Introduction

Clinically significant portal hypertension (CSPH) is a major prognostic factor in patients with hepatocellular carcinoma (HCC) complicated by cirrhosis, influencing both survival and treatment outcomes. Esophageal variceal hemorrhage, a severe complication of CSPH, is associated with a poor prognosis. The gold standard for diagnosing CSPH involves invasive procedures like hepatic venous pressure gradient (HVPG) measurement; however, these methods are not always feasible in clinical practice. The Baveno VII consensus recommends non-invasive strategies for variceal screening, but their applicability in HCC patients remains uncertain due to the potential confounding effects of HCC on liver stiffness measurements (LSM).

Aims & Methods

The primary objectives were to determine the prevalence and risk factors of varices in HCC patients, validate the predictive ability of the ALBI-PLT score for variceal screening in compensated cirrhosis, and identify a subgroup of patients who could safely forgo endoscopic variceal screening.This single-center, retrospective, cross-sectional study was conducted at the Department of Gastroenterology and Hepatology, Habib Bougatfa University Hospital, Tunisia, over six months (July 2024 - January 2025). A total of 50 patients with cirrhosis complicated by HCC were included. The ALBI score, ALBI grade, and ALBI-PLT score were calculated, and esophageal varices were assessed by esophagogastroduodenoscopy (EGD). The exclusion criteria were as follows:
(1) patients with incomplete information regarding HCC etiology, CTP score, cancer stage, treatment, or mortality,
(2) patients who did not undergo endoscopic screening of esophageal varices within three months of HCC diagnosis,
(3) patients who had undergone splenectomy or partial splenic arterial embolization, as these interventions could affect the ALBI-PLT score, and
(4) decompensated patients, defined as those with ascites, varices, hepatic encephalopathy, jaundice, or a CTP score >6. Statistical analysis was performed using SPSS v26, with p-values ≤ 0.05 considered statistically significant.

Results

The cohort had a mean age of 67.5 ± 12.20 years, with a male predominance (62%). Hepatitis C was the leading etiology (44%). Esophageal varices were present in 82% of patients, with 18% having no varices, 4% with grade I, 44% with grade II, and 34% with grade III varices. A statistically significant association was found between the ALBI-PLT score and the presence of high-risk varices (HRV) (Pearson Chi-square = 43.677, df = 4, p < 0.001), indicating that higher ALBI-PLT scores were associated with an increased risk of varices.ROC curve analysis yielded an area under the curve (AUC) of 0.908 (95% CI: 0.736–1.000, p < 0.001), indicating excellent discriminative ability. The optimal cutoff for the ALBI-PLT score was identified as ≥ 1.5, based on the Youden Index. At this threshold, the score demonstrated a sensitivity of 100% and a specificity of 88.9%, with a Youden Index of 0.889. This suggests that patients with an ALBI-PLT score below 1.5 are very unlikely to have varices and could potentially avoid unnecessary endoscopic screening. Logistic regression confirmed the ALBI-PLT score as an independent predictor of high-risk varices (OR = 6.35, p = 0.002), reinforcing its clinical utility for non-invasive screening.

Conclusion

The ALBI-PLT score provides a reliable, non-invasive tool for identifying HCC patients with compensated cirrhosis who are at low risk for varices and may safely avoid routine endoscopic screening. Further validation of this score in larger cohorts is warranted.

Disclosure

We declare no Conflict of interest.

Introduction

Sarcopenia is characterized by loss of skeletal muscle mass and strength, and commonly observed in patients with chronic liver disease (CLD). However, simple and practical assessment tools for consideration of early intervention in patients with risk of progression of muscle abnormalities remain limited, as muscle volume assessment requires specialized expensive equipment not generally used by a family physician, e.g., computed tomography (CT) or bioelectrical impedance analysis.

