Bladder cancer patients hospitalized in a medicine ward including three fuo cases following bacillus calmette-guérin immunotherapy

Introduction

Bladder cancer (BC) ranks as the 10th most prevalent cancer globally, the 6th most common cancer in males, and the 9th major cause of cancer-related mortality in men.1 Following transurethral resection of bladder tumor (TURBT), the intravesical administration of Bacillus Calmette-Guérin (iBCG) is currently the gold standard adjuvant treatment for patients with high-risk non-muscle invasive bladder cancer (NMIBC) and, in certain cases, of intermediate-risk NMIBC.2 Radical cystectomy is recommended for selected high-risk NMIBC patients, particularly those with persistent high-grade T1 disease or BCG-unresponsive tumours, in whom bladder-preserving strategies are unlikely to achieve durable oncologic control.2 The implementation of newer immunotherapies comprising the immune checkpoint inhibitors nivolumab,3 pembrolizumab,4 durvalumab,5 and other immunotherapies6 improved overall and progression-free survival in patients with high-risk muscle-invasive or metastatic BC over the last decade. Patients with muscle-invasive bladder cancer (MIBC) experience a high and predictable burden of symptoms and hospital utilization in the final year of life, with a substantial proportion of emergency admissions driven by preventable urological complications, particularly haematuria and severe urinary tract infections.7 In addition, the age of patients with BC who were hospitalized in the urological ward and the proportion of patients aged ≥80 years significantly increased over the last decade.8 However, the reasons for hospitalization in this patient population have not been explored in the real world.

The objective of this case-series study was to analyze the demographics, clinical characteristics, medical and urological history, causes of hospitalization, and outcomes of patients with BC admitted to the Internal Medicine ward of a tertiary referral hospital, and compared patients previously treated with iBCG immunotherapy with those receiving other treatments. Among patients previously treated with iBCG, we further focused on three individuals who presented with fever of unknown origin (FUO), attributable to distinct underlying causes, including metastatic bladder cancer, BCG-related infection (BCGitis), and Hodgkin’s lymphoma (HL).

Materials and Methods

Study design and data source

The study was approved by the Institutional Review Board of the Scientific Council of Hippokration General Hospital of Athens (Approval No. 26/11142023). Due to the retrospective nature of the study, the requirement for written informed consent was waived. We aimed to investigate the causes of hospitalization for BC patients in the internal medicine ward after three such patients, who had a history of BCG immunotherapy, presented with prolonged fever at our institution. Thus, a search was performed on the electronic discharge documents of the Internal Medicine unit of our tertiary referral hospital (General Hospital of Athens “Hippokration”, Athens, Greece) using the search term “C67,” the ICD 10 code for “bladder cancer,” covering the period from 1 January 2020, to 31 December 2024. The aforementioned period was selected because recent immunotherapies have predominantly been integrated into clinical practice within the last five years. Inclusion criteria were all adult patients identified through electronic data retrieval using the search term “C67” in the electronic discharge records during the period from 1 January 2020, to 31 December 2024, irrespective of the cause of hospitalization. Exclusion criteria were not applied; therefore, no patients meeting the inclusion criteria were excluded from the study. The primary aim of the study was to document the three cases of FUO, and the secondary objective was to examine the characteristics and causes of hospitalization among BC patients in our medicine ward.

Study population

This computer-based study identified 77 hospitalizations involving 67 distinct patients. The medical records of these patients were analyzed, and several variables were documented in tables. These variables included age, sex, medical history (which encompassed bladder cancer diagnoses and treatments), presenting symptoms, hospital course, outcomes, duration of hospitalization, and discharge diagnoses. In three cases of prolonged fever, a comprehensive recording was conducted, including blood tests, radiographic studies, additional diagnostic investigations for fever of unknown origin (FUO), and histologic analyses.

Statistical analysis

Mean values and standard deviations were presented for continuous variables, whereas categorical variables were expressed in terms of frequencies and percentages. The Fisher’s exact test was utilized for qualitative value comparisons, while the two-tailed unpaired Student’s t-test was employed for numerical value comparisons. A p-value of less than 0.05 was considered significant. Analyses were conducted utilizing the Microsoft Office Home and Student 2021 (Microsoft Corporation, One Microsoft Way, Redmond, WA 98052-6399, USA).

