Sjogren's syndrome due to immune checkpoint inhibitors (ICIs): Insights from a single-institution series and systematic review of the literature.

INTRODUCTION: Careful adverse event assessment and management are important when prescribing immune checkpoint inhibitors (ICIs) to cancer patients. Iatrogenic Sjogren's syndrome is a relatively rare immune-related adverse event (irAEs) that affects the moisture-producing glands. METHODS: We describe a series of four patients who developed Sjogren's syndrome while being treated with ICIs at a community cancer center in Southern California, USA (1/1/2017-12/31/2023). Patient, drug and disease-related data were collected by retrospective chart review. A systematic search of the PubMed database was performed to identify similar cases in the literature (1/1/2016-12/31//2023). RESULTS: Of 224 cancer patients at our center treated with ICIs, four (1.8%) developed iatrogenic Sjogren's syndrome. All of our patients were male; three received PD-1 inhibitors (nivolumab, pembrolizumab) and one received the PD-L1 inhibitor atezolizumab. The median time to development of Sjogren's syndrome was 24 weeks (range, 8-36 weeks); dry mouth symptoms were more prominent than dry eye symptoms. None of the patients had elevated SS-A, SS-B or antinuclear antibodies. One patient developed multiple tooth cavities and had several extractions, due to severe xerostomia. Management of all patients was primarily symptomatic. Two cases were irreversible; one was reversible and the 4th case is undermined as he is still on ICI therapy. Our systematic review of the literature identified 80 cases in five articles. Incidence of xerostomia was twice of that of xerophthalmia. The male/female ratio was 1.5:1. SS-A, SS-B, or antinuclear antibodies were found in only 9% of patients. Steroids were reported to have had only a limited role in management. CONCLUSIONS: The incidence of Sjogren's syndrome due to ICIs in our center was 1.8%. Details of clinical course and management in these patients are presented. Caring for patients with ICI-related Sjogren's syndrome is facilitated by a multidisciplinary effort including oncologists, otolaryngologists, dentists, ophthalmologists and rheumatologists. Expanding the knowledge base pertaining to iatrogenic Sjogren's syndrome in patients on ICIs will be helpful in promoting early detection and treatment, and improving outcomes.

Immune checkpoint inhibition in advanced colorectal cancer with inherited and acquired microsatellite instability: Current state and future directions.

OBJECTIVE: This paper reviews comprehensively the most relevant data on single-agent and combination therapies for advanced colorectal cancer with inherited and acquired microsatellite instability (MSI). DATA SOURCES: We performed a systematic search on PubMed and MEDLINE articles published from inception to December 2022. We have also searched independent websites including U.S. Food and Drug Administration and ClinicalTrials.gov. DATA SUMMARY: Performing microsatellite stability testing, tumor mutational burden (TMB), and germline mutation analysis could identify patients with metastatic colorectal cancer that benefit from immune checkpoint inhibitor (ICI) therapy. Single-agent pembrolizumab has proven superiority over traditional chemotherapy in these patients. The nivolumab-ipilimumab is the only combination ICI therapy approved in this space. Recently, the anti-PD-1 antibody dostarlimab was granted Food and Drug Administration approval in refractory tissue-agnostic advanced solid cancers with deficient mismatch repair (dMMR). ICIs are also being studied in the adjuvant/neoadjuvant setting in colon cancer patients with dMMR. Newer agents are being scrutinized in this space as well. More solid data on biomarkers predicting responses in patients with MSI-high or TMB-H to various therapies are needed. Given its both clinical and financial toxicity, it is imperative to determine the optimal duration of ICI therapy in individual patients. CONCLUSIONS: Overall, the outlook in advanced colorectal cancer patients with MSI appears optimistic as new and efficacious ICI drugs and combinations are being added to the existing therapeutic armamentarium.

Advanced uterine papillary serous cancer: Could there be a role for newer targeted therapeutic approaches or immune checkpoint inhibitors?

