Pituitary-adrenal axis dysfunction induced by tislelizumab immunotherapy for non-small cell lung cancer: a case series and literature review.

BACKGROUND: Adverse events of secondary adrenal insufficiency caused by anti-PD-1 immune agents are relatively rare in clinical practice, so in this article, we retrospectively analyzed three patients who suffered secondary adrenal cortex dysfunction caused by tislelizumab immunotherapy for Non-Small Cell Lung Cancer (NSCLC)and reviewed the literature. This rare immune-related adverse event was investigated by summarizing the clinical features of the patients. CASE PRESENTATION: We reported three NSCLC patients who suffered secondary adrenal cortex dysfunction induced by tislelizumab immunotherapy at our hospital from July 2021 to October 2023. We analyzed and summarized the clinical characteristic, laboratory examination, pathological staging, etc. We also reviewed related literature of pituitary inflammation and adrenal cortex dysfunction caused by immunotherapy. RESULTS: The median age of the three patients was 56 years. All the patients had a history of smoking. After receiving tislelizumab treatment (median cycle: 7), laboratory examination showed a decrease in morning cortisol and adrenocorticotropic hormone (ACTH), both were diagnosed with secondary adrenal insufficiency. Only one patient had symptoms of fatigue, vomiting, and weight loss. One of these patients also had simultaneous subclinical hypothyroidism. All three patients discontinued immunotherapy and received replacement therapy with glucocorticoids. At the last follow-up, none of the three patients restarted immunotherapy, because cortisol did not return to normal. This is similar to that of previous reports. CONCLUSION: Based on previous reports and our three cases, when laboratory tests of NSCLC patients receiving immunotherapy showed a decrease in morning cortisol and ACTH levels, especially when clinical symptoms were obvious, the possibility of immunotherapy-related pituitary inflammation causing secondary adrenal cortex dysfunction should be considered. Prompt monitoring and hormone replacement therapy should be provided to prevent adrenal crises.

Clinical characteristics and outcomes of immunocompromised critically ill patients with cytomegalovirus end-organ disease: a multicenter retrospective cohort study.

BACKGROUND: Cytomegalovirus (CMV) infection in patients with cellular immune deficiencies is associated with significant morbidity and mortality. However, data on CMV end-organ disease (CMV-EOD) in critically ill, immunocompromised patients are scarce. Our objective here was to describe the clinical characteristics and outcomes of CMV-EOD in this population. METHODS: We conducted a multicenter, international, retrospective, observational study in adults who had CMV-EOD and were admitted to any of 18 intensive care units (ICUs) in France, Israel, and Spain in January 2010-December 2021. Patients with AIDS were excluded. We collected the clinical characteristics and outcomes of each patient. Survivors and non-survivors were compared, and multivariate analysis was performed to identify risk factors for hospital mortality. RESULTS: We studied 185 patients, including 80 (43.2%) with hematologic malignancies, 55 (29.7%) with solid organ transplantation, 31 (16.8%) on immunosuppressants, 16 (8.6%) with solid malignancies, and 3 (1.6%) with primary immunodeficiencies. The most common CMV-EOD was pneumonia (n = 115, [62.2%] including 55 [47.8%] with a respiratory co-pathogen), followed by CMV gastrointestinal disease (n = 64 [34.6%]). More than one organ was involved in 16 (8.8%) patients. Histopathological evidence was obtained for 10/115 (8.7%) patients with pneumonia and 43/64 (67.2%) with GI disease. Other opportunistic infections were diagnosed in 69 (37.3%) patients. Hospital mortality was 61.4% overall and was significantly higher in the group with hematologic malignancies (75% vs. 51%, P = 0.001). Factors independently associated with higher hospital mortality were hematologic malignancy with active graft-versus-host disease (OR 5.02; 95% CI 1.15-27.30), CMV pneumonia (OR 2.57; 95% CI 1.13-6.03), lymphocytes < 0.30 × 109/L at diagnosis of CMV-EOD (OR 2.40; 95% CI 1.05-5.69), worse SOFA score at ICU admission (OR 1.18; 95% CI 1.04-1.35), and older age (OR 1.04; 95% CI 1.01-1.07). CONCLUSIONS: Mortality was high in critically ill, immunocompromised patients with CMV-EOD and varied considerably with the cause of immunodeficiency and organ involved by CMV. Three of the four independent risk factors identified here are also known to be associated with higher mortality in the absence of CMV-EOD. CMV pneumonia was rarely proven by histopathology and was the most severe CMV-EOD.

