Atezolizumab plus bevacizumab as first-line systemic therapy for hepatocellular carcinoma: a multi-institutional cohort study.

BACKGROUND: Atezolizumab plus bevacizumab is the standard of care for advanced hepatocellular carcinoma (HCC) in the first-line setting, although was only evaluated in patients with Child-Pugh (CP) A liver function in the IMbrave150 trial. We sought to determine the outcomes of these patients based on CP score and ALBI grade in the US population. METHODS: This multicenter cohort study included patients with HCC who received atezolizumab with bevacizumab as first-line systemic therapy between March 2018 and November 2023. Overall survival (OS) was determined using the Kaplan-Meier method and multivariate analyses were performed using Cox proportional hazard regression method. RESULTS: Among 322 patients, 226, 86, and 10 patients had CP-A, CP-B, and CP-C liver function, respectively. Median age was 66.5 years, 78.6% were male, and 82.6% were White. Median OS (mOS) was 21.6 months for those with CP-A, 9.1 months for those with CP-B7, and 4.7 months for those with CP-B8-C12 (P < .0001). Among patients with CP-A, those with ALBI grade 1 had an mOS of 34.9 months versus 14.2 months in those with grade 2. In multivariate analyses, CP score, ALBI grade, hepatitis B, performance status, and macrovascular invasion were significantly associated with survival. CONCLUSIONS: CP score is an important prognostic tool for patients with HCC receiving atezolizumab plus bevacizumab, and this regimen remains a viable option for patients with CP-B7 with no additional safety concern, although the benefit is significantly less than those with CP-A. ALBI score has independent predictive value in patients with CP-A liver function.

Metabolism, toxicity and management of fruquintinib: a novel drug for metastatic colorectal cancer.

INTRODUCTION: Colorectal cancer (CRC) is the third most diagnosed cancer globally and despite therapeutic strides, the prognosis for patients with metastatic disease (mCRC) remains poor. Fruquintinib is an oral vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI) targeting VEGFR -1, -2, and -3, and has recently received approval by the U.S. Food and Drug Administration for treatment of mCRC refractory to standard chemotherapy, anti-VEGF therapy, and anti-epidermal growth factor receptor (EGFR) therapy. AREAS COVERED: This article provides an overview of the pre-clinical data, pharmacokinetics, clinical efficacy, and safety profile of fruquintinib, as well as the management of clinical toxicities associated with fruquintinib. EXPERT OPINION: Fruquintinib is a valuable additional treatment option for patients with refractory mCRC. The pivotal role of vigilant toxicity management cannot be understated. While fruquintinib offers a convenient and overall, well-tolerated treatment option, ongoing research is essential to determine its efficacy in different patient subsets, evaluate it in combination with chemotherapy and immunotherapy, and determine its role in earlier lines of therapy.

Lutetium-177 PSMA for the treatment of metastatic castrate resistant prostate cancer: a systematic review.

INTRODUCTION: Metastatic castrate resistant prostate cancer (mCPRC) remains an aggressive form of prostate cancer that no longer responds to traditional hormonal treatment alone. Despite the advent of novel anti-androgen medications, many patients continue to progress, and as a result, there is a growing need for additional treatment options. AREAS COVERED: Lutetium-177 (177Lu) - PSMA-617 has become one of the new frontline treatment options for refractory metastatic castrate resistant prostate cancer after the failure of novel anti-androgen therapy and chemotherapy. Lu-177 has been used in real-world prospective trials and is now becoming utilized in newer phase III clinical trials. Here, we present a comprehensive overview of the current literature, covering retrospective studies, prospective studies, and clinical trials that established Lutetium-177-PSMA-617 (177Lu-PSMA-617) for the treatment of mCRPC. EXPERT OPINION: 177Lu - PSMA-617 has been approved for treatment of mCRPC based on positive phase III studies. While this treatment is tolerable and effective, biomarkers are necessary to determine which patients will benefit. In the future, radioligand treatments will likely be utilized in earlier lines of therapy and potentially in combination with other prostate cancer treatments.

Psoriasis Flare-Up in a Patient Treated With Docetaxel for Metastatic Prostate Cancer.