BACKGROUND: Although now available in oncology clinics, comprehensive germline mutation testing is being performed only in a minority of patients with advanced uterine papillary serous cancer (UPSC). Some of these patients might harbor various targetable mutations, either heritable or acquired.Data sources: We conducted a retrospective cohort study involving all consecutive patients with UPSC treated at our institution from 2009-2019. Data on epidemiology, with an accent on personal and family history of cancer, clinical presentation, disease stage, employed treatment modalities and cancer-specific survival (CSS) was sought. FINDINGS: Thirteen patients were seventy years of age or younger (≤70) while 15 were older than seventy (>70), and the two arbitrary patient cohorts were well-balanced for the TNM stage. Four UPSC patients >70 had a personal history of metachronous breast cancer. We also identified five cases of breast cancer, two cases of colon cancer, and one of each ovarian and uterine cancer in the first-degree relatives of UPSC patients >70. More than 90% of patients had surgical excision/debulking, and nearly half of the patients in each group received systemic chemotherapy. The most common chemotherapy regimen was carboplatin-paclitaxel every three weeks. Compared to patients ≤70, the UPSC patients >70 were less likely to undergo postoperative radiation therapy (6% vs 61.5%; p = 0.001) and had a worse CSS (21.8 vs. 27.4 months; HR 0.61, p = 0.03). CONCLUSIONS: Personal and family history in a cohort of older UPSC patients identified an excess of second primary cancers, and these patients displayed a shorter CSS. Comprehensive germline and tumor mutation analysis might identify optimal candidates for various targeted agents and immune checkpoint inhibitors, and ultimately improve survival. This may represent an unmet need in the UPSC patients, and further studies are needed to confirm the significance of our findings.

Severe left atrial enlargement due to carfilzomib use in multiple myeloma.

Several cardiovascular effects have been attributed to carfilzomib in the recent literature. These side effects must be recognized promptly by treating physicians and pharmacists. Special attention is required in patients with pre-existing cardiac conditions, liver function abnormalities and/or advanced age. This is the first report of a severe left atrial enlargement due to carfilzomib use in the setting of multiple myeloma. This condition improved dramatically seven months after cessation of carfilzomib. The authors discuss further various cardiac and vascular abnormalities linked with carfilzomib in the medical literature. Prompt withdrawal of this agent is essential in these cases as it may prevent dismal outcomes.

Inferior outcomes in immunocompromised Merkel cell carcinoma patients: Can they be overcome by the use of PD1/PDL1 inhibitors?

Cases of Merkel cell carcinoma have become increasingly more common in the last two decades, and its incidence has been predicted to climb further. Immunosenescence might explain in part the higher Merkel cell carcinoma prevalence in seniors aged 70 and older. This cancer might also be more aggressive in immunocompromised patients. In a subset of immunocompromised Merkel cell carcinoma patients, we identified significant lymphopenia and a more advanced disease stage compared with their immunocompetent counterparts. Time to death in this cohort was much shorter than in immunocompetent subjects, and their likelihood of death from Merkel cell carcinoma was five times higher. Avelumab approval in 2017 represents an important step forward in the therapy of Merkel cell carcinoma. Hopefully, PD1/PDL1 inhibitors will improve survival in immunocompromised Merkel cell carcinoma hosts, traditionally linked with inferior clinical outcomes.

Systemic therapy for relapsed/refractory meningioma: Is there potential for antiangiogenic agents?

Effective therapies for relapsed/refractory meningioma after surgery and radiation therapy represent an unmet need. Most meningiomas are highly vascularized tumors and, therefore, potentially amenable to antiangiogenic therapy. Herein, we review comprehensively the scientific literature on systemic therapy options for relapsed, persistent or metastatic meningioma, not amenable to local therapy. Also, this review offers insights into the function of vascular endothelial growth factor/receptor pathway both in health and disease. Further, we address the current status of the preclinical and clinical studies targeting vascular endothelial growth factor/receptor signaling in meningioma. Most relevant publications were identified through searching the PubMed/Medline database for articles published from inception to 1 February 2018. Vascular endothelial growth factor pathway activation might represent the primary driver of angiogenesis in meningioma. Positive findings of two prospective phase II trials, supported by the results of several retrospective cohorts, suggest a clinical benefit for the vascular endothelial growth factor inhibitor bevacizumab in refractory meningioma. Bevacizumab causes both peritumoral brain edema reduction and true meningioma shrinkage. Patients with WHO grades II-III meningioma appear to benefit more than patients with grade I disease. Similarly, responses have been documented with certain oral targeted anti-vascular endothelial growth factor/receptor agents. Further exploration of the role of vascular endothelial growth factor/receptor inhibitors in refractory meningioma seems warranted.

