Pyogenic liver abscess as the initial manifestation of underlying hepatocellular carcinoma

Background

Pyogenic liver abscess and hepatocellular carcinoma are common in Taiwan. We investigated the frequency of, risk factors for, and prognosis of pyogenic liver abscess as the initial manifestation of underlying hepatocellular carcinoma over a 12-year period in Taiwan.

Methods

We extracted 32,454 patients with pyogenic liver abscess from a nationwide health registry in Taiwan during the period 1997-2008. The frequency of and risk factors for pyogenic liver abscess as the initial manifestation of underlying hepatocellular carcinoma were determined. The prognosis of these patients was compared with patients with hepatocellular carcinoma but without liver abscess.

Results

A total of 698 (2.15%) patients presented with liver abscess as the initial manifestation of underlying hepatocellular carcinoma during the 12-year period. Liver cirrhosis, hepatitis B virus infection, hepatitis C virus infection, and age ≥65 years were independent risk factors for liver abscess as the initial manifestation of underlying hepatocellular carcinoma. Furthermore, these patients had a lower 2-year survival rate than patients with hepatocellular carcinoma but without liver abscess (30% vs 37%; P = .004).

Conclusions

The prognosis of patients who presented with pyogenic liver abscess as the initial manifestation of underlying hepatocellular carcinoma was poor. Physicians should not ignore the possibility of underlying hepatocellular carcinoma in patients with risk factors for the disease in regions with a high prevalence of both pyogenic liver abscess and hepatocellular carcinoma.     

Disproportionate Reduction of Serotonin Transporter May Predict the Response and Adherence to Antidepressants in Patients with Major Depressive Disorder: A Positron Emission Tomography Study with 4-[18F]-ADAM

Background:

Many lines of evidence suggest the role of serotonin transporter (SERT)-mediated reuptake of serotonin in the pathophysiology and treatment of major depressive disorder (MDD). This study aimed to examine whether the pretreatment of SERT binding potential or SERT binding ratio between terminal projection regions relative to the midbrain raphe nuclei was associated with treatment outcomes to SERT-targeted antidepressants.

Methods:

We recruited 39 antidepressant-naïve patients with MDD and 39 heathy controls. Positron emission tomography with N,N-dimethyl-2-(2-amino-4-[¹⁸F]fluorophenylthio)benzylamine (4-[¹⁸F]-ADAM) was used to measure in vivo SERT availability prior to antidepressant treatment. The 21-item Hamilton Depression Rating Scale (HDRS) was use to assess the severity of depression from baseline to week 6. All the patients with MDD had HDRS scores of 18 or more.

Results:

Pretreatment SERT binding in the thalamus and striatum positively correlated with an early reduction in HDRS scores at week 3. Nonresponders and dropout patients showed a proportionate reduction in SERT binding in the terminal projection regions and midbrain compared to healthy controls. In contrast, a disproportionate reduction in SERT binding in the terminal projection regions relative to midbrain was observed in responders.

Conclusions:

The results of this study suggested that a disproportionate reduction in SERT binding between terminal projection regions and midbrain may predict better treatment outcomes in patients with MDD.     

Infiltrating neutrophils promote renal cell carcinoma progression via VEGFa/HIF2α and estrogen receptor β signals

Neutrophils make up a significant portion of the infiltrated immune cells found in the tumor microenvironment. Here we found more infiltrated neutrophils in human renal cell carcinoma (RCC) lesions than adjacent benign areas. In vitro RCC studies showed that neutrophils (HL-60N cells) infiltrated toward RCC cells and subsequently enhanced RCC cell migration and invasion. Co-culture of RCC cells with HL-60N cells up-regulated ERβ, VEGFa and HIF2α mRNA levels. ERβ signals increased RCC cell migration via induction of the VEGFa/HIF2α pathway. Treatment of HIF inhibitor or rapamycin, or knockdown of ERβ in RCC cells reversed HL-60N-promoted RCC migration. In vivo data using orthotopically xenografted RCC mouse model confirmed that infiltrated neutrophils promoted RCC migration via modulating the expressions of ERβ, VEGFa and HIF2α signal pathways. Together, our studies revealed that neutrophils are favorably recruited to the RCC cells to promote the RCC migration and invasion. Targeting the infiltrating RCC tumor microenvironment with anti-estrogen or rapamycin may be a potential therapy to suppress RCC progression.     

