A comprehensive analysis of POLE/POLD1 genomic alterations in colorectal cancer.

INTRODUCTION: Pathogenic mutations in POLE/POLD1 lead to decreased fidelity of DNA replication, resulting in a high tumor mutational burden (TMB-H), defined as TMB ≥ 10 mut/Mb, independent of deficient mismatch repair (dMMR) and microsatellite instability high (MSI-H) status. METHODS: De-identified records of patients with colorectal cancer (CRC) profiled with the Tempus xT assay (DNA-seq of 595-648 genes at 500×) were identified from the Tempus Database. RESULTS: Among 9136 CRC samples profiled, the frequency of POLE/POLD1 genomic alterations was 2.4% (n = 217). Copy number loss was the most common genomic alteration (64%, n = 138) of POLE/POLD1, followed by copy number amplifications (18%, n = 40) and short variant mutations (18%, n = 39). The POLE/POLD1 mutated group presented with a higher frequency of TMB-H phenotype relative to wild type (WT; 22% vs. 9%, P < .001), with a median TMB of 127 mut/Mb in the TMB-H POLE/POLD1 subset. The TMB showed a dramatic contrast between POLE/POLD1 short variant mutations as compared to the group with copy number alterations, with a TMB of 159 mut/Mb vs 15 mut/Mb, respectively. Thus, the short variant mutations represented the so-called ultra-hypermutated phenotype. The POLE/POLD1 mutated group, as compared to WT, exhibited a higher rate of coexisting mutations, including APC, ALK, ATM, BRCA2, and RET mutations. CONCLUSION: Patients with POLE/POLD1 mutations exhibited significant differences across immunological markers (ie, TMB, MMR, and MSI-H) and molecular co-alterations. Those with short variant mutations represented 18% of the POLE/POLD1 cohort and 0.4% of the total cohort examined. This group of patients had a median TMB of 159 mut/Mb (range 34-488), representing the ultra-hypermutated phenotype. This group of patients is important to identify given the potential for exceptional response to immune checkpoint inhibitors.

Second-Line Treatment of Pancreatic Adenocarcinoma: Shedding Light on New Opportunities and Key Talking Points from Clinical Trials.

Despite improvements in overall cancer mortality, deaths related to pancreatic cancer continue to rise. Following first-line treatment, second-line options are significantly limited. Classically, first-line treatment consisted of either gemcitabine or 5-fluorouracil based systemic chemotherapy. Upon progression of disease or recurrence, subsequent second-line treatment is still gemcitabine or 5-fluorouracil based chemotherapy, depending on what was used in the first line and the timing of progression or recurrence. A better understanding of the molecular underpinnings of pancreatic adenocarcinoma (PDAC) has led to new treatment strategies including specifically targeting the desmoplastic stroma, cytokine signaling and actionable mutations. Furthermore, efforts are also directed to enhance the immunogenicity profile of PDAC's well-established immunologically "cold" tumor microenvironment. More recently, the outstanding response rates of chimeric antigen receptor T (CAR-T) cells in hematologic malignancies, have led to clinical trials to evaluate the treatment modality in PDAC. In this review, we summarize recently presented clinical trials for metastatic pancreatic adenocarcinoma with novel treatment approaches in the second line and beyond.

A real-world experience of pembrolizumab monotherapy in microsatellite instability-high and/or tumor mutation burden-high metastatic castration-resistant prostate cancer: outcome analysis.

BACKGROUND: The efficacy of pembrolizumab monotherapy in metastatic castration-resistant prostate cancer patients (mCRPC) when stratified by MSI-H and/or TMB-H is poorly defined. Additionally, outcomes based on sequencing source (i.e., tissue or liquid biopsy) have not been well described. We sought to assess outcomes of pembrolizumab monotherapy in patients with mCRPC and compare efficacy based on MSI-H and/or TMB-H when identified by tissue or liquid biopsy. METHODS: A retrospective analysis was performed of mCRPC patients treated at Mayo Clinic with pembrolizumab monotherapy between 2018 and 2023. Objective response rates (ORR), median progression-free survival (mPFS), and overall survival (mOS), were determined by RECIST v1.1 criteria. RESULTS: Twenty-two patients with mCRPC received pembrolizumab monotherapy for at least 3 cycles for a MSI-H or TMB-H indication. All patients had next generation sequencing (NGS) performed via tissue (n = 11) or liquid (n = 10) biopsy source. The ORR was 50% (27.3% complete response and 22.7% had partial response). The mPFS for TMB 10-14.9 mut/Mb (n = 4), TMB 15-24.9 mut/Mb (n = 6), and TMB ≥ 25 mut/Mb (n = 10) was 2.1, not reached (NR), and NR, respectively (p = 0.0003). The mOS for these same groups was 5.1 months, 20.5 months, and not reached, respectively. Among patients with TMB-H without co-occurring MSI-H or CDK12 (n = 6), none experienced a response and only one patient had stable disease compared to patients with MSI-H (n = 12) for whom the ORR was 75%. Immunotherapy responsive alterations such as ATRX and PTCH1 mutations were frequently noticed among patients who had complete response (CR). CONCLUSIONS: Our hypothesis-generating study suggests that MSI-H drives the efficacy of pembrolizumab in mCRPC with better survival outcomes as TMB increases. Clinicians should consider alternative treatment strategies for advanced prostate cancer when TMB-H is present without co-occurring MSI-H or CDK12.

