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.

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.

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.

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.

Bevacizumab in refractory higher-grade and atypical meningioma: the current state of affairs.

INTRODUCTION: Historically, systemic agents had shown limited efficacy in meningioma, at the expense of significant pharmacologic and/or financial toxicity. As meningiomas are highly vascularized, they might derive benefit from antiangiogenic therapy. AREAS COVERED: This review summarizes the literature regarding bevacizumab pharmacology, safety and efficacy in patients with refractory meningioma. We have searched PubMed/Medline database for pertinent articles published from inception to 1 September 2018. EXPERT COMMENTARY: Results of two prospective phase II trials, supported by several retrospective cohorts, suggest a clinical benefit for the vascular endothelial growth factor inhibitor bevacizumab in meningiomas refractory to surgery and radiation therapy. This agent has a tolerable toxicity profile and seems more effective in higher-grade histologies and atypical meningioma, although responses in low-grade meningiomas have also been documented. Our conclusions are restricted due to a small size and lack of control in the prospective trials as well as the retrospective design of other studies. Further study of bevacizumab in refractory higher-grade meningiomas seems warranted.

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.

Local Fibrinolysis in Spontaneous Supratentorial Hematomas: Comparison with Surgical and Medical Treatment.

OBJECTIVE: To evaluate the effectiveness of minimally invasive craniopuncture with local fibrinolysis in the management of supratentorial spontaneous intracerebral hemorrhage (SICH). METHODS: The study included 218 consecutive patients with supratentorial SICH who were assigned to one of three groups: treated with minimally invasive craniopuncture with local fibrinolysis, treated with craniotomy or other minimally invasive techniques without local fibrinolysis, or receiving conservative management alone. RESULTS: Minimally invasive craniopuncture with local fibrinolysis was associated with a lower rate of assisted ventilation, a shorter period of in-hospital stay, a more frequent initiation of early rehabilitation, and a lower mortality rate at all periods of assessment. The overall mortality at 12 months was 19.4% (vs. 50.0 and 33.3% in the two other therapy groups). Lobar (subcortical and cortical) SICHs treated with local fibrinolysis had an overall mortality of 4.8% (vs. 43.5 and 41.7% in the two other therapy groups). On the other hand, SICHs having mixed (basal ganglia and lobar) locations treated with medical therapy alone had an overall mortality of 28.6%, while associated surgery with or without local fibrinolysis increased the overall mortality to over 65%. CONCLUSIONS: The study demonstrated the applicability of minimally invasive craniopuncture with local fibrinolysis for the management of supratentorial SICHs and the advantages it may have in certain categories of patients. The method proved particularly useful in lobar SICHs, being associated with the lowest mortality. Mixed SICHs do not represent a predilection for surgical interventions; however, the results related to mixed supratentorial locations need confirmation in larger cohorts.

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.

Growing applications of FDG PET-CT imaging in non-oncologic conditions.

As the number of clinical applications of 2-[fluorine 18]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography/computed tomography (PET-CT) grows, familiarity with the conditions that can be diagnosed by this modality and when relevant pieces of additional information can be obtained becomes increasingly important for both requesting physicians and nuclear medicine physicians or radiologists who interpret the findings. Apart from its heavy use in clinical oncology, FDG PET-CT is widely used in a variety of non-oncologic conditions interconnecting to such disciplines as general internal medicine, infectious diseases, cardiology, neurology, surgery, traumatology, orthopedics, pediatrics, endocrinology, rheumatology, psychiatry, neuropsychology, and cognitive neuroscience. The aim of this review was to summarize the current evidence of FDG PET-CT applications in evaluating non-oncologic pathologies and the relevant information it can add to achieve a final diagnosis.

Radionuclide Salivagram and Gastroesophageal Reflux Scintigraphy in Pediatric Patients: Targeting Different Types of Pulmonary Aspiration.