Aims & Methods

Using the Geriatric Nutritional Risk Index (GNRI), calculated based only on body weight, height, and serum albumin (AJCN 2005), the present study aimed to examine a novel scoring system used to assess risk of sarcopenia and muscle abnormality development in CLD patients.
This retrospective analysis was conducted using medical records of 1063 Japanese CLD patients (median age 70 years; male:female = 676:387; HCV:HBV:HBV and HCV:alcohol:others = 573:146:4:127:213; Child-Pugh A:B:C = 927:115:21; hepatocellular carcinoma history or complication = 300) who underwent related examinations from 2015 to 2024. Muscle area at the middle of the L3 level shown by CT was evaluated using a 3D image analysis system, with the value for skeletal muscle index (SMI), determined based on muscle area (cm²), calculated using the mean value for L3 level/height (m²). Muscle volume loss (MVL) and handgrip strength decline (HGSD) were assessed according to the Japan Society of Hepatology criteria (SMI and HGSD cutoff values for male/female; 42/38 cm²/m² and 28/18 kg, respectively). Logistic regression analysis was then used to identify predictive factors for sarcopenia. Finally, a risk scoring system was developed based on the odds ratio (OR) values for significant factors.

Results

There were 145 patients (13.6%) with sarcopenia, 226 (21.3%) with HGSD, and 149 (14.0%) with MVL, with an abnormal GNRI status noted in 333 (31.3%). A scoring system was developed based on five predictive factors; abnormal GNRI (<98) (OR 4.88), elderly (65-74 years, OR 2.67), late-stage elderly (≥75 years, OR 6.09), female (OR 2.11), and advanced hepatocellular carcinoma (HCC) (TNM stage IV, OR 2.61), which remained following multivariate analysis. Points were assigned based on OR value, with1 point for OR ≤3 and 2 points for OR ≥4. The rate of prevalence of sarcopenia, HGSD, and MVL showed a significant increase with a higher score, with those conditions seen in 2.4%, 13.8%, and 6.9%, respectively, of patients with low risk (0/1 points), 9.0%, 23.7%, and 19.8%, respectively, of those with moderate risk (2 points), 22.0%, 29.0%, and 18.8%, respectively, of those with high risk (3 points), and 38.8%, 27.5%, and 16.9%, respectively, of those with very high/super-high risk (4/5/6 points) (p<0.001). Additionally, GNRI cutoff values for HGSD and MVL were 101.5 (AUC 0.670) and 97.5 (AUC 0.749), respectively, approximating the abnormal GNRI cutoff value of 98.

Conclusion

This GNRI-based scoring system is likely to be a simple, cost-effective tool that does not require any special equipment when assessing the risk of sarcopenia or muscle abnormalities. It may also be used in clinical practice as a method of identifying patients who require early intervention.

Introduction

Colorectal cancer (CRC) therapy faces significant challenges, including drug resistance, tumour heterogeneity, metastatic progression, and treatment-associated toxicity. CRC and other cancers exhibit increased levels of Fe(II) due to dysregulated iron metabolism, which can act as a trigger for selective prodrug activation. In this study, we explore the therapeutic potential of a novel tumour-activated prodrug platform based on 1,2,4,5-tetraoxane scaffold that is selectively activated in cancer cells with high levels of labile Fe(II). As a proof-of-concept, we evaluated the therapeutic potential of 5b, a prodrug coupled with doxorubicin (DOX), which releases this cytotoxic payload upon activation by the labile Fe(II) pool in the cytoplasm of cancer cells.

Aims & Methods

The therapeutic potential and mechanism of action of 5b was evaluated both in vitro and in vivo. IC₅₀ values were determined across multiple cancer cell lines and compared to non-tumorigenic cells. To confirm iron-dependency, HCT116 cell viability was assessed upon co-incubation with 5b and iron chelator deferoxamine (DFO). Co-incubation with apoptosis inhibitor Z-VAD-FMK (Zvad) or ferroptosis inhibitor liproxstatin-1 was used to assess cell death mechanism. The sub-cellular location of 5b activation was evaluated by fluorescence microscopy. In vivo efficacy was evaluated in a xenograft mouse model using immunocompromised mice implanted with HT29 cells and intraperitoneal administrations of 5b, assessing tumour burden and systemic toxicity.