Results

Whole patient cohort

During the study period, we identified 67 patients with BC who had been hospitalized a total of 77 times in the Internal Medicine ward. The majority of these patients were male (80.6%), with a mean age of 75.2 years. Their comorbidities, detailed in Table 1 (with comprehensive history data available for 61 patients), primarily included cardiovascular diseases, hypertension, diabetes mellitus, and dyslipidemia. Approximately a quarter of patients had a second malignancy in addition to their BC (22.9%), while nearly a third presented with metastatic BC (31.1%). All NMIBC patients had been previously subjected to TURBTs and local treatment (either with iBCG or local chemotherapy). Thirty-eight percent of patients had been treated with chemotherapies/immunotherapies and/or local radiation, besides those (24.6%) treated with iBCG instillations. In addition, almost half of patients (49.2%) had been subjected to urological interventions comprising cystectomy, cystoprostatectomy, ureterostomy, pigtail placement, nephrectomy, and nephrostomy (Table 1).

The most common reasons for hospitalization, according to their discharge diagnoses, were infections (59.4%), followed by anemia (23.4%), newly diagnosed metastatic disease (15.6%), acute renal failure (ARF, 10.9%), obstructive uropathy requiring placement of pigtails and/or nephrostomy (9.4%), anticancer treatment-related adverse events (9.4%), and electrolyte abnormalities (9.4%) (Table 2). The types of infections and their corresponding bacterial pathogens identified in discharge documents are presented in Table 3. The mean duration of hospitalization for recovering patients was 8.6 days (median: 7 days). The mortality rate during 77 hospitalizations was 16.9% (n = 13), with the most common cause being infections (77%), followed by advanced/metastatic BC (31%) and obstructive uropathy/ARF (15%).

Patients previously treated with iBCG (n = 15) including three FUO cases

Among the 67 hospitalized patients with BC, we identified 15 patients (19 hospitalizations, 25%) who had previously been treated with iBCG. Those were mostly males (73.3%), and they were significantly younger compared to the rest of the group. They also had a higher prevalence of hypertension, diabetes, dyslipidemia, chronic obstructive pulmonary disease (COPD), and a lower incidence of heart diseases compared to those not previously treated with iBCG (Table 1). In addition, patients being treated with BCG instillations had a lower incidence of metastatic disease, coexistence of other cancers, and therapeutic interventions (urological, chemotherapy, immunotherapy, and local radiation). Among the hospitalized patients, we identified three with FUO, all having previously been treated with iBCG. These patients overall had a longer duration of hospitalization compared to the rest of the patients (median: 19 days, p = 0.0005; two-tailed student’s t-test).

Patient 1:

An 80-year-old woman was admitted with a daily fever reaching a maximum of 38.5°C over the past 3 weeks, accompanied by abdominal pain, unresponsive to common antibiotics. She had a history of BC, which had been treated with multiple TURBTs and iBCG 6 years ago. The clinical examination was unremarkable, while laboratory tests revealed elevated inflammatory markers (Table 4). The patient was started on empirical antibiotic therapy with piperacillin/tazobactam. However, multiple blood and urine cultures as well as serological testing for atypical microbes and viruses were returned negative. Additionally, Ziehl-Nielsen stains and Lowenstein-Jensen cultures of urine and gastric fluid were negative. QuantiFERON TB Gold testing and PCR detection for mycobacteria in urine samples also yielded negative findings. A chest and abdomen CT revealed lymphadenopathy around the abdominal aorta and right common iliac chain, which were inaccessible to biopsy. She was initially given parecoxib and low-dose methylprednisolone for symptomatic relief. A PET-CT scan later in her hospital stay confirmed lymphadenopathy with increased uptake of a left supraclavicular lymph node. The cytology of the lymph node revealed infiltration by numerous squamous and papillary clusters of neoplastic epithelial cells, which were of moderate size and predominantly subround in shape. These cells exhibited central or eccentric hyperchromatic nuclei, coarse chromatin, irregular nuclear membranes, and scant dense cytoplasm. Additionally, clear intranuclear inclusions were noted in some of the cells. Numerous diffusely distributed spindle-shaped cells, binucleated and syncytial forms, as well as frequent atypical mitotic figures, were noted. The background contained abundant necrotic material and remnants of lymph node tissue. The cytological findings indicated secondary involvement of the lymph node by urothelial carcinoma. A definitive diagnosis was made 45 days after the onset of symptoms. The patient received chemotherapy, including cisplatin, paclitaxel, and gemcitabine, followed by immunotherapy. Figure 1 illustrates the dynamic laboratory trends observed during her hospitalization and in follow-up, both prior to and after therapeutic interventions.