Dermatologic toxicities, such as urticaria and mucositis, with docetaxel, have been commonly reported; however, fixed-plaque erythrodysesthesia is a rare adverse phenomenon with a reported incidence of less than 5% of patients. Docetaxel-induced psoriasis is extremely rare, and to date, very few cases have been reported in the literature. We present a literature review of psoriasis cases secondary to docetaxel and report our own case of severe docetaxel-induced psoriasis in the setting of treatment of metastatic prostate cancer. Our patient received topical steroids and narrow-band ultraviolet B (NBUVB) light therapy with resolution of their psoriasis and was able to complete their chemotherapy without discontinuation or interruption of their docetaxel.

Grade III solitary fibrous tumor/hemangiopericytoma: An enthralling intracranial tumor-A case report and literature review.

Hemangiopericytomas account for less than 1% of all intracranial tumors. In 2016, World Health Organization (WHO) unified the two terms into a single medical condition known as solitary fibrous tumor/hemangiopericytoma (SFT/HPC). Our patient is an 80-year-old woman with a past medical history of sick sinus syndrome status post pacemaker placement. She presented to the emergency department with progressive headaches for one month duration. Her headaches worsened at night, waking her up from sleep. They also increased in intensity by bending forward. Review of systems was significant for bilateral lower extremity weakness accompanied by difficulty walking. The motor exam was remarkable for right upper and right lower extremity 3/5 weakness. The gait was ataxic. A Computed tomography scan of the head without contrast revealed a large dural-based right parietal hyperdense mass with surrounding edema, mass effect, and compression of the right lateral ventricle atrium. A right-to-left midline shift was also noted. Given the fact that our patient had a pacemaker, she was not a candidate for a brain MRI. Neurosurgery successfully resected the mass. Histopathological studies confirmed WHO grade III anaplastic solitary fibrous tumor/hemangiopericytoma. The patient was discharged on adjuvant radiation with imaging surveillance given the grade and the extent of resection. This case highlights a rare type of intracranial mass that resembles meningioma on imaging studies. It also illustrates that solitary fibrous tumor/hemangiopericytoma should be kept as a differential diagnosis for brain masses, given its aggressive nature, and its potential of metastasis and recurrence.

Unfolded Protein Response Differentially Modulates the Platelet Phenotype.

BACKGROUND: Unfolded protein response (UPR) is a multifaceted signaling cascade that alleviates protein misfolding. Although well studied in nucleated cells, UPR in absence of transcriptional regulation has not been described. Intricately associated with cardiovascular diseases, platelets, despite being anucleate, respond rapidly to stressors in blood. We investigate the UPR in anucleate platelets and explore its role, if any, on platelet physiology and function. METHODS: Human and mouse platelets were studied using a combination of ex vivo and in vivo experiments. Platelet lineage-specific knockout mice were generated independently for each of the 3 UPR pathways, PERK (protein kinase RNA [PKR]-like endoplasmic reticulum kinase), XBP1 (X-binding protein), and ATF6 (activating transcription factor 6). Diabetes patients were prospectively recruited, and platelets were evaluated for activation of UPR under chronic pathophysiological disease conditions. RESULTS: Tunicamycin induced the IRE1α (inositol-requiring enzyme-1alpha)-XBP1 pathway in human and mouse platelets, while oxidative stress predominantly activated the PERK pathway. PERK deletion significantly increased platelet aggregation and apoptosis and phosphorylation of PLCγ2, PLCß3, and p38 MAPK. Deficiency of XBP1 increased platelet aggregation, with higher PLCß3 and PKCδ activation. ATF6 deletion mediated a relatively modest effect on platelet phenotype with increased PKA (protein kinase A). Platelets from diabetes patients exhibited a positive correlation between disease severity, platelet activation, and protein aggregation, with only IRE1α-XBP1 activation. Moreover, IRE1α inhibition increased platelet aggregation, while clinically approved chemical chaperone, sodium 4-phenylbutyrate reduced the platelet hyperactivation. CONCLUSIONS: We show for the first time, that UPR activation occurs in platelets and can be independent of genomic regulation, with selective induction being specific to the source and severity of stress. Each UPR pathway plays a key role and can differentially modulate the platelet activation pathways and phenotype. Targeting the specific arms of UPR may provide a new antiplatelet strategy to mitigate thrombotic risk in diabetes and other cardiovascular diseases.

