lengthy progression-free survival on T-DM1 chemotherapy.

Rare case of non-producer variant of plasma cell dyscrasias with circulating plasma cells.

Non-producing variant of plasma cell disorders with circulating plasma cells is an aggressive variant of plasma cell dyscrasias with relatively poor outcomes. A 75-year-old man was admitted due to anaemia (90 g/L) and thrombocytopenia (9×109/L). Comprehensive metabolic panel showed creatinine of 1.34 mg/dL, total protein of 6 g/dL, and corrected calcium was normal. Peripheral smear review showed 8% circulating atypical plasmacytoid cells. Bone marrow biopsy (BMB) confirmed plasma cell myeloma involving 90%-95% of bone marrow cellularity. Serum protein electrophoresis showed no monoclonal protein. Due to aggressive biology of non-producer variant and outcomes based on circulating plasma cells, he was started on VD-PACE (bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide and etoposide) chemotherapy. BMB after cycle 1 chemotherapy showed no morphologic, immunophenotypic, or flow cytometric features of a plasma cell neoplasm. Given excellent treatment response cycle 2 was changed to VRD (bortezomib, lenalidomide and dexamethasone). Following two cycles of VRD, he underwent autologous haematopoietic cell transplantation. Day 80 BMB suggested stringent complete response.

Leptomeningeal involvement by prostate carcinoma an ominous head of a well-known Hydra.

A 67-year-old male patient presents to the hospital complaining of severe nausea and vomiting failing oral antiemetics. He carries the history of initial diagnosis of stage III prostate cancer. He underwent radical prostatectomy followed by external beam radiation. After 5 years of initial excellent control with androgen deprivation therapy (ADT), imaging study showed retroperitoneal adenopathy denoting ADT failure. His prostate-specific antigen continued to rise while on enzalutamide and then abiraterone reflecting disease progression. He maintained excellent functional capacity through 23 cycles of docetaxel however he started developing hip pain after the last cycle with imaging studies suggesting new hip metastatic disease. Following the first cycle of radium-223, the patient presented with intractable nausea and vomiting. MRI showed a high suspicion of leptomeningeal spread which was confirmed through a meningeal biopsy after lumbar puncture showed negative results. The patient had excellent symptomatic response to high-dose dexamethasone. After receiving whole-brain radiation, the patient opted to be on best supportive care and succumbed to his illness 3 months later.

γ-Tocotrienol induces apoptosis in pancreatic cancer cells by upregulation of ceramide synthesis and modulation of sphingolipid transport.

BACKGROUND: Ceramide synthesis and metabolism is a promising target in cancer drug development. γ-tocotrienol (GT3), a member of the vitamin E family, orchestrates multiple effects that ensure the induction of apoptosis in both, wild-type and RAS-mutated pancreatic cancer cells. Here, we investigated whether these effects involve changes in ceramide synthesis and transport. METHODS: The effects of GT3 on the synthesis of ceramide via the de novo pathway, and the hydrolysis of sphingomyelin were analyzed by the expression levels of the enzymes serine palmitoyl transferase, ceramide synthase-6, and dihydroceramide desaturase, and acid sphingomyelinase in wild-type RAS BxPC3, and RAS-mutated MIA PaCa-2 and Panc 1 pancreatic cancer cells. Quantitative changes in ceramides, dihydroceramides, and sphingomyelin at the cell membrane were detected by LCMS. Modulation of ceramide transport by GT3 was studied by immunochemistry of CERT and ARV-1, and the subsequent effects at the cell membrane was analyzed via immunofluorescence of ceramide, caveolin, and DR5. RESULTS: GT3 favors the upregulation of ceramide by stimulating synthesis at the ER and the plasma membrane. Additionally, the conversion of newly synthesized ceramide to sphingomyelin and glucosylceramide at the Golgi is prevented by the inhibition of CERT. Modulation ARV1 and previously observed inhibition of the HMG-CoA pathway, contribute to changes in membrane structure and signaling functions, allows the clustering of DR5, effectively initiating apoptosis. CONCLUSIONS: Our results suggest that GT3 targets ceramide synthesis and transport, and that the upregulation of ceramide and modulation of transporters CERT and ARV1 are important contributors to the apoptotic properties demonstrated by GT3 in pancreatic cancer cells.