FIGURE 1. The time trends of blood test results for patient 1 from admission (day 1) through follow-up, including the treatment interventions administered. (A): Hematological indices (WBC, Hb); (B): inflammatory markers (CRP, PLTs, fibrinogen) and LDH; (C): liver biochemistry (AST, ALT, ALP, and γ-GT). BC: Bladder cancer; WBC: white blood cells; Hb:hemoglobulin; PLTs: platelets; LDH: lactate dehydrogenase; CRP: c-reactive protein; Fib: fibrinogen; AST: aspartate transaminase; ALT: alanine transaminase; γ-GT: g-glutamyl transferase; ALP: alkaline phosphatase

Patient 2:

A 62-year-old male with a history of BC diagnosed 3 years ago was admitted to the hospital with a high-grade fever (up to 40°C) for 10 days right after his last iBCG instillation. He had been receiving iBCG for the last year. He was initially given ciprofloxacin for a suspected urinary tract infection for five days without a response. On presentation, he was febrile, and his laboratory tests revealed elevated inflammatory markers and slightly impaired liver biochemistry (Table 4). Urinalysis demonstrated pyuria and hematuria. Multiple blood and urine cultures for common pathogens were negative. Ziehl-Nielsen stains, Lowenstein-Jensen cultures, and PCR for detection of mycobacteria in urine, sputum, and gastric fluid were also negative. The CT scans of the chest and abdomen were unremarkable. During hospitalization, the patient experienced a persistent high fever, with early morning spikes reaching 40–40.5°C between 4:00 and 6:00 a.m., which was unresponsive to common antibiotics. Given a high suspicion of BCGitis, the patient underwent a liver and bone marrow (BM) biopsy. He was also started on empirical anti-tuberculous therapy (ATT), which included isoniazid, rifampin, and ethambutol, along with glucocorticoids (methylprednisolone). Over the coming days, his fever gradually subsided, and the inflammatory markers and cholestatic enzymes began to decrease. The histology results of both the liver and BM revealed granulomatous inflammation, with epithelioid histiocytes and multinucleated giant cells surrounded by lymphocytes. In BCGitis, pathology findings reveal granulomas that are predominantly non-caseating in liver and bone marrow (BM) tissue due to the rich reticuloendothelial system present in these organs,9 as observed in this case. The presence of non-caseating granulomas is strongly suggestive of BCGitis. Consequently, the diagnosis of disseminated BCGitis with liver and BM involvement was established 35 days after the onset of fever. He was discharged with continued ATT, while corticosteroids were tapered and discontinued within 2 weeks. Three months post-discharge, the patient remained asymptomatic while receiving ATT treatment. Figure 2 displays the longitudinal trends of his blood tests during hospitalization and follow-up.

FIGURE 2. The time trends of blood test results for patient 2 from admission (day 1) through follow-up, including the treatment interventions administered. (A): Hematological indices (WBC, Hb); (B): inflammatory markers (CRP, PLTs, fibrinogen) and LDH; (C): liver biochemistry (AST, ALT, ALP, and γ-GT). BCGitis: infection caused by Bacillus Calmette–Guérin; ATT: anti-tuberculous treatment; WBC: white blood cells; Hb: hemoglobulin; PLTs: platelets; LDH: lactate dehydrogenase; CRP: c-reactive protein; Fib: fibrinogen; AST: aspartate transaminase; ALT: alanine transaminase; γ-GT: g-glutamyl transferase; ALP: alkaline phosphatase