An Unusual Presentation of Spontaneous Rupture of Dermoid Cyst.

Intracranial dermoid cysts are exceptionally rare tumors. Interestingly, this condition has a low mortality rate but a high morbidity rate due to its numerous complications. We report a case of a 62-year-old man who presented with a headache and was found to have a ruptured dermoid cyst, complicated with the dissemination of lipid droplets within the subarachnoid space.

Status Epilepticus as a Life-Threatening Manifestation of Myxedema Crisis.

Myxedema coma is a rare life-threatening emergency that usually presents in the elderly during the winter months. The neurological changes caused by uncontrolled hypothyroidism may precipitate seizure activity and its deleterious consequences. A 65-year-old homeless man with a history of non-Hodgkin lymphoma in remission for over 20 years presented to the emergency department (ED) following an episode of syncope. His physical examination was remarkable for hypothermia and bradycardia. Shortly after the admission, he had two tonic-clonic seizures with sphincter relaxation and no recovery between the convulsions. His thyroid-stimulating hormone (TSH) level was 304 uIU/ml. He received appropriate treatment for his condition and was discharged after a full recovery. This case illustrates the catastrophic consequences of long-term uncontrolled hypothyroidism. A high index of clinical suspicion is essential for beginning prompt hormone supplementation in such patients.

Life-threatening sustained hypocalcemia following Denosumab use in metastatic prostate cancer.

INTRODUCTION: Prostate cancer is the second most frequently diagnosed cancer among men worldwide in 2020. Skeletal-related events (SRE) like pathologic fracture or spinal cord compression are commonly seen in metastatic prostate cancer. Denosumab, a monoclonal antibody, acts by inhibiting osteoclast-mediated bone resorption in bone metastasis from solid tumors and reduces bone turnover and destruction. However, there is an increased risk of life-threatening denosumab-induced hypocalcemia with an incidence of 0.1 to 12.8%. CASE REPORT: Our patient is a 69-year-old man with widespread skeletal metastatic disease from primary prostate cancer who presented to the hospital complaining of generalized fatigue and joint pain. Due to severe debilitating low back pain secondary to osteochondral lesions, the patient was started on Denosumab 120 mg. On presentation, serum calcium was found to be severely low at 5.9 mg/dl (serum calcium level prior to Denosumab was 9.1 mg/dl). MANAGEMENT AND OUTCOME: Denosumab was discontinued immediately, and the patient was started on IV calcium gluconate. Repeat serum calcium level continued to be low at 6.7 likely due to the long elimination half-life of Denosumab (25-30 days). He was transferred to a long-term acute care facility for long-term IV calcium replacement, where he succumbed to illness six weeks later. DISCUSSION: Denosumab, an anti-resorptive treatment for skeletal metastasis from solid tumors, is shown to cause severe life-threatening hypocalcemia. The maximum serum drug level of Denosumab reaches 7-21 days after administration. Sustained hypocalcemia is rare and life-threatening. Clinicians should use this medication with caution due to its unpredictable side effect profile.

Acute Eosinophilic Pneumonia Secondary to Daptomycin.

Daptomycin is an antimicrobial agent with activity against gram-positive bacteria that is usually reserved for severe infections. Acute eosinophilic pneumonia (AEP) is an increasingly rare side effect that can manifest after its use. Our patient is a 79-year-old male who was admitted for a left total knee arthroplasty infection. After daptomycin was started, he developed AEP. The offending agent was stopped, the appropriate medical treatment was given, and his symptoms significantly improved. This case illustrates an uncommon side effect of daptomycin. Prompt medical recognition is paramount for medication discontinuation and adequate medical care.

Spontaneous pneumomediastinum: A collaborative sequelae between COVID-19 and self-inflicted lung injury - A case report and literature review.