Drug interaction between idelalisib and diazepam resulting in altered mental status and respiratory failure.

In recent years, several new oral anticancer drugs have been approved, many via an accelerated approval process. These new agents have the potential for drug interactions, but lack of familiarity with these drugs by clinicians may increase the risk for drug interactions. We describe an interaction between the new anticancer agent idelalisib (CYP 3A4 inhibitor) and diazepam (CYP 3A4 substrate) that resulted in altered mental status and type II respiratory failure resulting in hospitalization. After discontinuation of both agents, the patient recovered quickly. Idelalisib was reinitiated after discharge. Lorazepam was substituted for diazepam since it is not metabolized via CYP 3A4. Both agents were tolerated well thereafter. This interaction was only flagged by two of four commonly used drug interaction databases. Clinicians should exercise caution with initiating new oral anticancer agents and consider the potential for drug interactions without solely relying on drug interaction databases.

Cardiovascular Toxicity and Management of Targeted Cancer Therapy.

The advent of effective oral, molecular-targeted drugs in oncology has changed many incurable malignancies such as chronic myeloid leukemia into chronic diseases similar to coronary artery disease and diabetes mellitus. Oral agents including monoclonal antibodies, kinase inhibitors and hormone receptor blockers offer patients with cancer incremental improvements in both overall survival and quality of life. As it is imperative to recognize and manage side effects of platelet inhibitors, beta blockers, statins, human immunodeficiency virus drugs and fluoroquinolones by all healthcare providers, the same holds true for these newer targeted therapies; patients may present to their generalist or other subspecialist with drug-related symptoms. Cardiovascular adverse events are among the most frequent, and potentially serious, health issues in outpatient clinics, and among the most frequent side effects of targeted chemotherapy. Data support improved patient outcomes and satisfaction when primary care and other providers are cognizant of chemotherapy side effects, allowing for earlier intervention and reduction in morbidity and healthcare costs. With the implementation of accountable care and pay for performance, improved communication between generalists and subspecialists is essential to deliver cost-effective patient care.

Thyroid nodule: not as clear-cut as it seems.

Benign etiologies and primary thyroid cancers are the most common causes of incidental thyroid nodules. Clinically evident metastases to the thyroid gland are not common and account for 2%-3% of thyroid cancers, though the incidence of thyroid metastases reaches 24% in autopsy studies.1 The most common clinically detected thyroid metastases originate from renal cell carcinoma (RCC; 48.1%).2 We report here a rare case of a man with clear-cell RCC with late recurrence in the thyroid gland as a solitary metastasis, 13 years after the primary diagnosis. The patient received neo-adjuvant targeted therapy with sunitinib, then underwent thyroidectomy. The surgical margins were positive, and the patient had adjuvant radiation therapy. He is currently on long-term surveillance.

Synergistic growth inhibition of PC3 prostate cancer cells with low-dose combinations of simvastatin and alendronate.

The mevalonate pathway plays an important role in cancer biology and has been targeted with farnesyl transferase inhibitors, although their efficacy is limited due to significant adverse effects. Statins and bisphosphonates inhibit the mevalonate pathway at different steps, thus having negative effects at various levels on cancer cells. A combination of these drugs may result in an amplified cytotoxic effect and allow for use of significantly lower doses of the drugs involved. Statins inhibit the mevalonate pathway at 3-hydroxy-3-methylglutaryl coenzyme A reductase and bisphosphonates at farnesyl pyrophosphate synthase. Our results show that low-dose combinations of simvastatin and alendronate have a synergistic cytotoxic effect on androgen-independent prostate cancer PC-3 cells, but not on androgen-dependent LNCaP or DU 145 prostate cancer cells. These two drugs cause a sequential blockade of the mevalonate pathway and significantly affect survival and apoptotic pathways by down-regulating phospho-AKT and activating c-JUN and ERK.