Patient 3:

A 73-year-old male presented with a fever for two weeks (up to 37.8°C) and worsening fatigue. He had been diagnosed with BC two years before, and he had been managed with TURBTs followed by 9 iBCG instillations. On clinical examination, he had enlarged, painless inguinal lymph nodes bilaterally. Laboratory workup revealed leukocytosis, anemia, and elevated inflammatory markers (Table 4). The patient was given empirical piperacillin-tazobactam therapy without response. Multiple blood and urine cultures, serological testing for atypical pathogens, and a QuantiFERON TB Gold test returned negative. Ziehl-Nielsen stains, Lowenstein-Jensen cultures, and PCR for the detection of mycobacteria in urine, sputum, and gastric fluid were negative. An abdominal CT scan showed lymphadenopathy extending from the para-aortic space to the right inguinal region. A PET-CT scan revealed multiple, enlarged, hypermetabolic lymph nodes (<1 cm in size) below the diaphragm, as well as in the left supraclavicular region. During hospitalization, he exhibited 1–2 daily fever spikes (up to 39°C). A biopsy of an inguinal lymph node confirmed the diagnosis of Hodgkin’s lymphoma (HL) with mixed cellularity. This diagnosis was established 42 days after the onset of fever. Subsequently, he was transferred to the Hematology Unit of our department. Following 4 courses of chemotherapy, which included vinblastine, chlorambucil, procarbazine, and steroids, the patient went into remission (Figure 3).

FIGURE 3. The time trends of blood test results for patient 3 from admission (day 1) through follow-up, including the treatment interventions administered. (A): Hematological indices (WBC, Hb); (B): inflammatory markers (CRP, PLTs, fibrinogen) and LDH; (C): liver biochemistry (AST, ALT, ALP, and γ-GT). DVT: deep vein thrombosis; WBC: white blood cells; Hb: hemoglobulin; PLTs: platelets; LDH: lactate dehydrogenase; CRP: c-reactive protein; Fib: fibrinogen; AST: aspartate transaminase; ALT: alanine transaminase; γ-GT: g-glutamyl transferase; ALP: alkaline phosphatase.

Discussion

In this case series, we present real-world data on the characteristics of patients with BC who were hospitalized in a Medicine ward of a tertiary referral hospital. The majority of BC patients were elderly, with a mean age of 75.2 years. A study investigating age trends in hospitalized patients with urological cancer revealed that the average age of these individuals rose from 2005–2013 to 2014–2021.8 Common comorbidities observed in our cohort included cardiovascular disease, hypertension, diabetes mellitus, dyslipidemia, and COPD, which aligns with findings from previous studies for BC patients.10,11 Several meta-analyses have suggested that individuals with diabetes,12–14 hypertension,15 and other metabolic syndrome components15 may have an increased risk for BC. In addition, COPD has been reported as a prevalent comorbidity in BC cohorts and is associated with increased mortality and poorer prognosis.11,16 Interestingly, one-quarter of patients had a second primary malignancy, a proportion slightly higher than that reported in the literature for BC patients.17,18 Furthermore, nearly one-third had advanced BC at the time of admission to the internal medicine ward, while in 15% of them, new metastases were identified during hospitalization. These findings indicate an increased cancer burden in this patient population.

Infections were the most common cause (~60%) of hospitalization in admitted BC patients, mainly from the urinary tract. This could be due to several factors, including their advanced age, local anatomical factors, comorbidities, overall cancer burden, and anti-cancer therapies. Among those who died during hospitalization (17%), the leading cause of death was again an infection (77%). Conclusively, our data indicates the unmet need for better strategies in infection protection and management in this vulnerable patient population.