Spontaneous pneumomediastinum is an infrequent complication of COVID-19. The mechanism is still unknown and thought to be related to patient self-inflicted lung injury. Our patient is a 49-year-old male who presented with shortness of breath and cough. A COVID-19 Polymerase Chain Reaction was positive. He required a high-flow nasal cannula, but he did not demand mechanical ventilation. Computed tomography angiography scan of the chest revealed pneumomediastinum. He was managed conservatively, and a complete recovery was achieved. This case highlights the emerging association of COVID-19, patient self-inflicted lung injury, and pneumomediastinum. Furthermore, spontaneous pneumomediastinum should be suspected even in patients who were not mechanically ventilated.

COVID-19, Necrotizing Pancreatitis, and Abdominal Compartment Syndrome: A Perfect Cytokine Storm?

Coronavirus disease 2019 (COVID-19) induces a dysregulated immune response, leading to a drastic elevation of proinflammatory cytokines. This cytokine storm has the potential to aggravate any prior ongoing inflammation. Moreover, acute pancreatitis can cause local necrosis, thereby causing extensive abdominal inflammation. This condition increases the risk of abdominal compartment syndrome (ACS) and its deleterious consequences. We report the case of a 37-year-old male with a past medical history of chronic pancreatitis and alcohol use disorder who presented to the emergency department complaining of abdominal pain. Physical examination revealed a tender abdomen. Initial workup showed elevated amylase and lipase, a positive COVID-19 polymerase chain reaction (PCR) test, and elevated inflammatory markers. The patient denied any respiratory symptoms. Initial abdominal CT scan revealed mild pancreatic inflammation. The patient was admitted to the respiratory ICU and managed with fluid resuscitation and pain control. However, the patient had increasing oxygen requirements, leukocytosis, and worsening kidney function. A trans-bladder measurement of intra-abdominal pressure revealed severe ACS. Broad-spectrum antibiotics were started; however, after 72 hours of treatment, the patient had a cardiopulmonary arrest. He returned to spontaneous circulation after advanced cardiovascular life support (ACLS) protocol and intubation. A repeat CT scan of the abdomen showed necrotizing pancreatitis with a large-volume hemoperitoneum. Urgent pancreatic necrosectomy was performed with drainage of the hemoperitoneum. The patient was transferred to a long-term acute care facility for extended antibiotic therapy where he eventually recovered. This case illustrates the catastrophic consequences of necrotizing pancreatitis complicated by sepsis and ACS in a COVID-19-positive patient.

A Rare Case of Gemella haemolysans Infection of Knee Arthroplasty.

Gemella haemolysans is a facultative, catalase-negative, anaerobic, gram-positive cocci. It is known to mostly cause endocarditis, meningitis, peritonitis, and cerebral abscesses. However, it is extremely rare for this organism to cause infections of an orthopedic nature, with only a single report of infection in total knee arthroplasty (TKA). We present a rare case of knee arthroplasty infection caused by G. haemolysans four years after an uncomplicated TKA procedure.

Zonisamide-Induced Hallucinations: An Anticonvulsant's Psychosis.

Zonisamide is a new-generation anticonvulsant that works by altering the sodium and T-type calcium channels in the brain. It is currently approved for partial seizures, and trials are ongoing to evaluate the effectiveness against mania and chronic pain in adults. Psychosis is a rare side effect with an incidence of 2%. Our patient, a 52-year-old female with a past medical history of osteoarthritis and chronic pain only relieved by zonisamide is brought to the emergency department (ED) after a two-day history of altered mental status, agitation and visual hallucinations. One month prior, she had undergone total knee arthroplasty complicated with right knee cellulitis managed by IV (intravenous) long-term antibiotics of vancomycin and ertapenem. Physical examination was remarkable for disorientation to person, place, and time with intact remainder of the neurological exam. Initial laboratory work was unremarkable and a computerized tomography (CT) scan of the brain showed no acute intracranial abnormalities. The patient was treated as ertapenem-induced with altered mental status and the antibiotic was switched to meropenem upon discharge. Two weeks later, the patient presented to the ED with similar non-resolving complaints. As the patient's symptoms didn't improve after ertapenem discontinuation, the decision was made to stop zonisamide and carefully monitor for possible withdrawal symptoms. Progressively, our patient had a timely resolution of symptoms with a full return to baseline within a week. This case demonstrates the potential severity of zonisamide-induced psychosis. Additional studies are warranted to analyze the mechanism explaining its neurological side effect profile.