Merkel cell carcinoma: long-term follow-up of a single institution series and clinical outcomes by immunological status.

Merkel cell carcinoma (MCC) usually arises in sun-exposed areas of older patients and might be more aggressive in the immunocompromised. We performed a retrospective chart review of 40 consecutive MCC patients treated at our institution between the years 2006-2017. Clinical and epidemiologic data were utilized and therapy and survival were analyzed. Compared to Surveillance, Epidemiology, and End Results (SEER) data, our population was entirely Caucasian (100% versus 95%; P=0.11) and male predominant (75% versus 63%; P=0.11). The median age was 76. The patients more often had Tumor-Node-Metastasis (TNM) stage I disease (50% versus 39%; P=0.00003) and a primary tumor size <2cm (57.5% versus 34%; P<0.01). They received more frequently lymph node dissection (70% versus 63%, P=0.002) compared with the SEER findings. We identified a subset of immunocompromised patients (n=10) who presented with more stage III disease (40% versus 33%; P=0.021). Time to death averaged 290.1 days in this subset versus 618.2 days (P<0.001) in immunocompetent patients and their likelihood of death was 5 times higher. As clinical outcomes in MCC patients vary by immunological status, a multidisciplinary tumor-board approach may better optimize individual patient management.

Prevalence and Pattern of Autoimmune Conditions in Patients with Marginal Zone Lymphoma: A Single Institution Experience.

BACKGROUND: Increased risk of B-cell non-Hodgkin lymphoma (NHL) in patients with autoimmune diseases is a known fact. An association may exist between marginal zone lymphoma (MZL) and certain autoimmune conditions and vice-versa. METHODS: Herein, we present the analysis of a series of consecutive patients (n = 24) diagnosed with MZL at our institution between 2008-2014. Our series, analyzed both retrospectively and prospectively, consisted of a blend of nodal, extranodal and splenic MZL. The median age was 71.8 years; M/F ratio was 2:1. The presence of autoimmune conditions was compared to their documented prevalence in the general population and tested for statistical significance using both chi-square test (χ2) and Fisher test for small number of observations (95% confidence). A P-value < 0.05 was considered significant. FINDINGS: A total of 50% of MZL patients had documented autoimmune conditions. In addition, 3 of 24 patients presented with more than one autoimmune disease. Statistically significant differences in our MZL patients were recorded for immune thrombocytopenia [ITP] (P < 0.01), autoimmune hemolytic anemia [AIHA] (P < 0.01), Hashimoto thyroiditis (P = 0.037) and rheumatoid arthritis [RA] (P = 0.021). The difference did not reach statistical significance for systemic lupus erythematosus (SLE) and psoriasis. ITP and AIHA in our cohort were synchronous with MZL diagnosis in all patients, while all non-hematologic autoimmune conditions were metachronous and diagnosed prior to MZL. CONCLUSIONS: In the course of caring for patients with MZL, a number of associated autoimmune disorders are recognized. Knowing these entities is important not only for making a correct diagnosis, but also for being able to recognize certain clinical events occurring during the course of the disease. A catalogue of autoimmune disorders associated with this type of NHL is important as they can pose formidable clinical problems for the MZL patients and their physicians.

Western variant of brain intravascular lymphoma displaying three distinct evolutive radiologic stages.