In the present study, iBCG-treated patients were younger with lower mortality rates compared to the rest of the cohort. Those differences could be attributed to the fact that the subgroup of BC patients subjected to BCG immunotherapy are diagnosed in earlier disease stages (NMIBC, Ta) compared to those diagnosed with MIBC or metastatic BC. On the other hand, the high incidence of comorbidities in iBCG-treated patients, such as diabetes, hypertension, dyslipidemia, heart diseases, and COPD, is consistent with literature,9,19 while the differences estimated in this descriptive study compared to those not previously treated with iBCG are statistically non-significant. Furthermore, iBCG-treated patients experienced longer hospital stays compared to other BC patients. This finding can be explained by the inclusion of three cases of FUO in the iBCG-treated group, which represents approximately 4.5% of our hospitalized BC patients. These cases necessitated extensive diagnostic workups to determine their underlying causes. Despite significant advancements in medical diagnostics and imaging, FUO continues to be a complex clinical condition, with its etiology evolving over time. Noninfectious inflammatory diseases and infections are currently the predominant causes, followed by connective tissue disorders and malignancies.20 Unexpectedly, despite the identical clinical settings, each of our three patients with FUO had distinct diagnoses, requiring tailored management strategies. In the first case, metastatic BC was diagnosed in a patient with a remote history of iBCG therapy who presented with lymphadenopathy. In the literature, urinary tract cancer has been listed as a potential cause of FUO, finally diagnosed 1–12 months after fever onset,21 as in our case. The second case was a typical BCGitis that developed shortly after iBCG treatment. BCGitis is a well-documented adverse event of iBCG immunotherapy.9 The patient had histological evidence of liver and bone marrow granulomas, which, despite the absence of Mycobacterium bovis in the tissue and body fluid samples, indicated BCGitis. His symptoms and laboratory abnormalities completely resolved with prolonged ATT therapy.

The diagnosis in the third case of a 73-year-old man with a history of BC was rather unexpected, as was HL. In a literature case, a mediastinal mass that tested positive for BCG was suspected to be lymphoma.22 Additionally, in another case following iBCG treatment, bilateral adrenal and testicular tumors were diagnosed as diffuse large B-cell lymphoma.23 To our knowledge, this is the first reported case of Hodgkin lymphoma (HL) diagnosed in a patient with BC who had previously undergone treatment with iBCG. Some literature suggests a potential association between BCG vaccination and HL,24 while other studies contradict this claim.25 Hodgkin and Reed-Sternberg (HRS) cells are germinal center B lymphocytes that have transformed during maturation, losing the ability to express immunoglobulins and other characteristics of normal B cells.26 HRS cells have developed mechanisms to survive by escaping immune surveillance.27 Many of the complex immune modulation mechanisms that are engaged in the treatment of iBCG are also implicated in the pathophysiology of HL. iBCG activates Th2 immune responses, which, via secretion of IL-4, IL-10, and TGF-β, induces macrophage M2 polarization and their transformation into tumor-associated macrophages, thereby promoting pro-tumoral activities.28,29 The secretion of IL-10 and TGF-β is one mechanism implicated in the immune escape of HRS cells by inhibiting the activation of cytotoxic T lymphocytes and antigen-presenting cells (APCs).27,30 Furthermore, Th2 induction from iBCG instillations may also result in both the induction of regulatory T cells (Tregs) and the secretion of IL-13, which attracts monocytes within the tumor microenvironment, transforming them into monocyte-myeloid-derived suppressor cells that inhibit T cell proliferation.31 The recruitment of immunosuppressive Tregs and myeloid-derived suppressor cells into the classic HL microenvironment represents another mechanism by which these cells evade immune surveillance.32 After BCG ingestion by APCs, various mycobacterial cell wall molecules (PAMPS) are released both intracellularly and extracellularly, which subsequently regulate the NF-kB signaling pathway through MyD88 and other intracellular messengers, leading to the secretion of Th1 proinflammatory cytokines.33,34 PAMPS also induce a metabolic shift toward glycolysis via the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway, which involves epigenetic histone modifications such as methylation, resulting in increased access to the promoter regions of genes associated with differentiation, proliferation, inflammation, and apoptosis.9 A damage-associated molecular pattern molecule, IL-1-α, which is also induced by BCG, interacts with the IL-1 receptor (IL-1R) to regulate intranuclear transcription factors (TFs) through MAPK/ERK signaling pathways, subsequently affecting cell differentiation, proliferation, inflammation, and apoptosis.34,35 In the pathogenesis of HL, the activation of the NF-kB and MAPK/ERK signaling pathways is essential for the evasion of apoptosis, enabling HRS cells to circumvent programmed cell death.36 Given that the aforementioned immunomodulatory mechanisms involved in BCG treatment overlap with those that help HRS cells evade immune surveillance, it can be suggested that BCG treatment may enhance the survival of HRS cells by aiding their evasion of immune detection and apoptosis, provided that mutated HRS cells are already present. From a clinical perspective, when BC patients experience a fever lasting more than seven days after BCG instillation, which exceeds the typical course of the very common self-limited adverse events—defined as short-term, mild reactions resolving spontaneously or with symptomatic treatment—beyond which more severe BCG-related complications may occur,9 they should be referred to an internal medicine department for further evaluation, regardless of whether an antibiotic regimen has been prescribed.