Arnold-Chiari Malformation and Scoliosis: A Chronic Lung Collapse Mimicking Sepsis.

Scoliosis is a deformity of the spine caused by excessive lateral curvature. Compared to other variants, neuromuscular scoliosis is more likely to progress, altering the body's normal architecture in a relatively short period of time. Furthermore, patients with Arnold-Chiari malformation or Chiari malformation (CM) type 2 have intrinsic neurological complications that might entangle the initial clinical assessment. A 24-year-old woman with a history of scoliosis and CM type 2 status post-tracheostomy was admitted from a skilled nursing facility after a one-day history of low blood pressure, leukocytosis, and an outpatient chest X-ray suspicious for pneumonia. Physical examination was remarkable for hypotension and decreased breath sounds at the left pulmonary base. A tracheostomy tube and central venous catheter were noticed. Initial laboratory results revealed leukocytosis with borderline bandemia and a chest X-ray with a left lower lung consolidation. She was treated as a case of sepsis, for which broad-spectrum antibiotics were immediately started. However, upon review of charts, the patient's objective findings were similar to a previous admission. Chest computed tomography scan revealed atelectasis in the left lower lung with no signs of consolidation, effusions, or abscesses. After extensive workup, no identifiable cause was found to suggest an acute process. Antibiotic therapy was halted and the patient was discharged to her nursing home. This case presents a patient with CM type 2 and scoliosis complicated by chronic and worsening atelectasis. Accurate initial assessment and communication between providers are paramount to avoid overtreatment.

Elective Colectomy in a Patient with Active Ulcerative Colitis and Metastatic Melanoma Enabling Successful Treatment with Immune Checkpoint Inhibitors.

Checkpoint inhibitor immunotherapy has significantly advanced treatment of a growing number of advanced malignancies. A consequences of immune system activation that leads to tumor cell destruction by checkpoint inhibitor therapy is the development of immune-related adverse events, some of which can be life threatening. There are limited data on the use of checkpoint inhibitor therapy in patients with preexisting autoimmunity owing to concerns that underlying autoimmune disease may be exacerbated by checkpoint inhibitor treatment. Decisions to treat these patients are made after careful consideration of the risks and benefits of treatment. We describe a patient with active and severe ulcerative colitis with metastatic melanoma who underwent elective colectomy prior to initiation of anti-PD-1 and anti-CTLA-4. The patient had excellent tumor response without flare of his ulcerative colitis suggesting that in select patients with high-risk inflammatory bowel disease, elective colectomy may be an effective treatment option.

Age associated non-linear regulation of redox homeostasis in the anucleate platelet: Implications for CVD risk patients.

BACKGROUND: Aging is a complex physiological phenomenon, intricately associated with cardiovascular pathologies, where platelets play a central pathophysiological role. Although antiplatelets are commonly employed to prevent and treat major adverse cardiovascular events, aging associated intraplatelet changes remain largely unexplored. METHODS: Platelets were studied in high cardiovascular risk patients (aged 40-100 years) comparing them to younger healthy subjects. This was followed by cross sectional and longitudinal mice studies. Flow cytometry, biochemical and molecular assays were used to study platelets comprehensively. FINDINGS: CVD Patients were categorized in the age groups 40-59, 60-79, and 80-100 years. Progressive decline in platelet health was observed in the 40-79 years age cohort, marked by increase in oxidative stress, hyperactivation and apoptotic markers. Paradoxically, this was reversed in patients aged above 79 years and the improved platelet phenotype was associated with lower oxidative damage. The platelets from the very old (80-100 year) group were found to be preloaded with increased antioxidants, which also contributed to higher resistance against induced redox insults. Cross sectional mouse studies excluded the effect of comorbidities and medications. Longitudinal mouse studies implicate an adaptive increase in antioxidant levels as the mechanism. INTERPRETATION: We report a novel age associated, non-linear redox regulation in platelets in both humans and mice. In advanced age, there occurs an adaptive increase in platelet antioxidants, reducing the intracellular ROS and leading to a healthier platelet phenotype. Clinically, our results advocate the use of less aggressive antiplatelet therapies for CVD in the elderly population. FUND: Study funded by NIH-NHLBI, RO1-HL122815 and RO1-HL115247.