Intravascular lymphoma is a rare type of extranodal diffuse large B-cell lymphoma characterized by proliferation of clonal lymphocytes within small- and medium-sized blood vessels and a relative sparing of surrounding tissues. It commonly affects the central nervous system (CNS), but its atypical presentation often leads to a delayed diagnosis. We report a unique case of a 53-year-old man presenting with confusion and ataxic gait. The initial magnetic resonance imaging (MRI) of the brain showed multifocal plaque-like CNS lesions suggestive of multiple sclerosis. His condition worsened rapidly, accompanied by persistent low-grade fever and further alteration in mental status. Follow-up MRI studies suggested new parenchymal brain lesions consistent with multiple evolving embolic strokes and subsequently with brain infarcts. Biopsy showed intravascular lymphomatous brain involvement. His condition continued to deteriorate, resulting in multiorgan failure and demise. To the best of our knowledge, these clear-cut MRI stages of brain intravascular lymphoma have not been previously reported in the scientific literature. Our findings are important as the diagnosis intravascular lymphoma is commonly made postmortem, given its rapidly progressive course and lack of typical symptomatology.

Operated bronchial carcinoids: clinical outcomes and long-term follow-up of a single institution series of 30 patients.

BACKGROUND: Bronchial carcinoids (BCs) are infrequent neoplasms that account for only 1% to 2% of all lung tumors. We reviewed the outcomes and long-term follow-up data of all patients diagnosed with BC and treated surgically at our institution between the years 2002-2009. PATIENTS AND METHODS: We analyzed the records of all patients with BC treated between January 1, 2002 and December 31st, 2009. The results were subsequently compared with the previously published data. RESULTS: Our records identified a total of 28 patients with typical carcinoids (TC) and two patients with atypical carcinoids (AC). Of these, 22 were women and eight were men with a median age of 62 (range, 23-91 years). About two-thirds of patients were symptomatic at presentation. Central and peripheral tumor location was encountered with equal frequency, with 63.3% of tumors being located in the right lung. Bronchoscopic biopsy revealed the diagnosis in 92.3% of cases. Twenty percent of patients underwent lung sparing procedures, 73.3% underwent lobectomies, and 6.7% had pneumonectomies. Mediastinal lymphadenectomy was performed in all patients. Two patients had positive nodal metastases, one of whom survived for only 10 months. Tumor recurrence was noted in two patients with TC (7.14%) and in one patient with AC. The overall five-year survival was 90% (27/30) for the entire cohort. CONCLUSIONS: Histological characteristics and nodal status probably represent the most important prognostic factors in persons with operated BCs. The female prevalence recorded in our cohort appears to contrast with previously reported almost equal gender distribution. The slightly lower percentage of lung-sparing procedures in our patients could be explained by their more advanced disease state, with tumor extension to more than one lung lobe.

Evaluation of infectious morbidity due to BTK inhibitors in indolent B-cell lymphomas: latest research findings and systematic analysis.

INTRODUCTION: Randomized clinical trials (RCTs) have suggested that BTK inhibitors (BTKis) might increase infectious disease (ID) risk. Systematic analysis of this topic as derived from RCTs and clinical practice is needed. AREAS COVERED: An extensive Medline, Embase, and Cochrane search of peer-reviewed sources reporting on ID morbidity in patients on BTKis was performed (1 January 2014 - 31 December 2013). Contribution of intrinsic immune defects in indolent B-cell lymphomas to this morbidity was carefully considered. EXPERT OPINION: Patients with indolent B-cell lymphomas display a wide range of innate and adaptive immune defects. In addition, BTKi use is linked with an increased signal of upper respiratory tract infections (URTIs) and pneumonias, mainly grade 1-2. These agents also increase the risk of rare invasive fungal infections (IFIs), mainly due to Cryptococcus and Aspergillus spp. with a peak within several months after the start of therapy. More than half of these IFIs are fatal. Research suggests a similar ID risk across 1st, 2nd and 3rd generations of BTKis, all causing B-cell dysfunction due to BTK inhibition, along with off-target functional neutrophil/macrophage alterations. Expanding the knowledge base on ID morbidity in patients on BTKis would facilitate timely diagnosis and treatment, and improve clinical outcomes.