Limitations of the study

This is a single-centre, retrospective analysis that selected patients based on an examination of computerized health data; hence, a selection bias may be present. Furthermore, some individuals may have been overlooked in case the search term “C67” was not included in the discharge diagnoses documents, as they could have been hospitalized for many other medical conditions, leading to a residual confounding. The limited number of patients in the analysis constrains its statistical power. The study’s five-year duration, during which newer immunotherapies for BC patients were more extensively utilized, may have resulted in the omission of hospitalization trends and outcomes from prior decades, thereby diminishing generalizability.

Conclusions

This study investigates the reasons for hospitalizations among BC patients in an internal medicine ward. Due to the implementation of new management strategies, BC has evolved into a “chronic disease,” leading to an increase in the frequency of patient admissions to internal medicine wards. In our patient population, infections constituted the leading cause of both admission and mortality, indicating the need to develop improved prevention and treatment strategies for infectious complications. The subgroup of patients who were previously treated with iBCG exhibited distinct characteristics compared to the entire group, such as younger age, an increased but non-significant incidence of metabolic parameters, longer hospitalization, and lower mortality rates, which are expected due to the earlier disease stage in this subgroup. A small percentage of patients exhibited FUO, posing several diagnostic and treatment challenges for physicians. One was diagnosed with Hodgkin’s lymphoma, a previously unreported association. We propose possible mechanisms via which BCG immunotherapy could interfere with Reed-Sternberg cells to escape immune surveillance and develop into Hodgkin’s lymphoma. In conclusion, a comprehensive evaluation and a multidisciplinary approach are typically necessary for these patients to attain an accurate diagnosis, and they should probably be hospitalized in a medicine ward.

Acknowledgement

None.

Funding Statement

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. The authors have no relevant financial or non-financial interests to disclose.

Author Contributions

George Liatsos: Writing of the draft manuscript and conception of the idea for the study; Kalliopi Zioutou, Konstantinos Vamvakaris: data collection, preparation of tables; Konstantinos Avramidis, Maria Potamiti-Komi: data process, statistical analysis; Dimitrios Vassilopoulos: supervising of the study, correction of the final version of the manuscript. All authors reviewed and approved the final version of the manuscript.

Availability of Data and Materials

The data that support the findings of this study are available from the Corresponding Author, George Liatsos, upon reasonable request

Ethics Approval

The study was approved by the Institutional Review Board of the Scientific Council of Hippokration General Hospital of Athens (Approval No. 26/11142023). Due to the retrospective nature of the study, the requirement for written informed consent was waived.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

References

1. Sung H, Ferlay J, Siegel RL et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71(3):209–249. [Google Scholar] [PubMed]

2. Holzbeierlein JM, Bixler BR, Buckley DI et al. Diagnosis and treatment of non-muscle invasive bladder cancer: AUA/SUO guideline: 2024. J Urol 2024;212(6):936. [Google Scholar]

3. Galsky MD, Bajorin DF, Witjes JA et al. Disease-free survival analysis for patients with high-risk muscle-invasive urothelial carcinoma from the randomized checkMate 274 trial by PD-L1 combined positive score and tumor cell score. Eur Urol 2023;83(5):432–440. doi:10.1016/j.eururo.2023.01.016. [Google Scholar] [PubMed] [CrossRef]

4. Apolo AB, Ballman KV, Sonpavde G et al. Adjuvant pembrolizumab versus observation in muscle-invasive urothelial carcinoma. N Engl J Med 2025;392(1):45–55. [Google Scholar] [PubMed]