A case report of a malignant melanoma in the cardiologic diagnostic workup.

Background: Cardiovascular imaging plays an important role in identifying pre-existing cardiac comorbidity prior to the decision on cancer therapy and serves as a reference for detecting changes during treatment and long-term follow-up and also in the further identification of a possible cardiac manifestation of the underlying oncological disease. Case summary: We report the case of an 81-year-old patient with a malignant melanoma. The patient initially was presented before the start of adjuvant therapy with serine/threonine-protein kinase B-Raf/mitogen-activated extracellular signal-regulated kinase inhibitors. Cardiologic staged diagnostics using transthoracic echocardiography, transoesophageal echocardiography, and cardiovascular magnetic resonance imaging (CMR) revealed with a high probability a cardiac manifestation of the underlying disease. The echocardiographic and CMR results as well as the diagnostic workup are presented. Discussion: Cardiac masses in general have a variety of differential diagnoses. Cardiac metastases are much more common than primary neoplasms in a ratio of about 10:1. Cardiovascular risk stratification is recommended in all patients with cancer before starting potentially cardiotoxic anticancer therapy. Cardiovascular imaging plays an important role for baseline risk stratification but is also the leading diagnostic tool in the differential diagnosis of cardiac tumours and the planning of a potential therapy.

Teratoma to Angiosarcoma: A Metamorphosis in the Mediastinum.

We describe a rare and remarkable transformation of an immature mediastinal teratoma into high-grade angiosarcoma in a 21-year-old male. Mediastinal teratomas, particularly immature ones, are exceedingly rare, representing a small fraction of germ cell tumors (GCTs). Our case describes the clinical journey of the patient, who initially presented with acute chest pain and was subsequently diagnosed with an immature teratoma following imaging studies and elevated tumor markers. Despite an initial positive response to cisplatin-based chemotherapy, surveillance imaging revealed liver masses, which a biopsy confirmed as angiosarcoma. This transformation underscores the aggressive nature of immature teratomas and the propensity for sarcomatous differentiation, particularly in the mediastinum. The case contributes valuable insight into the management and surveillance of mediastinal non-seminoma germ cell tumors (MNGCT), a subset of GCTs with limited literature. We believe this case is the first in the literature to describe a transformation from an immature teratoma in the mediastinum to a high-grade angiosarcoma.

Role of miRNA­122 in cancer (Review).

MicroRNAs (miRNAs) are small non­coding RNAs that serve key roles in cell proliferation, migration, invasion and apoptosis by regulating gene expression. In malignant tumors, miRNA­122 serves either as a tumor suppressor or oncogene, influencing tumor progression via downstream gene targeting. However, the precise role of miRNA­122 in cancer remains unclear. miRNA­122 is a potential biomarker and modulator of radiotherapy and chemotherapy. The present review aimed to summarize the roles of miRNA­122 in cancer, its potential as a biomarker for diagnosis and prognosis and its implications in cancer therapy, including radiotherapy and chemotherapy, alongside strategies for systemic delivery.

A multicenter, phase 1, Adult Brain Tumor Consortium trial of oral terameprocol for patients with recurrent high-grade glioma (GATOR).