Results

Prodrug 5b effectively reduced cell viability in CRC cells HCT116 and HT29, as well as in glioblastoma (U251), prostate cancer (PC3) and breast cancer (MCF7) cells, with IC₅₀ values ranging from 1.64 to 6.69 µM. Notably, 5b was over 2000 times less toxic than DOX in non-tumorigenic cells AML12 (5b IC₅₀ = 398.2 µM vs. DOX IC₅₀ = 0.18 µM). Taking advantage of DOX intrinsic fluorescence properties (while 5b pro-drug is non-fluorescent), we used fluorescence microscopy analysis to confirm that 5b released its fluorescent DOX payload in the cytoplasm, after activation by labile Fe(II). The significant decrease in cell viability induced by 5b (p < 0.0001) was rescued by the iron chelator DFO and by the ferroptosis inhibitor liproxstatin-1 (p < 0.01) but not by pan-caspase inhibitor Zvad, suggesting that ferroptosis may be the primary mechanism of cell death. In vivo, 5b significantly reduced the relative tumour volume (p < 0.05), demonstrating greater efficacy than DOX, with only minor cardiotoxicity side-effects (multifocal loci of fibrosis affecting of 0.2% of left ventricle volume).

Conclusion

Prodrug 5b efficiently released its DOX payload in response to the cytoplasmatic labile Fe(II), effectively reducing cancer cell viability both in vitro and in vivo, while demonstrating significantly lower toxicity compared to DOX itself. Given its Fe(II)-dependent activation, 5b represents a promising strategy to exploit cancer cell iron addiction for cancer therapy. Future work should further validate ferroptosis as cell death mechanism, optimize the selection of cytotoxic payloads for tumours with dysregulated iron metabolism, and assess its efficacy in relation to KRAS mutational status. Funding: CMPR: PTDC/MED-FAR/3492/2021, LCF/PR/HR21/52410028; RM: 2022.07857.PTDC, PTDC/MED-QUI/30021/2017; VM: 10.54499/2023.11531.PEX; DMS: LCF/TR/CI22/52660003

Disclosure

The authors declare that this work is associated with intellectual property protection under the following patents/patent requests:
- Diogo Magalhães e Silva, Rui Moreira, Francisca Lopes, Cecília Rodrigues, Vanda Marques, “1,2,4,5-tetraoxane compounds, a drug delivery system based in said compounds useful in diagnoses and therapy, and methods thereof”, Portuguese Patent Application nº PT117644 from 16-12-2021;
- Diogo Magalhães e Silva, Rui Moreira, Francisca Lopes, Cecília Rodrigues, Vanda Marques, “Drug delivery systems based on endoperoxides useful in diagnosis and therapy, and methods thereof”, PCT Application nº PCT/IB2022/062107 from 13-12-2022;
- Diogo Magalhães e Silva, Rui Moreira, Francisca Lopes, Cecília Rodrigues, Vanda Marques, “Drug delivery systems based on endoperoxides useful in diagnosis and therapy, and methods thereof”, European Patent Office Application nº EP4448107 from 23-10-2024;
- Diogo Magalhães e Silva, Rui Moreira, Francisca Lopes, Cecília Rodrigues, Vanda Marques, “Drug delivery systems based on endoperoxides useful in diagnosis and therapy, and methods thereof”, United States Patent and Trademark Office patent application nº US20250064840 from 27-02-2025.

Clinical Case Summary

A 69-year-old male presented with dysphagia, food regurgitation, weight loss, and halitosis with a 12-month evolution. An upper endoscopy revealed, at 32 cm from the dental arch, a large food bolus impacted in an area consistent with a large esophageal diverticulum (Figure 1), along with isolated esophageal contractions suggestive of tertiary contractions. A barium swallow study confirmed a distal esophageal diverticulum measuring 6x5 cm (Figure 2). Subsequently, a chest CT scan showed the diverticulum with a large amount of food content inside (Figure 3). High-resolution esophageal manometry (HRM) demonstrated a hypercontractile pattern of the esophageal body in more than 20% of swallows, consistent with a diagnosis of hypercontractile esophagus or Jackhammer esophagus (Figures 4 and 5). Due to the symptoms and the size of the diverticulum, thoracoscopic diverticulectomy was performed, with favorable outcomes.
Esophageal diverticulum are uncommon, with a reported prevalence of 0.06% to 4%. In the case of hypercontractile esophagus, a pulsion mechanism is involved, with mucosal and submucosal protrusion secondary to increased intraesophageal pressure. HRM is useful for diagnosing underlying and triggering motility disorders, as well as guiding therapeutic decisions. Management should be individualized and may range from peroral endoscopic myotomy (POEM) to laparoscopic or open surgery.