Severe Cytokine Release Syndrome and Hemophagocytic Lymphohistiocytosis (HLH)-Like Syndrome Following Administration of Combined Brentuximab Vedotin and Nivolumab for Recurrent Classical Hodgkin Lymphoma: A Case Report.

Brentuximab vedotin (BV) and nivolumab are increasingly utilized as a novel regimen in patients with relapsed/refractory classical Hodgkin lymphoma (cHL). A 26-year-old male presented to the hospital with refractory diabetic ketoacidosis and multiple electrolyte abnormalities, 9 days after the first dose of brentuximab vedotin and nivolumab for recurrent classical Hodgkin lymphoma. During his hospitalization, he developed multi-organ failure. His workup showed elevated cytokine levels concerning severe cytokine release syndrome (CRS) and hemophagocytic lymphohistiocytosis (HLH)-like syndrome. Despite treatment with CRS- and HLH-directed therapies, his clinical status deteriorated due to ongoing multifactorial shock and worsening multi-organ dysfunction, and comfort care measures were eventually pursued. To our knowledge, there have been no other cases reported of HLH-like syndrome after the combination of BV and nivolumab in patients with cHL. This case of a fatal adverse event following one dose of BV and nivolumab underscores the vital need for close monitoring of patients receiving this treatment regimen.

Tyrosine Kinase Inhibitors and Immunotherapy Updates in Neuroendocrine Neoplasms.

Neuroendocrine tumors (NETs) represent a heterogeneous group of malignancies that arise from neuroendocrine cells dispersed throughout the organs/tissues of the body. Treatment of advanced/metastatic disease varies depending on tumor origin and grade. Somatostatin analogs (SSA) have been the mainstay first-line treatment in the advanced/metastatic setting for tumor control and managing hormonal syndromes. Treatments beyond SSAs have expanded to include everolimus (mTOR inhibitor), tyrosine kinase inhibitors (TKI) (e.g., sunitinib), and peptide receptor radionuclide therapy (PRRT) with the choice of therapy to some extent dictated by the anatomic origin of the NETs. This review will focus on emerging systemic treatments for advanced/metastatic NETs, particularly TKIs, and immunotherapy.

Efficacy and Safety of Direct Oral Anticoagulants in Patients With Antiphospholipid Syndrome: A Systematic Review and Meta-Analysis.

Due to a high risk of recurrent thromboembolism in patients with antiphospholipid syndrome (APS), long-term anticoagulation is recommended. For decades, vitamin K antagonists (VKAs) have been the gold standard for thromboprophylaxis in these patients. Due to the widespread use of direct oral anticoagulants (DOACs) in various thromboembolic conditions and their potential advantages compared to VKAs, several studies have been conducted to evaluate their safety and efficacy in APS. We performed a literature search using PubMed, Embase, and Cochrane databases for studies comparing DOACs to VKAs in patients with APS. Relative risk (RR) and the corresponding 95% confidence intervals (95% CI) were estimated for recurrent thromboembolic events, bleeding, and mortality. A total of 1437 patients pooled from 12 studies were analyzed. The risk of recurrent thrombosis, especially arterial thrombosis, doubled with DOACs compared to VKAs (RR 2.61, 95% CI 1.44-4.71; p=0.001). The risk further increased in patients with a triple-positive antiphospholipid antibody profile (RR 4.50, 95% CI 1.91-10.63; p=0.0006) and with the use of rivaroxaban (RR 1.95, 95% CI 1.10-3.45; p=0.02). The risk of major bleeding and mortality were not significantly different between the two arms. A trend favoring DOACs compared to VKAs was observed for all bleeding events.  This meta-analysis comes in agreement with previous studies and supports the use of VKAs in APS. Our study revealed that VKAs remain the gold standard for the management of APS, especially triple-positive APS. DOACs, particularly rivaroxaban, are not as effective in preventing recurrent thromboembolism in high-risk APS patients. Further studies are needed to evaluate the role of DOACs apart from rivaroxaban with a focus on their efficacy in the management of isolated or double-positive APS.