Recurrent high-grade gliomas (rHGGs) have a dismal prognosis, where the maximum tolerated dose (MTD) of IV terameprocol (5 days/month), a transcriptional inhibitor of specificity protein 1 (Sp1)-regulated proteins, is 1,700 mg/day with median area under the plasma concentration-time curve (AUC) of 31.3 µg∗h/mL. Given potentially increased efficacy with sustained systemic exposure and challenging logistics of daily IV therapy, here we investigate oral terameprocol for rHGGs in a multicenter, phase 1 trial (GATOR). Using a 3 + 3 dose-escalation design, we enroll 20 patients, with median age 60 years (range 31-80), 70% male, and median one relapse (range 1-3). Fasting patients tolerate 1,200 mg/day (n = 3), 2,400 mg/day (n = 6), 3,600 mg/day (n = 3), and 6,000 mg/day (n = 2) oral doses without major toxicities. However, increased dosage does not lead to increased systemic exposure, including in fed state (6,000 mg/day, n = 4), with maximal AUC <5 µg∗h/mL. These findings warrant trials investigating approaches that provide sustained systemic levels of transcription inhibitors to exploit their therapeutic potential. This study was registered at ClinicalTrials.gov (NCT02575794).

Papules to Pseudovesicular Lesions over Chest: A Mirror to Breast Malignancy.

Here, we present a case of carcinoma telangiectoides in an unknown case of breast carcinoma presenting as multiple discrete to confluent, raised, solid, erythematous to skin-colored papules to plaques approximately 0.5-2 cm in size over an erythematous base over the chest. On the basis of clinical, histopathological, and immunohistochemical findings, a diagnosis of carcinoma telangiectoides was made. Diagnosis is difficult due to varying clinical presentations, but histopathology aids in the diagnosis. Through the present case, dermatologists should become aware of the diverse manifestations of cutaneous involvement of breast cancer. Early detection of cutaneous involvement may provide a window of opportunity for timely diagnosis and treatment of the primary tumor and prevent spread.

Impact of Palliative Care Referral on End-of-Life Outcomes for Patients With Hematologic Malignancy.

CONTEXT: Compared to patients with solid malignancies, less is known about the role of palliative care in patients with hematologic malignancies, leading to underutilization of palliative care. OBJECTIVES: Evaluate the timing and impact of palliative care referrals on end-of-life outcomes over a 5-year period with intent to improve the utilization of palliative care in patients with advanced hematologic malignancies. METHODS: A retrospective cohort of patients from an urban, NCI-designated comprehensive cancer center, aged 18 years and older with a diagnosis of an advanced hematologic malignancy were separated into groups of early, late, very late, or no specialty palliative care. Logistic regression models were constructed to examine variables associated with timing of palliative care referral. Groups were compared using the Kruskal Wallis test and Dunn's test with a Bonferroni correction method. RESULTS: 222 patients with advanced hematologic malignancies who died between July 1, 20218 and June 30, 2023 were included. 50 (23%), 41 (18%), and 51 (23%) patients received an early, late, and very late palliative care referral, respectively and 80 (36%) patients did not receive a palliative care referral. There was a significantly high completion of ACP documentation among the palliative care cohorts. There was no significant difference among all cohorts in end-of-life outcomes in the last 14 or 30 days of life. CONCLUSION: ACP documentation improved with palliative care, however, end-of-life outcomes did not. These results are likely due to the majority of late, inpatient palliative care referrals. Future studies with targeted interventions are needed to improve these outcomes.

Exploring tonsillar cancer associations in patients with base of tongue cancer: insights from a single-center study.

PURPOSE: To explore the prevalence of synchronous and metachronous tonsillar cancer in patients with base of tongue cancer, as well as identifying potential risk factors linked to these secondary malignancies. We aim to answer the following question: Should bilateral tonsillectomy be recommended to patients diagnosed with base of tongue cancer? METHODS: A case-series study was conducted at Aarhus University Hospital, including all patients with histologically confirmed base of tongue squamous cell carcinoma treated between January 2012 and December 2021. Data from electronic patient records, including diagnosis of prior, synchronous or metachronous tonsillar cancer, demographics, and clinical features were analysed. Fisher's exact test was performed to assess factors associated with synchronous and metachronous tonsillar cancer. RESULTS: Among 198 patients with base of tongue cancer, 5.6% had a history of tonsillar cancer, either prior to (4.5%), synchronous (0.5%), or metachronous (0.5%) to the base of tongue diagnosis. The prevalence of synchronous or metachronous tonsillar cancer among patients without previous bilateral tonsillectomy was 1.2%. Patients with tonsillar cancer were older, had heavier smoking histories, and exhibited less frequent P16-overexpression. CONCLUSION: Our findings deepen understanding of tonsillar cancer in patients with base of tongue cancer. The prevalence of synchronous or metachronous tonsillar cancer was found to be relatively low, suggesting that routine tonsillectomy for all base of tongue cancer patients is not warranted.