5. Powles T, Catto JWF, Galsky MD et al. NIAGARA investigators. perioperative durvalumab with neoadjuvant chemotherapy in operable bladder cancer. N Engl J Med 2024;391(19):1773–1786. [Google Scholar] [PubMed]

6. Roviello G, Santoni M, Sonpavde GP, Catalano M. The evolving treatment landscape of metastatic urothelial cancer. Nat Rev Urol 2024;21(10):580–592. [Google Scholar] [PubMed]

7. Matson M, Tien T, Yardy G, Allchorne P, Green JSA. The use of hospital services by patients with muscle invasive bladder cancer in the last year of life: identifying the areas to improve care. Cureus 2023;15(11):e49175. [Google Scholar] [PubMed]

8. Ishii N, Hatakeyama S, Miura H et al. Trends in the age of hospitalized patients with urological cancers: A17-year experience. Int J Urol 2023;30(7):572–578. [Google Scholar] [PubMed]

9. Liatsos GD, Mariolis I, Hadziyannis E, Bamias A, Vassilopoulos D. Review of BCG immunotherapy for bladder cancer. Clin Microbiol Rev 2025;38(1):e0019423. [Google Scholar] [PubMed]

10. Garg T, Young AJ, O’Keeffe-Rosetti M et al. Association between metabolic syndrome and recurrence of nonmuscle-invasive bladder cancer in older adults. Urol Oncol 2020;38(9):737.e17–737.e23. [Google Scholar] [PubMed]

11. Barone B, Finati M, Cinelli F et al. Bladder cancer and risk factors: data from a multi-institutional long-term analysis on cardiovascular disease and cancer incidence. J Pers Med 2023;13(3):512. [Google Scholar] [PubMed]

12. Larsson SC, Orsini N, Brismar K, Wolk A. Diabetes mellitus and risk of bladder cancer: a meta-analysis. Diabetologia 2006;49(12):2819–2823. [Google Scholar] [PubMed]

13. Xu X, Wu J, Mao Y et al. Diabetes mellitus and risk of bladder cancer: a meta-analysis of cohort studies. PLoS One 2013;8(3):e58079. [Google Scholar] [PubMed]

14. Zhu Z, Wang X, Shen Z, Lu Y, Zhong S. Risk of bladder cancer in patients with diabetes mellitus: an updated meta-analysis of observational studies. BMC Cancer 2013;13:310. [Google Scholar] [PubMed]

15. Ahmadinezhad M, Arshadi M, Hesari E, Sharafoddin M, Azizi H, Khodamoradi F. The relationship between metabolic syndrome and its components with bladder cancer: a systematic review and meta-analysis of cohort studies. Epidemiol Health 2022;44:e2022050. [Google Scholar] [PubMed]

16. Naka M, Shuto S, Konishi C, Maekawa K. High prevalence of airway obstruction and pulmonary emphysema in urothelial (renal pelvis, ureter, and bladder) cancer patients. Respir Investig 2020;58(4):239–245. [Google Scholar] [PubMed]

17. Khanal A, Budhathoki N, Singh VP, Shah BK. Second primary malignancy in bladder carcinoma—a population-based study. Anticancer Res 2017;37(4):2033–2036. [Google Scholar] [PubMed]

18. Othmane B, Yi Z, Zhang C, Chen J, Zu X, Fan B. Filling the gaps in the research about second primary malignancies after bladder cancer: focus on race and histology. Front Public Health 2022;10:1036722. [Google Scholar] [PubMed]

19. Lenis AT, Asanad K, Blaibel M, Donin NM, Chamie K. Association between metabolic syndrome and recurrence of nonmuscle invasive bladder cancer following bacillus calmette-guérin treatment. Urol Pract 2018;5(2):132–138. [Google Scholar] [PubMed]

20. Zenone T. Fever of unknown origin in adults: Evaluation of 144 cases in a non-university hospital. Scand J Infect Dis 2006;38(8):632–638. [Google Scholar] [PubMed]