Advanced Case of Cardiac Amyloidosis Presents With Chronic Diarrhea.

Late diagnosis of light chain (AL) amyloidosis can lead to catastrophic consequences on the quality of life of affected patients and overall disease prognosis. Therefore, clinicians should have high suspicion and recognize clinical red flags for amyloidosis. This case report presents a 65-year-old female who presented to the emergency department with chronic diarrhea and significant weight loss with significant hypotension. The patient was treated four weeks prior to admission with a five-day course of nitrofurantoin for urinary tract infection. The initial workup was positive for Clostridium difficile(C.diff), which was treated medically; however, the patient started to complain of mild shortness of breath accompanied by mildly elevated brain natriuretic peptide (BNP). Later on, the patient had a cardiac arrest and was appropriately resuscitated. Subsequent ECHO showed significant left ventricular hypertrophy, raising high suspicion of myocardial infiltration. Because of persistent diarrhea despite aggressive medical management and an inconclusive workup, the patient underwent colonoscopy with duodenum biopsy, which revealed amyloid deposition confirmed by Congo red staining. The patient afterward suffered from a stroke and recurrent syncopal episodes requiring critical care admission. Due to a compromised quality of life, the patient eventually opted for hospice care. In view of insufficient prospective data spotlighting AL amyloidosis, all patients should be treated within clinical trials whenever possible and ideally evaluated for autologous hematopoietic cell transplantation (HCT) eligibility.

A Rare Case of Advanced Synchronous Primary Ovarian and Cervical Cancer.

Synchronous gynecological malignancies are rarely encountered, with a growing tide to recognize these primary tumors. However, the most observed synchronous gynecological malignancies remain ovarian and endometrial cancer. This case report presents a 35-year-old female who presented to her gynecologist with lower back pain and dysuria. Transvaginal ultrasound demonstrated a 3-4 cm irregular mass in the cervix and lower uterine segment. Pathology from cold knife conization and endometrial curetting showed serous adenocarcinoma with probable lymphovascular invasion. The patient underwent a positron emission tomography scan that demonstrated an abnormal-appearing cervix, a small number of ascites, peritoneal carcinomatosis, and abnormal left adnexa. Eighteen days later, the patient underwent exploratory laparotomy with total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, lymphadenectomy, and bowel resection. Surgical histopathological findings confirmed the presence of two primary malignant tumors, namely, cervical adenosquamous carcinoma and bilateral ovarian high-grade serous carcinoma, with extensive metastatic lesions. Although synchronous ovarian and cervical cancer is rarely encountered, patients might benefit from early identification and subsequent debulking surgery with curative intent, as well as adding an immune checkpoint inhibitor in case it is positive on checking as it might improve long-term outcomes.

Extra-Axial Skeletal Metastasis of Malignant Melanoma: Case Report and Literature Review.

The incidence of malignant melanoma is increasing worldwide and is one of the major causes of skin cancer deaths in the United States. Although melanoma has the potential to metastasize to any organ, the incidence of bone metastasis is low (~25%) compared to liver or lung metastasis. However, when a bone is involved, metastasis occurs to the axial skeleton in most cases (80%-90%), and involvement of the appendicular skeleton is relatively rare. We here describe the case of a patient who presented with a pathological fracture due to extra-axial skeletal metastasis of a widespread malignant melanoma.  A 45-year-old female with an unremarkable past medical history presented to the ED with acute left hip pain. X-ray demonstrated left intertrochanteric femur fracture with an abnormal, suspicious lesion at the fracture site. Detailed physical examination revealed various skin nodules on the anterior chest wall, right upper back, and left cheek. CT of the chest/abdomen/pelvis (CT C/A/P) showed multiple lytic bone lesions and metastatic lesions in lungs, soft tissue, and mediastinal lymph nodes. She underwent surgical stabilization of the fracture, and a biopsy of the bone lesion revealed metastatic malignant melanoma with BRAF V600E mutation. She was started on localized radiotherapy followed by targeted therapy (dabrafenib and trametinib) and denosumab for her stage IV (cTX, cN2, cM1b(1)) (American Joint Committee on Cancer [AJCC] cancer staging 8th edition) disease. Despite treatment, her disease progressed as evidenced by the presence of new metastatic foci on a positron emission tomography-computed tomography (PET-CT) scan performed at a three-month follow-up. Her clinical course was complicated by hemoperitoneum due to bleeding from metastatic liver lesions and respiratory failure requiring a prolonged stay in the ICU before she was deceased. In most cases, malignant melanoma presents with skin lesions at an early stage. Very few patients (4%) have metastatic disease at presentation. Although metastasis to bone is known to occur in advanced disease, involvement of the extra-axial skeleton is relatively rare. Malignant melanoma, initially presenting as pathological fracture of the appendicular skeleton, is not commonly encountered. Our case emphasizes the aggressive nature of malignant melanoma with an aim to raise physicians' awareness of this uncommon presentation. A brief review of the literature exploring prognosis and currently available treatment options is discussed.