Internist's tumour into thyroid: A case report.

Renal cell carcinoma (RCC) is well known for its unpredictable and diverse behaviour, with tendency to cause synchronous or metachronous metastasis to unusual site, which is why it is called the "internist's tumour."Although thyroid gland is an infrequent site for metastasis of different primary malignancies, metastatic RCC is one of the most common secondary thyroid malignancies. Diagnosis relies on a high index of suspicion in patients with prior RCC, combined with cross-sectional imaging and biopsy. A case of secondary thyroid neoplasm from RCC after 13 years of radical nephrectomy is described with clinicopathological features and literature review.

Investigating the relationship between postoperative radiotherapy and intestinal flora in rectal cancer patients: a study on efficacy and radiation enteritis.

Objective: This study aimed to investigate the impact of radiation therapy and radiation enteritis on intestinal flora, providing insights for treatment and prevention. Methods: Fecal samples were collected from 16 patients undergoing pelvic radiotherapy at Qingdao Hiser Hospital Affiliated of Qingdao University (Qingdao Traditional Chinese Medicine Hospital). Samples were collected before and after radiotherapy (27-30Gy), and analyzed using DNA sequencing and biostatistical methods. Results: Patients with radiation enteritis showed increased α-diversity and ß-diversity of intestinal flora compared to those without radiation enteritis. Differences in flora composition were observed, with higher abundance of secondary pathways such as amino acid metabolism, carbohydrate metabolism, cofactors and vitamins metabolism, and lipid metabolism. Conclusion: The study revealed that patients developing radiation enteritis during pelvic radiation therapy had increased diversity and abundance of intestinal flora compared to those who did not develop radiation enteritis. Additionally, patients without radiation enteritis showed significantly higher diversity and abundance of intestinal flora post-radiation compared to pre-radiation.

The risk and survival of multiple myeloma as the second primary malignancy in a single Chinese center.

Background: As the overall survival (OS) of patients with multiple myeloma (MM) improves, the incidence of second primary malignancy (SPM) in long-term complications increases. However, there are limited data regarding MM as a SPM. Therefore, this study aimed to determine the time trends in the incidence of MM, as well as the incidence and survival of patients with MM as the SPM. Methods: Kaplan-Meier survival analysis was performed to determine the survival curve, while a log-rank test was used to determine OS. Results: A total of 794 patients were diagnosed with MM among 7,921 patients with hematologic malignancy between 2009 and 2017. The incidence of MM showed an annual upward trend, increasing from 9.3% [2009-2011] to 10.8% [2015-2017]. Of the 794 patients with MM, 16 were diagnosed as the SPM commonly secondary to cancers of the lung (n=4), colon (n=3), breast (n=3), and other (n=6). The median survival of patients with MM as the SPM was 24.5 months (range, 1-95 months). The patients with MM without multiple malignancies had significantly longer survival (median, 46.5 months; range, 17-132 months; P=0.04). Conclusions: This retrospective study suggests that the incidence of MM may be increasing annually and that the survival of patients with MM as the second primary malignant was significantly shorter than that of those without multiple malignancies.

Evaluation of the diagnostic and prognostic clinical values of circulating tumor DNA and cell-free DNA in pancreatic malignancies: a comprehensive meta-analysis.