References

Figure 1. Endoscopic view of the esophageal diverticulum. A: esophageal lumen. B: diverticular lumen with food bolus inside.

Figure 2. Barium swallow study showing an epiphrenic esophageal diverticulum with a 1 cm diverticular neck.

Figure 3. Chest computed tomography showing a large esophageal diverticulum with food content and an air-fluid level. A: sagittal view. B: axial view.

Figure 4. High-resolution manometry: hypercontractile contraction pattern (Distal Contractile Integral -DCI- >8000 mmHg·s·cm). Horizontal notch in the wave contour (arrow) corresponding to the diverticular neck.

Figure 5. Image of the resected diverticulum compared with a standard surgical scissor (18 cm long).

Introduction

Chronic liver disease—including alcoholic liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and liver fibrosis/cirrhosis (LFC)—has emerged as a major global health challenge, accounting for over 2 million deaths annually^1-2. Often progressing silently, chronic liver disease is frequently diagnosed at advanced stages, underscoring the urgent need for early identification of at-risk populations through reliable markers³. While recognized risk factors such as insulin resistance, alcohol overuse, and aging contribute to disease development, recent attention has focused on biological ageing acceleration (BioAgeAccel) as a comprehensive, integrative metric reflecting physiological decline, yet the utility in large populations remains underexplored^4-6. In parallel, genetic susceptibility and phenotypic data hold promise for identifying individuals predisposed to chronic liver disease⁷.

Aims & Methods

We conducted research to explore the association between BioAgeAccel, the risk of chronic liver diseases, incorporating genetic susceptibility.

This study included participants from the UK Biobank (UKB) and the All of Us (AoU) two cohort databases. BioAgeAccel was defined as the deviation between an individual’s phenotypic age (PhenoAge) or Klemera-Doubal age (KDMAge) and chronological age. Cox proportional hazards models analyzed the associations between BioAgeAccel and the risk of MASLD, ALD, and LFC, with hazard ratios (HRs) and 95% confidence intervals (CIs), and combined polygenic risk scores (PRS) to quantify genetic predisposition to chronic liver diseases.

Results

In the UKB cohort, accelerated PhenoAge was associated with significantly higher risks of ALD (HR 2.29; 95% CI 2.03-2.58), MAFLD (1.10; 1.04-1.16), and LFC (2.22; 2.01-2.46). Similarly, in the AoU cohort, accelerated PhenoAge was associated with higher risks of ALD (1.97; 1.00-3.88), MAFLD (1.35; 1.15-1.58), and LFC (2.19; 1.48-3.22). Comparable trends were observed for KDMAgeAccel in the UKB. Greater BioAgeAccel was associated with progressively higher risks of ALD and LFC, with these trends consistently. In the UKB, accelerated biological ageing was associated with chronic liver diseases independently of genetic risk and remained significant across PRS levels. Furthermore, compared to individuals with biologically younger ages and low genetic risk, participants with high genetic risk and accelerated PhenoAgeAccel exhibited the highest risk of developing chronic liver diseases, and LDSC revealed a positive genetic correlation between ageing and ALD, with SMR identifying three shared genes.

Table 1: Association between biological ageing acceleration (PhenoAgeAccel) and incident of chronic liver diseases in two datasets

PhenoAgeAccel	Non-accelerated ageing	Accelerated ageing
		HR (95% CI)		P value
UK Biobank
ALD	1 (Ref)	2.29 (2.03-2.58)		<0.001
MASLD		1.10 (1.04-1.16)		0.001
LFC		2.22 (2.01-2.46)		<0.001
All of us
ALD	1 (Ref)	1.97 (1.00-3.88)		0.049
MASLD		1.35 (1.15-1.58)		<0.001
LFC		2.19 (1.48-3.22)		<0.001

Conclusion

Accelerated biological ageing was associated with increased risk of chronic liver diseases, independently of genetic risk. Identifying individuals with higher BioAgeAccel is crucial for predicting the risk of chronic liver diseases, and indicators related to the calculation of BioAgeAccel can serve as potential targets for interventions.