OBJECTIVE: Both gastroesophageal reflux (GER) scintigraphy and radionuclide salivagram are commonly used in the detection of pulmonary aspiration in pediatric patients. This investigation is to compare the diagnostic value of these 2 imaging methods. METHODS: This retrospective study included 4186 pediatric patients (aged 1 week to 16 years; mean age, 28 months) who underwent a GER scintigraphy and/or radionuclide salivagram. Detection rate of pulmonary aspiration by the 2 imaging techniques was compared. RESULTS: The detection rate for pulmonary aspiration in patients undergoing both procedures was 1.9% (5 of 266) for GER scintigraphy and 22.2% (59 of 266) for radionuclide salivagram. Fifty-six of 59 patients with proven aspiration on radionuclide salivagram demonstrated no such findings on GER scintigraphy, whereas 2 of 5 patients with proven aspiration on GER scintigraphy demonstrated no such findings on radionuclide salivagram. In patients who underwent only 1 procedure (either GER scintigraphy or salivagram), the detection rate for pulmonary aspiration was 0.4% (15 of 3551) for GER scintigraphy and 20.3% (75 of 369) for radionuclide salivagram. CONCLUSIONS: Radionuclide salivagram showed a much higher detection rate for pulmonary aspiration compared with GER scintigraphy. However, this may be related to a significantly higher prevalence of antegrade versus retrograde aspiration in our study population. Our results also suggest that not all episodes of retrograde aspiration can be detected by a radionuclide salivagram, and the requested scan should be tailored to the type of suspected aspiration.

Horseshoe Kidney Incidentally Revealed on Meckel Scintigraphy.

An 8-year-old male patient with history of bloody stools underwent a Meckel diverticulum scintigraphy to evaluate for ectopic gastric mucosa. The static images showed 2 abnormal foci of radiotracer accumulation in the mid-abdomen. Contrary to the renal activity, the foci appeared more prominent on the anterior view and localized anteriorly to the expected kidneys location on the left lateral view. Carefully reviewed dynamic acquisition revealed faint catenary-shaped activity in this region on earlier images, gradually evolving into 2 prominent foci on later images. A horseshoe kidney was suspected, the pathology being confirmed by abdominal ultrasonography.

Non-Hodgkin lymphoma dominated by multiple organ extranodal disease revealed on FDG PET/CT.

The definition of primary extranodal lymphoma is rather controversial and often complicated by the variety of lymphoma types. Here we describe FDG PET/CT findings in 3 pediatric patients with diffuse large B-cell non-Hodgkin lymphomas dominated by extranodal lesions involving multiple organs. Lymphomas arising primarily in extranodal sites can present significant diagnostic challenges due to their morphological diversity and lack of uniformity in histopathological classification.

Increased MIBG activity in the uterine cervix due to menstruation.

A 21-year-old woman with history of presacral ganglioneuroblastoma underwent I-MIBG scan for restaging. Planar images revealed increased MIBG activity in the upper pelvis, suggestive of disease recurrence. Complementary SPECT/CT images, however, localized the activity to the uterine cervix. Upon further questioning, it has been established that the patient was menstruating. Subsequent follow-up scans proved normal, confirming the benign etiology of these findings. The case shows that radioactive blood accumulation in the uterine cervix can interfere with MIBG scan interpretation in menstruating patients.

Application of partial volume effect correction and 4D PET in the quantification of FDG avid lung lesions.

PURPOSE: The aim of this study is to assess a software-based method with semiautomated correction for partial volume effect (PVE) to quantify the metabolic activity of pulmonary malignancies in patients who underwent non-gated and respiratory-gated 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG)-positron emission tomography (PET)/x-ray computed tomography(CT). PROCEDURES: The study included 106 lesions of 55 lung cancer patients who underwent respiratory-gated FDG-PET/CT for radiation therapy treatment planning. Volumetric PET/CT parameters were determined by using 4D PET/CT and non-gated PET/CT images. We used a semiautomated program employing an adaptive contrast-oriented thresholding algorithm for lesion delineation as well as a lesion-based partial volume effect correction algorithm. We compared respiratory-gated parameters with non-gated parameters by using pairwise comparison and interclass correlation coefficient assessment. In a multivariable regression analysis, we also examined factors, which can affect quantification accuracy, including the size of lesion and the location of tumor. RESULTS: This study showed that quantification of volumetric parameters of 4D PET/CT images using an adaptive contrast-oriented thresholding algorithm and 3D lesion-based partial volume correction is feasible. We observed slight increase in FDG uptake by using PET/CT volumetric parameters in comparison of highest respiratory-gated values with non-gated values. After correction for partial volume effect, the mean standardized uptake value (SUVmean) and total lesion glycolysis (TLG) increased substantially (p value <0.001). However, we did not observe a clinically significant difference between partial volume corrected parameters of respiratory-gated and non-gated PET/CT scans. Regression analysis showed that tumor volume was the main predictor of quantification inaccuracy caused by partial volume effect. CONCLUSIONS: Based on this study, assessment of volumetric PET/CT parameters and partial volume effect correction for accurate quantification of lung malignant lesions by using respiratory non-gated PET images are feasible and it is comparable to gated measurements. Partial volume correction increased both the respiratory-gated and non-gated values significantly and appears to be the dominant source of quantification error of lung lesions.