21. Søgaard KK, Farkas DK, Leisner MZ, Schmidt SAJ, Lash TL, Sørensen HT. Fever of unknown origin and incidence of cancer. Clin Infect Dis 2022;75(6):968–974. [Google Scholar]

22. Somoskovi A, Carlyn C, Dormandy J, Salfinger M. Mediastinal mass mimicking a tumor in a patient with bladder cancer after Bacillus Calmette-Guerin treatment. Eur J Clin Microbiol Infect Dis 2007;26(12):937–940. [Google Scholar] [PubMed]

23. Grootemaat M, Tjiam I, Sampimon D, Bot F, Roshani H. Bilateral adrenal and testicular tumours; when a simple diagnosis becomes complicated. Urology 2023;175:e11–e12. [Google Scholar] [PubMed]

24. Salmon C, Conus F, Parent MÉ, Benedetti A, Rousseau MC. Association between Bacillus Calmette-Guérin vaccination and lymphoma: a population-based birth cohort study. J Intern Med 2019;286(5):583–595. [Google Scholar] [PubMed]

25. Salmon C, Conus F, Parent MÉ, Benedetti A, Rousseau MC. Association between Bacillus Calmette-Guerin (BCG) vaccination and lymphoma risk: a systematic review and meta-analysis. Cancer Epidemiol 2020;65:101696. [Google Scholar] [PubMed]

26. Marafioti T, Hummel M, Anagnostopoulos I et al. Origin of nodular lymphocyte-predominant Hodgkin’s disease from a clonal expansion of highly mutated germinal-center B cells. N Engl J Med 1997;337(7):453–458. [Google Scholar] [PubMed]

27. Opinto G, Agostinelli C, Ciavarella S, Guarini A, Maiorano E, Ingravallo G. Hodgkin lymphoma: a special microenvironment. J Clin Med 2021;10(20):4665. [Google Scholar] [PubMed]

28. Rodríguez-Izquierdo M, Del Cañizo CG, Rubio C et al. Immune predictors of response after bacillus Calmette-Guérin treatment in non-muscle-invasive bladder Cancer. Cancers 2023;15(23):5554. [Google Scholar]

29. Pichler R, Fritz J, Zavadil C, Schäfer G, Culig Z, Brunner A. Tumor-infiltrating immune cell subpopulations influence the oncologic outcome after intravesical Bacillus Calmette-Guérin therapy in bladder cancer. Oncotarget 2016;7(26):39916–39930. [Google Scholar] [PubMed]

30. Skinnider BF, Mak TW. The role of cytokines in classical Hodgkin lymphoma. Blood 2002;99(12):4283–4297. [Google Scholar] [PubMed]

31. Chevalier MF, Trabanelli S, Racle J et al. ILC2-modulated T cell-to-MDSC balance is associated with bladder cancer recurrence. J Clin Invest 2017;127(8):2916–2929. [Google Scholar] [PubMed]

32. Marshall NA, Christie LE, Munro LR et al. Immunosuppressive regulatory T cells are abundant in the reactive lymphocytes of Hodgkin lymphoma. Blood 2004;103(5):1755–1762. [Google Scholar] [PubMed]

33. Latz E, Schoenemeyer A, Visintin A et al. TLR9 signals after translocating from the ER to CpG DNA in the lysosome. Nat Immunol 2004;5(2):190–198. [Google Scholar] [PubMed]

34. Bisiaux A, Boussier J, Duffy D et al. Deconvolution of the response to bacillus calmette-guérin reveals NF-κB-induced cytokines as autocrine mediators of innate immunity. Front Immunol 2017;8:796. [Google Scholar] [PubMed]

35. De Boer EC, De Jong WH, Steerenberg PA et al. Induction of urinary interleukin-1 (IL-1IL-2, IL-6, and tumour necrosis factor during intravesical immunotherapy with bacillus Calmette-Guérin in superficial bladder cancer. Cancer Immunol Immunother 1992;34(5):306–312. [Google Scholar] [PubMed]

36. Bienz M, Ramdani S, Knecht H. Molecular pathogenesis of hodgkin lymphoma: past, present, Future. Int J Mol Sci 2020;21(18):6623. [Google Scholar] [PubMed]