References

1. GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396(10258):1204-1222. doi:10.1016/S0140-6736(20)30925-9
2. Devarbhavi H, Asrani SK, Arab JP, Nartey YA, Pose E, Kamath PS. Global burden of liver disease: 2023 update. J Hepatol. 2023;79(2):516-537. doi:10.1016/j.jhep.2023.03.017
3. Wang Y, Huang Y, Chase RC, et al. Global Burden of Digestive Diseases: A Systematic Analysis of the Global Burden of Diseases Study, 1990 to 2019. Gastroenterology. 2023;165(3):773-783.e15. doi:10.1053/j.gastro.2023.05.050
4. Lee YB, Ha Y, Chon YE, et al. Association between hepatic steatosis and the development of hepatocellular carcinoma in patients with chronic hepatitis B. Clin Mol Hepatol. 2019;25(1):52-64. doi:10.3350/cmh.2018.0040
5. Klemera P, Doubal S. A new approach to the concept and computation of biological age. Mech Ageing Dev. 2006;127(3):240-248. doi:10.1016/j.mad.2005.10.004
6. Cohen AA, Milot E, Yong J, et al. A novel statistical approach shows evidence for multi-system physiological dysregulation during aging. Mech Ageing Dev. 2013;134(3-4):110-117. doi:10.1016/j.mad.2013.01.004
7. Martin K, Hatab A, Athwal VS, Jokl E, Piper Hanley K. Genetic Contribution to Non-alcoholic Fatty Liver Disease and Prognostic Implications. Curr Diab Rep. 2021;21(3):8. doi:10.1007/s11892-021-01377-5

Disclosure

The authors have declared no conflict of interest.

Introduction

Esophageal squamous cell carcinoma (ESCC) is a major global health concern, with a high recurrence rate after chemoradiotherapy (CRT). Despite being a curative approach, CRT alone is often insufficient, leading to local recurrence in 30–40% of cases (1). Salvage treatments such as surgery and endoscopic resection have limitations, particularly in patients with comorbidities or advanced lesions (2). Photodynamic therapy (PDT) using talaporfin sodium (TS) has emerged as a promising, minimally invasive salvage treatment, offering advantages such as reduced phototoxicity and repeatability (3). Since its approval in Japan in 2015, TS-PDT has gained traction, yet further clinical evidence is needed to validate its efficacy and safety. This study aims to evaluate the clinical outcomes of TS-PDT as a salvage treatment for locally recurrent or residual ESCC following CRT or radiotherapy (RT).

Aims & Methods

A retrospective study was conducted at Nagoya City University Hospital between May 2016 and December 2023. A total of 29 patients with histologically confirmed local recurrence or residual ESCC post-CRT/RT were included. Eligible patients had lesions classified as ≤T2, without lymph node or distant metastasis. TS-PDT was administered with a diode laser (664 nm) 4–6 hours post-intravenous TS injection (40 mg/m²). Patients were monitored for adverse events, local complete response (L-CR), progression-free survival (PFS), and overall survival (OS). Kaplan–Meier analysis was used for survival estimation, and comparisons between single and multiple PDT sessions were evaluated.

Results

Table 1. The best response to PDT
	Local-CR	Non L-CR	L-CR rate
patients	22	5	81.5%
lesions	36	5	87.8%
T1b lesions	28	1	96.6%
T2 lesions	8	4	66.7%

Among the 29 patients (23 males, 6 females; median age, 72 years), TS-PDT achieved an L-CR rate of 82.1% per patient and 87.8% per lesion, with superior outcomes in T1b lesions (96.6%) compared to T2 lesions (66.7%) (Table1). The median local PFS was 1,324 days, and the median PFS was 912 days. OS was not reached during follow-up, with a 3-year survival rate of 70.7%. Seventeen patients underwent a single PDT session, while 12 required multiple sessions. The 3-year OS rate was 83.3% in the single-session group and 44.4% in the multiple-session group. No skin phototoxicity was observed. Adverse events included esophageal strictures (1 case, asymptomatic) and esophageal perforations (2 cases), one of which required surgical intervention.