Lapatinib increases motility of triple-negative breast cancer cells by decreasing miRNA-7 and inducing Raf-1/MAPK-dependent interleukin-6

Lapatinib, a dual epidermal growth factor receptor (EGFR) and HER2 tyrosine kinase inhibitor (TKI), has been approved for HER2-positive breast cancer patients. Nevertheless, its inhibitory effect on EGFR did not deliver clinical benefits for triple-negative breast cancer (TNBC) patients even EGFR overexpression was frequently found in this disease. Moreover, lapatinib was unexpectedly found to enhance metastasis of TNBC cells, but the underlying mechanisms are not fully understood. In this study, we explored that the level of interleukin-6 (IL-6) was elevated in lapatinib-treated TNBC cells. Treatment with IL-6 antibody abolished the lapatinib-induced migration. Mechanistically, the signaling axis of Raf-1/mitogen-activated protein kinases (MAPKs), c-Jun N-terminal kinases (JNKs), p38 MAPK, and activator protein 1 (AP-1) was activated in response to lapatinib treatment to induce IL-6 expression. Furthermore, our data showed that microRNA-7 directly binds and inhibits Raf-1 3′UTR activity, and that down-regulation of miR-7 by lapatinib contributes to the activation of Raf-1 signaling pathway and the induction of IL-6 expression. Our results not only revealed IL-6 as a key regulator of lapatinib-induced metastasis, but also explored the requirement of miR7/Raf-1/MAPK/AP-1 axis in lapatinib-induced IL-6 expression.     

Surgical management of hepatocellular carcinoma after Fontan procedure

The Fontan operation has successfully prolonged the lives of patients born with single-ventricle physiology. A long-term consequence of post-Fontan elevation in systemic venous pressure and low cardiac output is chronic liver inflammation and cirrhosis, which lead to an increased risk of hepatocellular carcinoma (HCC). Surgical management of patients with post-Fontan physiology and HCC is challenging, as the requirement for adequate preload in order to sustain cardiac output conflicts with the low central venous pressure (CVP) that minimizes blood loss during hepatectomy. Consequently, liver resection is rarely performed, and most reports describe nonsurgical treatments for locoregional control of the tumors in these patients. Here, we present a multidisciplinary approach to a successful surgical resection of a HCC in a patient with Fontan physiology.     

Mechanical comparison of biodegradable femoral fixation devices for hamstring tendon graft – A biomechanical study in a porcine model

Background

Initial fixation strength is critical for the early post-operative rehabilitation of patients with anterior cruciate ligament reconstructions. However, even the best femoral fixation devices remain controversial. We compared the biomechanical characteristics of tendon grafts fixed by different biodegradable femoral fixation devices following anterior cruciate ligament reconstruction.

Methods

The Bio-TransFix, Rigidfix, Bioscrew with EndoPearl augmentation and Bioscrew devices were used to fix porcine flexor digitorum profundus tendon grafts in 32 porcine femora. Displacement of each tendon graft was evaluated after cyclic loading testing. Stiffness, ultimate failure load and failure mode of these fixation devices were measured with load-to-failure testing.

Findings

The displacement of the femur–graft–cement complex in response to cyclic loading was lower (P < 0.05) for the Bio-TransFix than the Rigidfix, Bioscrew with EndoPearl augmentation, and Bioscrew groups. The fixation stiffness values of the Rigidfix and the Bioscrew were significantly greater (P < 0.05) than that of the Bio-TransFix. The ultimate failure load was significantly greater for the Bio-TransFix and the Rigidfix than the Bioscrew with EndoPearl augmentation or the Bioscrew (P < 0.05).

Interpretation

The Bio-TransFix provided the least graft displacement under cyclic loading. However, this device gave less stability. The Rigidfix device provided better stability and stiffness of the tendon graft among those fixation devices that showed no significant differences in graft displacement under cyclic loading. However, no single fixation device provided less displacement along with a larger failure load and stiffness in this study.     

Ciltacabtagene autoleucel in patients with relapsed/refractory multiple myeloma: CARTITUDE‐1 (phase 2) Japanese cohort