Background: The diagnostic and prognostic clinical value of circulating tumor DNA (ctDNA) and cell-free DNA (cfDNA) in pancreatic malignancies are unclear. Herein, we aimed to perform a meta-analysis to evaluate ctDNA and cfDNA as potential diagnostic and prognostic biomarkers. Methods: PRISMA reporting guidelines were followed closely for conducting the current meta-analysis. The PubMed/Medline, Scopus, and Web of Science (WoS) databases were scanned in detail to identify eligible papers for the study. A quality assessment was performed in accordance with the REMARK criteria. The risk ratios (RRs) of the diagnostic accuracy of ctDNA compared to that of carbohydrate antigen 19.9 (CA 19.9) in all disease stages and the hazard ratios (HRs) of the prognostic role of ctDNA in overall survival (OS) were calculated with 95% confidence intervals (CIs). Results: A total of 18 papers were evaluated to assess the diagnostic accuracy and prognostic value of biomarkers related to pancreatic malignancies. The pooled analysis indicated that CA19.9 provides greater diagnostic accuracy across all disease stages than ctDNA or cfDNA (RR = 0.64, 95% CI: 0.50-0.82, p < 0.001). Additionally, in a secondary analysis focusing on prognosis, patients who were ctDNA-positive were found to have significantly worse OS (HR = 2.00, 95% CI: 1.51-2.66, p < 0.001). Conclusion: The findings of this meta-analysis demonstrated that CA19-9 still has greater diagnostic accuracy across all disease stages than KRAS mutations in ctDNA or cfDNA. Nonetheless, the presence of detectable levels of ctDNA was associated with worse patient outcomes regarding OS. There is a growing need for further research on this topic. Systematic review registration: https://doi.org/10.37766/inplasy2023.12.0092, identifier INPLASY2023120092.

Autophagy modulation in cancer therapy: Challenges coexist with opportunities.

Autophagy, a crucial intracellular degradation process facilitated by lysosomes, plays a pivotal role in maintaining cellular homeostasis. The elucidation of autophagy key genes and signaling pathways has significantly advanced our understanding of this process and has led to the exploration of autophagy as a promising therapeutic approach. This review comprehensively assesses the latest developments in small molecule modulators targeting autophagy. Moreover, the review delves into the most recent strategies for drug discovery, specifically focusing on selective agents that exploit autophagosomes and lysosomes for targeted protein degradation. Additionally, this article highlights the prevailing challenges and outlines potential future advancements in the field. By amalgamating the cutting-edge knowledge in the field, we aim to offer valuable insights and references for the anti-cancer drug development of autophagy-targeted therapies, thus contributing to the advancement of novel therapeutic interventions.

A rare case of hidradenocarcinoma with anaplastic and invasive features arising from a nodulocystic hidradenoma.

A 91-year-old man presented with a cutaneous left abdominal mass. The mass was longstanding (over 5 years) and slow-growing. Examination revealed a violaceous, multinodular, and exophytic non-tender mass surrounded by patchy erythema. Excisional biopsy was performed and revealed a nodular and cystic dermal proliferation of predominately basaloid cells with focal duct formation, surrounded by prominent hyalinized stroma. The superficial portion of the mass was identified as a nodulocystic hidradenoma. Along the deep aspect and in association with the benign hidradenoma, sheets of markedly atypical epithelioid cells invaded the surrounding tissue, consistent with malignant transformation. Perineural and lymphovascular invasion were seen among areas with anaplastic features. This case supports that some hidradenocarcinoma originates from benign counterparts, and as such, ample sampling is required to definitively exclude a more sinister diagnosis. Diagnostic, prognostic, histopathological, and molecular characteristics, and current knowledge limitations are briefly discussed.

Infant with diffuse large B-cell lymphoma identified postmortem with homozygous founder Slavic RAG1 variant: a case report and literature review.