A 'double-hit' bone marrow rare co-occurrence of 2 different pathologies.

A patient is diagnosed with chronic lymphocytic leukemia 6 months after he was diagnosed with chronic myeloid leukemia for which he initially received imatinib.

Tocotrienols inhibit AKT and ERK activation and suppress pancreatic cancer cell proliferation by suppressing the ErbB2 pathway.

Tocotrienols are members of the vitamin E family but, unlike tocopherols, possess an unsaturated isoprenoid side chain that confers superior anti-cancer properties. The ability of tocotrienols to selectively inhibit the HMG-CoA reductase pathway through posttranslational degradation and to suppress the activity of transcription factor NF-κB could be the basis for some of these properties. Our studies indicate that γ- and δ-tocotrienols have potent antiproliferative activity in pancreatic cancer cells (Panc-28, MIA PaCa-2, Panc-1, and BxPC-3). Indeed both tocotrienols induced cell death (>50%) by the MTT cell viability assay in all four pancreatic cancer cell lines. We also examined the effects of the tocotrienols on the AKT and the Ras/Raf/MEK/ERK signaling pathways by Western blotting analysis. γ- and δ-tocotrienol treatment of cells reduced the activation of ERK MAP kinase and that of its downstream mediator RSK (ribosomal protein S6 kinase) in addition to suppressing the activation of protein kinase AKT. Suppression of activation of AKT by γ-tocotrienol led to downregulation of p-GSK-3ß and upregulation accompanied by nuclear translocation of Foxo3. These effects were mediated by the downregulation of Her2/ErbB2 at the messenger level. Tocotrienols but not tocopherols were able to induce the observed effects. Our results suggest that the tocotrienol isoforms of vitamin E can induce apoptosis in pancreatic cancer cells through the suppression of vital cell survival and proliferative signaling pathways such as those mediated by the PI3-kinase/AKT and ERK/MAP kinases via downregulation of Her2/ErbB2 expression. The molecular components for this mechanism are not completely elucidated and need further investigation.

Differential effects of pravastatin and simvastatin on the growth of tumor cells from different organ sites.

3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) inhibitors, commonly known as statins, may possess cancer preventive and therapeutic properties. Statins are effective suppressors of cholesterol synthesis with a well-established risk-benefit ratio in cardiovascular disease prevention. Mechanistically, targeting HMGCR activity primarily influences cholesterol biosynthesis and prenylation of signaling proteins. Pravastatin is a hydrophilic statin that is selectively taken up by a sodium-independent organic anion transporter protein-1B1 (OATP1B1) exclusively expressed in liver. Simvastatin is a hydrophobic statin that enters cells by other mechanisms. Poorly-differentiated and well-differentiated cancer cell lines were selected from various tissues and examined for their response to these two statins. Simvastatin inhibited the growth of most tumor cell lines more effectively than pravastatin in a dose dependent manner. Poorly-differentiated cancer cells were generally more responsive to simvastatin than well-differentiated cancer cells, and the levels of HMGCR expression did not consistently correlate with response to statin treatment. Pravastatin had a significant effect on normal hepatocytes due to facilitated uptake and a lesser effect on prostate PC3 and colon Caco-2 cancer cells since the OATP1B1 mRNA and protein were only found in the normal liver and hepatocytes. The inhibition of cell growth was accompanied by distinct alterations in mitochondrial networks and dramatic changes in cellular morphology related to cofilin regulation and loss of p-caveolin. Both statins, hydrophilic pravastatin and hypdrophobic simvastatin caused redistribution of OATP1B1 and HMGCR to perinuclear sites. In conclusion, the specific chemical properties of different classes of statins dictate mechanistic properties which may be relevant when evaluating biological responses to statins.

A bone to pick about chest pain.

Chest pain is an extremely common presenting symptom that is usually related to a cardiac cause. This case illustrates an unusual presentation of multiple myeloma as a cause of atypical chest pain. This case presentation shows the importance of having a broad differential diagnosis while evaluating patients with atypical chest pain. It also illustrates the potential role of Tc-99m sestamibi imaging as a diagnostic modality in patients with multiple myeloma.