Chimeric antigen receptor (CAR) T cells targeting B‐cell maturation antigen have shown positive responses in patients with multiple myeloma (MM). The phase 2 portion of the CARTITUDE‐1 study of ciltacabtagene autoleucel (cilta‐cel) included a cohort of Japanese patients with relapsed/refractory MM. Following a conditioning regimen of cyclophosphamide (300 mg/m²) and fludarabine (30 mg/m²), patients received a single cilta‐cel infusion at a target dose of 0.75 × 10⁶ (range, 0.5–1.0 × 10⁶CAR‐positive viable T cells/kg). The primary endpoint was overall response rate (ORR; defined as partial response or better) by International Myeloma Working Group criteria. A key secondary endpoint was the rate of very good partial response (VGPR) or better (defined as VGPR, complete response, stringent complete response). This first analysis was performed at 6 months after the last patient received cilta‐cel. Thirteen patients underwent apheresis, nine of whom received cilta‐cel infusion. Eight patients who received cilta‐cel at the target dose responded, yielding an ORR of 100%. Seven of eight (87.5%) patients achieved a VGPR or better. One additional patient who received a below‐target dose of cilta‐cel also achieved a best response of VGPR. MRD negativity (10⁻⁵ threshold) was achieved in all six evaluable patients. Eight of nine (88.9%) patients who received cilta‐cel infusion experienced a grade 3 or 4 adverse event, and eight (88.9%) patients experienced cytokine release syndrome (all grade 1 or 2). No CAR‐T cell neurotoxicity was reported. A positive benefit/risk profile for cilta‐cel was established for heavily pretreated Japanese patients with relapsed or refractory MM.     

Effects of Achieving SVR on Clinical Characteristics and Surgical Outcomes in Patients Who Developed Early-Stage HCV-Related Hepatocellular Carcinoma and Received Curative Resection: Preoperative versus Postoperative SVR

The high accessibility to healthcare and increasing awareness of hepatocellular carcinoma (HCC) surveillance after sustained virologic response (SVR) to HCV treatment allow early detection of operable HCC in Taiwan. However, the effects of achieving SVR on patient characteristics and surgical outcomes after curative resection remain elusive. We aimed to compare the clinical presentation and postoperative prognosis among patients with early-stage HCV-related HCC and different viral status. We retrospectively analyzed 208 patients with BCLC stage 0 or A-HCC, including 44 patients who remained HCV viremic, 90 patients who developed HCC after achieving SVR (post-SVR HCC), and 74 patients who subsequently achieved SVR after resection. Patients with post-SVR HCC had a lower degree of hepatitis and better liver function than those who achieved SVR or remained viremic after resection. Notably, 75.6% of patients with post-SVR HCC did not have cirrhosis. Patients with post-SVR HCC and those achieving SVR after resection exhibited comparable recurrence rates and recurrence-free survival, while patients with persistent viremia had the worst surgical outcomes. We concluded that patients with post-SVR HCC had a better liver function but similar surgical outcomes compared with patients who achieved SVR after resection. The low prevalence of cirrhosis in patients with post-SVR HCC highlights the importance of regular surveillance after SVR.     

In vitro and in vivo study of GSK2830371 and RG7388 combination in liver adenocarcinoma

Intrahepatic cholangiocarcinoma (iCCA) is an adenocarcinoma arising from the intrahepatic bile duct and accounts for the second highest incidence of primary liver cancers after hepatocellular carcinoma. The lack of effective treatment leads to a poor prognosis for advanced iCCA, so new targeted therapy is needed. The impairment of wild-type (WT) p53 tumor suppressor function by its negative regulators frequently occurs in iCCA. Therefore, restoration of WT p53 function by inhibiting its negative regulators is a therapeutic strategy being explored for cancer treatment. Combining an MDM2 inhibitor (MDM2i, RG7388) to stabilize p53 and a WIP1 inhibitor (WIP1i, GSK2830371) to increase p53 phosphorylation enhances p53 function. The combination of MDM2 and WIP1 inhibitors has been reported in several cancer types but in vivo studies are lacking. In the current study, liver adenocarcinoma cell lines, RBE and SK-Hep-1, were treated with RG7388 alone and in combination with GSK2830371. Cell proliferation, clonogenicity, protein and mRNA expressions, and cell cycle distribution were performed to investigate the effect and mechanism of growth suppression. To evaluate the antitumor efficacy of RG7388 and GSK2830371 in vivo, SK-Hep-1 xenografts in NOD-SCID mice were treated with combination therapy for two weeks. The combination of MDM2i and WIP1i significantly increased the growth inhibition, cytotoxicty, p53 protein expression, and phosphorylation (Ser15), leading to transactivation of downstream targets (p21^WAF1 and MDM2). The in vivo results demonstrated that the combination treatment can significantly inhibit tumor growth. In this study, the liver adenocarcinoma cell lines responded to combination treatment via reactivation of p53 function evidenced by increased p53 expression, phosphorylation and expression of its downstream targets. This efficacy was also demonstrated in vivo. The current research provides a novel strategy for targeting the p53 pathway in liver adenocarcinoma that warrants further investigation.