Conclusion

TS-PDT demonstrated high local control rates and favorable survival outcomes, making it a promising salvage therapy for ESCC recurrence post-CRT/RT (4). Despite some adverse events, its minimal invasiveness and reduced phototoxicity enhance its applicability, particularly in elderly or high-risk patients. The effectiveness of multiple PDT sessions supports its role as a flexible treatment strategy. Further multicenter prospective trials are warranted to optimize patient selection, treatment protocols, and long-term outcomes, solidifying TS-PDT as a key salvage therapy for recurrent ESCC (5).

References

1. Hironaka S, Ohtsu A, Boku N, et al.: Nonrandomized comparison between definitive chemoradiotherapy and radical surgery in patients with T(2-3)N(any) M(0) squamous cell carcinoma of the esophagus. Int J Radiat Oncol Biol Phys 57: 425-433, 2003.
2. Tachimori Y, Kanamori N, Uemura N, Hokamura N, Igaki H and Kato H: Salvage esophagectomy after high-dose chemoradiotherapy for esophageal squamous cell carcinoma. J Thorac Cardiovasc Surg 137: 49-54, 2009.
3. Yano T, Kasai H, Horimatsu T, et al.: A multicenter phase II study of salvage photodynamic therapy using talaporfin sodium (ME2906) and a diode laser (PNL6405EPG) for local failure after chemoradiotherapy or radiotherapy for esophageal cancer. Oncotarget 8: 22135-22144, 2017.
4. Ikebuchi Y, Yoshida A, Kurumi H, et al.: Salvage Photodynamic Therapy Using Talaporfin Sodium for Local Failure of Esophageal Squamous Cell Carcinoma. Yonago Acta Med 64: 120-125, 2021.
5. Kai K, Nakashima K, Kawakami H, et al.: Clinical Impact of the Charlson Comorbidity Index on the Efficacy of Salvage Photodynamic Therapy Using Talaporfin Sodium for Esophageal Cancer. Intern Med 63: 903-910, 2024.

Clinical Case Summary

A middle-aged man underwent screening colonoscopy during which a diminutive (3–4 mm) polyp was removed by cold snare polypectomy. The procedure was uneventful. Within hours, he developed painless scrotal swelling. Examination revealed subcutaneous emphysema confined to the scrotum (scrotal crepitus) with a soft, non-tender abdomen. He remained afebrile with stable vital signs. Abdominal computed tomography (CT) demonstrated retroperitoneal free air tracking into the scrotum (pneumoscrotum) with no intraperitoneal free air or fluid. Despite the absence of peritoneal signs, the atypical location of free air prompted surgical consultation. An exploratory laparotomy was performed. Intraoperatively, no colonic perforation or contamination was identified, including at the polypectomy site. The air leak was presumed to stem from a sealed microperforation or mucosal defect that allowed retroperitoneal air dissection. The patient had an uneventful recovery and was discharged on postoperative day five. Pneumoscrotum is a rare but recognized complication of colonoscopy, usually resulting from retroperitoneal air dissection without overt perforation (1–3). Most reported cases have been managed conservatively; however, when air dissects into atypical anatomical compartments or if clinical uncertainty exists, surgical exploration may be warranted to exclude a full-thickness injury (2,3). This case highlights the need for individualized management based on clinical and radiological findings, and underscores a rare complication of a routine colonoscopic polypectomy.

References

1) Singh S, Thakur M. Pneumoscrotum after colonoscopy. Can J Gastroenterol. 2008;22(4):411–413.
— This case report describes an instance of pneumoscrotum following colonoscopic polypectomy, managed conservatively. It highlights air dissection from retroperitoneum into the scrotum and notes the rarity of the condition.

2) Graepler F, Lauer UM, Horger MS, et al. Pneumoscrotum after colonoscopic polypectomy. Endoscopy.2007;39(Suppl 1):E90.
— A rare case of post-polypectomy pneumoscrotum requiring laparotomy. No perforation was found intraoperatively, underscoring that extensive air can dissect without overt bowel rupture.

3) Fu KI, Sano Y, Kato S, et al. Pneumoscrotum: a rare manifestation of perforation associated with therapeutic colonoscopy. World J Gastroenterol. 2005;11(32):5061–5063.
— This article presents pneumoscrotum as a clinical manifestation of colonic microperforation and describes the potential retroperitoneal air pathway into the scrotum.