Severe Epistaxis Secondary to Dabrafenib and Trametinib Toxicity in Non-small Cell Lung Carcinoma With Small Bowel Metastasis.

BRAF mutations are estimated to be present in 2-4% of non-small cell lung carcinoma (NSCLC) cases. BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib) are currently approved to treat NSCLC harboring the BRAF V600E mutation. However, the use of this new combined targeted therapy can be associated with severe and life-threatening toxicities. Here, we describe the case of a 77-year-old male with a history of BRAF-positive lung adenocarcinoma with metastasis to the brain, adrenals, and small bowel (jejunum), currently on dual therapy with dabrafenib and trametinib, who presented with refractory epistaxis. The dual therapy regimen was started one month prior to his presentation. After initial stabilization with anterior nasal packing, intravenous and nebulized tranexamic acid (TXA) in the emergency department (ED), he suddenly developed respiratory decompensation. He needed emergent intubation for acute hypoxic respiratory failure and airway protection secondary to profuse bleeding. He was extubated 24 hours later as the epistaxis was manageable, and the nasal packing was removed. Shortly after extubating, he started coughing copious amounts of blood and developed respiratory distress with stridor requiring re-intubation. A large blood clot was noted to be partially occluding the vocal cords on laryngoscopy and was removed during intubation. An emergent flexible fiberoptic bronchoscopy was performed with the retrieval of a large blood clot extending from the oropharynx down into the distal trachea. There was no evidence of acute bleeding within the lung after the clot was removed. Workup to explore the cause of his bleeding included a coagulation profile, which was unrevealing. His bleeding was most likely consistent with a side effect of his treatment with dabrafenib and trametinib. Life-threatening bleeding has been reported as a side effect of the combination therapy with dabrafenib and trametinib in metastatic melanoma. Also, in the phase 2 clinical trial (BRF113928) of dabrafenib plus trametinib in patients with previously untreated BRAF V600E-mutant metastatic NSCLC, 3.2% of subjects developed a grade III or IV hemorrhage. Our case aims to raise physicians' awareness of one of the significant side effects of this combination therapy especially since this combination is being used more frequently and now also in lung cancer.

Atypical Presentation of Cutaneous Squamous Cell Carcinoma of the Head and Neck: A Case Report.

Tumors of the head and neck can spread by direct extension, hematogenous spread, or lymphatic dissemination. However, a process known as perineural invasion (PNI) allows nerves to act as a direct conduit for tumor growth away from the primary site. Perineural invasion is a rare, atypical presentation of cutaneous squamous cell carcinoma of the head and neck that affects about 2.5%-14% of the population. It is known to be associated with an increased risk of local recurrent and distant metastasis, thus adversely affecting the patient's prognosis. The majority of PNI cases are asymptomatic, often discovered during pathological evaluation. We report the case of a patient who presented with a 1-year history of right-sided face pain and symptoms suggestive of trigeminal facial neuralgia. A skin biopsy taken from a lesion on his right cheek showed PNI secondary to cutaneous squamous cell carcinoma of the head and neck. We treated the patient with radiotherapy and chemotherapy and his clinical condition improved significantly. We are publishing this case report to increase awareness of practicing physicians and nurses to PNI as an atypical presentation of squamous cell carcinoma that may affect selection of treatment modality and the patient's prognosis.

Ectopic ACTH Production Caused by Metastatic Parotid Gland Acinic Cell Carcinoma.