Plasmablastic haemato-lymphoid neoplasm with a complex genetic signature of Burkitt lymphoma responding to bortezomib.

Plasmablastic lymphoma shares many morphologic features with plasmablastic plasma cell myeloma. The activation of MYC oncogene in these lymphomas may be an important pathogenetic element associated with Epstein-Barr virus infection. We describe herein an elderly man with a plasmablastic lymphoid neoplasm displaying unique morphologic, cytogenetic and clinical features. This case might offer additional insights to the complex but fascinating topic of hybrid haemato-lymphoid neoplasms such as plasmablastic lymphoma-myeloma. In addition, the patient responded to the treatment with bortezomib. Newer antimyeloma agents such as bortezomib have shown promise in the treatment of these neoplasms and should further be explored for their therapy.

Fluorodeoxyglucose-induced allergic reaction: a case report.

The number of diagnostic positron emission tomography/computed tomography (PET/CT) procedures performed in the USA and worldwide is rapidly increasing. Although the benefits of these procedures are obvious, the increasing use of radiopharmaceuticals requires a better understanding of potential adverse affects and their proper management. We present herein the first report of an allergic reaction to fluorodeoxyglucose in the setting of repeated PET/CT scans for restaging purposes in a patient with pyriform sinus cancer.

Mediastinal choriocarcinoma presenting with syncope.

Mediastinal choriocarcinomas are rare germ-cell tumors that occur almost exclusively in young males. These tumors grow rapidly, causing compression of mediastinal structures, and are usually associated with a poor prognosis. We report herein a unique case documenting syncope as initial clinical presentation of a mediastinal choriocarcinoma causing a superior vena cava (SVC) syndrome. The patient was treated with a standard chemotherapy triplet, with normalization of the tumor markers after the first chemotherapy cycle. He remains with no evidence of disease relapse 18 months later. Clinicians should consider the diagnosis of a mediastinal germ-cell tumor in a younger male patient presenting with a syncopal episode.

Gastrointestinal stromal tumor of small intestine and synchronous bilateral papillary renal cell carcinoma.

Association of gastrointestinal stromal tumors (GISTs) with other primary malignant neoplasms has previously been reported. In addition, coexistence of unilateral renal cell cancer and a GIST of the stomach has been documented in the literature. We report herein a unique case of a GIST of the small intestine and bilateral papillary renal cell carcinomas in a patient presenting with melena and dizziness. Literature shows that GIST arising from the small intestine is the most common location of GIST accompanied by a second primary neoplasm. However, a unique feature in our GIST patient is the presence of synchronous (bilateral) papillary renal cell carcinomas.

Hodgkin lymphoma as Richter transformation in chronic lymphocytic leukaemia: a retrospective analysis of world literature.

Richter transformation in chronic lymphocytic leukaemia (CLL) represents an entity of considerable genetic, molecular, immunological and clinical heterogeneity. A rare occurrence, Hodgkin variant of Richter syndrome, has not been comprehensively characterized or systematized to date. We conducted a retrospective analysis of the existing cases of Hodgkin lymphoma as Richter syndrome reported in the medical literature in the previous three and a half decades. Our search identified 86 such patients; this entity affects predominantly older men and the most common histological subtype is mixed cellularity. Interval between the diagnosis of CLL and subsequent development of Hodgkin lymphoma is circa 4.3 years. The overall survival of patients was approximately 1.7 years in our analysed cohort. However, our pooled data showed that patients in whom CLL had been treated with fludarabine had a shorter survival after transformation compared to the ones not treated with this agent. The role of immunosuppression and Epstein-Barr virus infection in the aetiopathogenesis of this entity remains to be clarified.

Normobaric hypoxia impairs human cardiac energetics.