Background and aims: There is an increased risk of lymphomas in inborn errors of immunity (IEI); however, germline genetic testing is rarely used in oncological patients, even in those with early onset of cancer. Our study focuses on a child with a recombination-activating gene 1 (RAG1) deficiency who was identified through a screening program for Slavic founder genetic variants among patients who died with malignancy at an early age in Belarus. Results: We identified one homozygous founder RAG1 variant out of 24 available DNA samples from 71 patients who developed lymphoma aged <3 years from the Belarusian cancer registry between 1986 and 2023. Our patient had an episode of pneumonia at 3 months of age and was hospitalized for respiratory distress, candida-positive lung disease, and lymphadenopathy at 14 months of age. The diagnosis of Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) was established. The patient had a normal lymphocyte count that decreased over time. One month after chemotherapy initiation, the patient died due to sepsis and multiple organ failure without a genetic diagnosis. In a retrospective analysis, T-cell receptor excision circles (TRECs) and kappa-deleting recombination excision circles (KRECs) were undetectable in peripheral blood. Conclusions: A targeted screening program designed to detect a Slavic founder variant in the RAG1 gene among children revealed a 14-month-old Belarusian male infant with low TREC levels who died of EBV-driven DLBCL and complications of chemotherapy including infections. This case highlights how patients with IEI and recurrent infections may develop serious non-infectious complications, such as fatal malignancy. It also emphasizes the importance of early identification, such as newborn screening for severe combined immune deficiency. Earlier diagnosis of RAG deficiency could have prompted hematopoietic stem cell transplant well before the DLBCL occurrence. This likely would impact the onset and/or management strategies for the cancer.

Advances in the management of parathyroid carcinoma.

Parathyroid carcinoma (PCA) is a rare malignancy accounting for approximately 1% of all patients with primary hyperparathyroidism. It is characterised by excessive parathyroid hormone (PTH) production. This manuscript reviews recent advances in the management of parathyroid carcinoma, focusing on molecular insights, diagnostic modalities, surgical innovations, adjuvant therapies, and emerging targeted treatments. Recently published manuscripts (between 2022 and 2023) were obtained from Medical Literature Analysis and Retrieval System Online (Medline), Excerpta Medica (Embase), Cochrane Central Register of Controlled Trials (CENTRAL), and European Union Drug Regulating Authorities Clinical Trials (EudraCT). These were assessed for their relevance in terms of the diagnosis and management of patients with PCA. This manuscript explores the role of genetic profiling and presents case studies illustrating successful management strategies. The manuscript also discusses the ongoing challenges in the management of parathyroid carcinoma, suggesting future research directions and potential therapeutic avenues.

Alteration of salivary LPO, MDA, LDH, glutathione, GPx, SOD and vitamins in oral submucous fibrosis: A three-level meta-analysis study.

This study aims to investigate the alteration of salivary biomarker profiling in the development of oral submucous fibrosis (OSMF) and to explore the influence of saliva in the diagnosis of OSMF. A systematic search of published articles using the PRISMA guidelines was conducted to identify relevant studies on OSMF and saliva. All eligible studies, including case-control, cross-sectional studies, cohort, and pilot studies, contained the evaluation of salivary biomarker profiling in patients with OSMF. Salivary biomarker data from 28 selected articles were categorized into nine groups, and their mean values were determined. A three-step meta-analysis was performed by grouping salivary biomarker profiling into more heterogeneous categories based on OSMF classification, considering functional, histological, and clinical grading. The salivary biomarker profiling analysis revealed significant alterations in all markers, indicating their efficacy in OSMF diagnosis. Subgroup analyses highlighted significant associations in oxidative stress and protein with increased mean values, particularly emphasizing lipid peroxidase (LPO), malondialdehyde (MDA), and lactate dehydrogenase (LDH). Conversely, decreased mean values were observed in glutathione, glutathione peroxidase (GPx), superoxide dismutase (SOD), and vitamins. Notably, OSMF grading analysis demonstrated a significant difference in weighted effect sizes for histological grading, particularly in stage IV. The study underscores the alteration of specific salivary biomarkers, particularly those associated with LPO, MDA, LDH, glutathione, GPx, SOD, and vitamins, in diagnosing and grading OSMF.