OBJECTIVE: To present a case of adrenocorticotropic hormone (ACTH) hypersecretion caused by a metastatic acinic cell carcinoma (AcCC) of the parotid. Only 6 cases have been reported prior to October 2019. We believe that this condition is under-reported and hope that improved recognition will improve its reporting. METHODS: Diagnosis in this case was done using surgical pathology of the primary tumor, involving lymph nodes, and a metastatic lesion. Following an initial misdiagnosis, a final diagnosis of AcCC was made using immunohistochemical staining. ACTH hypersecretion was diagnosed by testing for random ACTH, cortisol, and 24-hour urine aldosterone and cortisol levels. RESULTS: A 57-year-old man presented with hypokalemia, lower-extremity edema, and left-side rib pain 7 months following excision of a 4-cm left-parotid tumor. Immunostaining positive for DOG-1, CK7, pan-cytokeratin (including CAM5.2), and SOX10 led to the diagnosis of AcCC. ACTH hypersecretion was diagnosed based on a random ACTH level of 307 pg/mL (normal morning value, 7.2-63 pg/mL), a cortisol level of 33 µg/dL (normal morning value, 4.3-19.8 µg/dL; normal PM value, 3.1-15.0 µg/dL), a 24-hour urine aldosterone level of <0.7 U (normal, 2.0-20 U), and a 24-hour urine cortisol level of 4564 U (normal, 3.5-45 U). The patient's ACTH hypersecretion and hypokalemia were treated with potassium replacement, amiloride, and ketoconazole. His metastatic recurrence was treated with radiotherapy, chemotherapy, and immunotherapy. The patient died after being diagnosed with sepsis secondary to multifocal postobstructive pneumonia 4 months after the diagnosis of his metastatic recurrence. CONCLUSION: Ectopic ACTH production caused by metastatic AcCC is a rare phenomenon but has been increasingly described over the last 15 years. We believe that this condition likely has a greater prevalence than what is reported and that improved recognition will lead to improved outcomes.

Adenoid cystic carcinoma of the labium oris with rare metastasis to the pleural cavity.

A 57-year-old Southeast Asian woman with a remote history of adenoid cystic carcinoma (ACC) of the right labium superius oris (upper lip) presented to the hospital with vague epigastric pain. On workup, she was found to have multiple pleural nodules. Histopathology confirmed the diagnosis of metastatic ACC. After 8 months of active surveillance, evidence of disease progression was found and the patient was started on pembrolizumab. Follow-up after starting pembrolizumab showed stable disease with no significant side effects.

Bilateral breast masses as a presentation for T-cell acute lymphoblastic leukaemia.

Here we describe a 27-year-old woman, 5 months post partum, who presented to the emergency department with bilateral breast masses. She was initially treated as lactational mastitis with no improvement. Breast ultrasound showed bilateral breast and axillary lymphadenopathy suggestive of metastatic/neoplastic process, and chest X-ray showed a large anterior mediastinal mass. Further work-up led to the diagnosis of T-cell acute lymphoblastic leukaemia. The patient was started on a paediatric regimen using the children's oncology group AALL0434 protocol. The patient achieved a complete remission following induction chemotherapy with resolution of her presenting symptoms.

Pulmonary embolism as the primary presentation of IgA vasculitis.

A 47-year-old man presented to the emergency department with acute onset of dyspnoea and a week history of painful erythematous rash on both of his legs. CT angiogram of the chest showed saddle pulmonary embolism resulting in right ventricular strain and obstructive shock. Due to the atypical nature of his skin rash, a skin biopsy from one of these lesions was done and came consistent with the diagnosis of IgA vasculitis.

Pyomyositis as an Unusual Presentation of Colonic Adenocarcinoma.

INTRODUCTION: Pyomyositis has been described in association with hematological malignancies. It is rarely associated with solid cancers, particularly colorectal carcinoma. Colorectal carcinoma can present with local or systemic abscesses by causing perforation of the colonic mucosa, followed by local or hematogenous spread of infection. CASE PRESENTATION: A 68-year-old male with a history of hypertension and type II diabetes mellitus presented to the emergency department with a 3-day history of left thigh pain. Magnetic resonance imaging of the thigh showed extensive intramuscular edema in the left thigh adductor and psoas muscles consistent with pyomyositis. An urgent debridement and irrigation of the left thigh revealed pan-sensitive Escherichia coli and Streptococcus viridans. Due to the suspicion of a gastrointestinal or genitourinary source of infection, computed tomography of the abdomen and pelvis showed an apple-core lesion along the mid-distal segment of the descending colon. Colonoscopy and biopsy confirmed the diagnosis of colonic adenocarcinoma. The patient underwent a laparoscopic left hemicolectomy with an end colostomy and was started on an adjuvant chemotherapy regimen with no significant side effects. CONCLUSION: Colorectal carcinoma can be associated with local or systemic abscess formation. When cultures from an abscess show enteric pathogens, it is essential to look to gastrointestinal or genitourinary tracts for the source of infection. Although rare, the diagnosis of pyomyositis should warrant further investigations to unmask the possible underlying cause.