Hypoxia causes left ventricular dysfunction in the human heart, but the biochemical mechanism is poorly understood. Here, we tested whether short-term normobaric hypoxia leads to changes in cardiac energetics and early cardiac dysfunction. Healthy male volunteers (n=12, age 24 ± 2 yr) were exposed to normobaric hypoxia in a purpose-built hypoxic chamber. The partial pressure of oxygen during end-tidal expiration (P(ET)o2) was kept between 50 and 60 mmHg, and peripheral oxygen saturation (Sao2) was kept above 80%. Cardiac morphology and function were assessed using magnetic resonance imaging and echocardiography, both before and after 20 h of hypoxic exposure, and high-energy phosphate metabolism [measured as the phosphocreatine (PCr)/ATP ratio] was measured using ³¹P magnetic resonance spectroscopy. During hypoxia, P(ET)o2 and Sao2 averaged 55 ± 1 mmHg and 83.6 ± 0.4%, respectively. Hypoxia caused a 15% reduction in cardiac PCr/ATP (from 2.0 ± 0.1 to 1.7 ± 0.1, P<0.01) and reduced diastolic function (measured as E/E', rising from 6.1 ± 0.4 to 7.5 ± 0.7, P<0.01). Normobaric hypoxia causes a rapid decrease in high-energy phosphate metabolism in the human cardiac left ventricle, which may lead to a decline in diastolic function. These findings are important in understanding the response of normal individuals to environmental hypoxia, and to situations in which disease reduces cardiac oxygen delivery.

Short-term consumption of a high-fat diet impairs whole-body efficiency and cognitive function in sedentary men.

We recently showed that a short-term high-fat diet blunted exercise performance in rats, accompanied by increased uncoupling protein levels and greater respiratory uncoupling. In this study, we investigated the effects of a similar diet on physical and cognitive performance in humans. Twenty sedentary men were assessed when consuming a standardized, nutritionally balanced diet (control) and after 7 d of consuming a diet comprising 74% kcal from fat. Efficiency was measured during a standardized exercise task, and cognition was assessed using a computerized assessment battery. Skeletal muscle mitochondrial function was measured using (31)P magnetic resonance spectroscopy. The diet increased mean ± se plasma free fatty acids by 44% (0.32±0.03 vs. 0.46±0.05 mM; P<0.05) and decreased whole-body efficiency by 3% (21±1 vs. 18±1%; P<0.05), although muscle uncoupling protein (UCP3) content and maximal mitochondrial function were unchanged. High-fat diet consumption also increased subjects' simple reaction times (P<0.01) and decreased power of attention (P<0.01). Thus, we have shown that a high-fat diet blunts whole-body efficiency and cognition in sedentary men. We suggest that this effect may be due to increased respiratory uncoupling.

Cardiac response to hypobaric hypoxia: persistent changes in cardiac mass, function, and energy metabolism after a trek to Mt. Everest Base Camp.

We postulated that changes in cardiac high-energy phosphate metabolism may underlie the myocardial dysfunction caused by hypobaric hypoxia. Healthy volunteers (n=14) were studied immediately before, and within 4 d of return from, a 17-d trek to Mt. Everest Base Camp (5300 m). (31)P magnetic resonance (MR) spectroscopy was used to measure cardiac phosphocreatine (PCr)/ATP, and MR imaging and echocardiography were used to assess cardiac volumes, mass, and function. Immediately after returning from Mt. Everest, total body weight had fallen by 3% (P<0.05), but left ventricular mass, adjusted for changes in body surface area, had disproportionately decreased by 11% (P<0.05). Alterations in diastolic function were also observed, with a reduction in peak left ventricular filling rates and mitral inflow E/A, by 17% (P<0.05) and 24% (P<0.01), respectively, with no change in hydration status. Compared with pretrek, cardiac PCr/ATP ratio had decreased by 18% (P<0.01). Whether the abnormalities were even greater at altitude is unknown, but all had returned to pretrek levels after 6 mo. The alterations in cardiac morphology, function, and energetics are similar to findings in patients with chronic hypoxia. Thus, a decrease in cardiac PCr/ATP may be a universal response to periods of sustained low oxygen availability, underlying hypoxia-induced cardiac dysfunction in healthy human heart and in patients with cardiopulmonary diseases.