Organ and function preservation in gastrointestinal cancer: Current and future perspectives on endoscopic ablation

The escalating prevalence of gastrointestinal cancers underscores the urgency for transformative approaches.Current treatment costs amount to billions of dollars annually,combined with the risks and comorbidities associated with invasive surgery.This highlights the importance of less invasive alternatives with organ preservation being a central aspect of the treatment paradigm.The current standard of care typically involves neoadjuvant systemic therapy followed by surgical resection.There is a growing interest in organ preservation approaches by way of minimizing extensive surgical resections.Endoscopic ablation has proven to be useful in precursor lesions,as well as in palliative cases of unrese-ctable disease.More recently,there has been an increase in reports on the utility of adjunct endoscopic ablative techniques for downstaging disease as well as contributing to non-surgical complete clinical response.This expansive field within endoscopic oncology holds great potential for advancing patient care.By addressing challenges,fostering collaboration,and embracing technological advancements,the gastrointestinal cancer treatment paradigm can shift towards a more sustainable and patient-centric future emphasizing organ and function preservation.This editorial examines the evolving landscape of endoscopic ablation strategies,emphasizing their potential to improve patient outcomes.We briefly review current applications of endoscopic ablation in the esophagus,stomach,duodenum,pancreas,bile ducts,and colon.

Advances in Cryopreservation of Organs

Organ transplantation is an effective approach for the treatment of end-stage organ failures. Currently, the donor organs used for clinical transplantation are all preserved at above-zero temperatures. These preservation methods are well-established and simple but the storage time lasts for only 4–12 h. Some researchers tried to extend the organ storage time by improving protectant and HLA matching to raise the use of stored organs and prolong the long-term survival of organs. These efforts still fall short of the clinical demand for organ transplantation. Moreover, a great many organs were wasted due to limited storage time, HLA mismatch, patients＇ conditions or distance involved. Therefore, preserving organs for several weeks or even months and establishing Organ Bank are the tough challenges and have become a shared goal of global scholars. This article reviews some issues involved in the cryopreservation of organs, such as use of cryoprotecting agents, freezing and thawing methods in the cryopreservation of hearts, kidneys and other organs.

Liver graft preservation:an overview

BACKGROUND: The quality of liver graft and outcome of liver transplantation is affected by the length of ischemia time during the donor operation. The retrieved graft may have a serious damage during the time of stoppage of the circulation in the donor until revascularization in the recipient. It is very important to develop a suitable preservation fluid to minimise the damage caused by the ischemic period and to make the surgical procedure semi- elective. DATA SOURCES: An English-language literature search was conducted using MEDLINE (1960-2006) on liver preservation solution, liver transplantation, kidney transplantation and other related subjects. RESULTS: Since 1960 until 2006 many preservation solutions have been introduced. Most of them are based on the effect of hypothermia to minimise the metabolic pathway in the liver graft. In the earlier studies electrolyte solutions were used to perfuse the liver through the portal vein. The first modification in preservation solution was done by Collins who was able to extend the kidney preservation time up to 30 hours. In recent years, the introduction of University of Wisconsin (UW) preservation solution has made a revolution in the field of organ preservation. The UW solution is based on lactobionate and raffinose as impermeants to suppress hypothermic-induced tissue swelling, replacing glucose and mannitol in Collin's solution and hypertonic citrate respectively. Recently a research group in Kyoto University works to produce a more reliable preservation solution. They investigated the importance of saccharides and electrolytes in lung preservation and developed their original ET-Kyoto solution. However, more studies are still needed to evaluate the new ET-Kyoto solution. CONCLUSIONS: The development of new preservation solutions represents a corner stone in the field of organtransplantation. In the future we might be able to extend the time of organ preservation from hours to days.

Apoptosis of rat liver in cold preservation with custom-designed KYL solution

BACKGROUND: A suitable perfusate is very important in reducing various problems in liver preservation, prolonging the time of organ preservation and enhancing the quality of donor tissue. University of Wisconsin (UW) solution is the most successful solution for preserving multiple organs at present, but it has many shortcomings. We set out to develop a new liver preservation solution (KYL solution) and study its effects on apoptosis in rat liver undergoing cold preservation. METHODS: Using non-circulated isolated perfused rat liver (IPRL), we randomly preserved Sprague-Dawley rat livers for 0, 4, 8, 16, 24, and 48 hours with KYL solution or UW solution. The effects were assessed by measuring the content of free radicals in Krebs-Henseleit solution and the intracellular calcium content of hepatocytes, assessing hepatocellular apoptosis and related-gene expression, and observing the morphological changes in liver. To evaluate the protection by KYL and UW solutions in rat liver perfusion and preservation, we chosed normal saline for negative comparison. RESULTS: The intracellular calcium content of the liver preserved in KYL solution was less than that preserved in UW solution. At every different period of preservation, the malonaldehyde and superoxide dismutase content in Krebs-Henseleit solution, the percentage of apoptotic cells and the expression patterns of apoptosis-related-genes were similar in livers preserved in KYL and UW solutions. Morphological changes in the two groups were almost the same. The variables in both groups were better than those of livers preserved in normal saline. Both KYL and UW solutions protected rat liver from ischemia-reperfusion injury. CONCLUSIONS: KYL solution is superior to UW solution in preventing calcium overload. More severe hepatocyte damage may appear in the KYL group than in the UW group and the effect of KYL solution on apoptosis in rat liver preservation is similar to that of UW solution.

Experimental Study on the Cryopreservation of LLC-PK1 Epithelial Cells with Hypoxic UW Solution

The effects of oxygen partial pressure on cryopreservation of the cells with organ preservation solution were explored. Hypoxic UW solution was made by purging the UW solution with argon. The pig proximal tubule epithelial cells （LLC-PK1 cells） were cryopreserved in hypoxic UW solution （Ar-UW group） or standard UW solution （UW group） at 4℃ for 48 h. Trypan blue staining and LDH detection were performed to evaluate the injury of the cells. The results showed that the oxygen partial pressure in Ar-UW group was significantly declined from 242±6 mmHg to 83±10 mmHg. After cryopreservation at 4℃ for 48 h, LDH leakage rate and Trypan blue-stained rate in Ar-UW group were （11.3±3.4）% and （10.5±4.7）%, respectively, which were significantly lower than in UW group [（49.5±6.9）% and （47.6±9.3）% respectively, both P〈0.01]. It was concluded that lower oxygen partial pressure of UW solution was more beneficial to the cryopreservation of LLC.

Preparation and Preservation of Hypoxia UW Solution

In order to explore the method to prepare hypoxia UW solution and the stability and preservation of hypoxia UW solution, UW solution was purged by argon or air for 15 min or 60 at a flow rate of 0.8 or 2 L/min, and the oxygen partial pressure of UW solution was detected. The hypoxia UW solution was exposed to the air or sealed up to preserve by using different methods, and the changes of oxygen partial pressure was tested. The results showed that oxygen partial pressure of 50 mL UW solution, purged by argon for 15 min at a flow rate of 2 L/min, was declined from 242±6 mmHg to 83±10 mmHg. After exposure to the air, oxygen partial pressure of hypoxia UW solution was gradually increased to 160±7 mmHg at 48 h. After sealed up by the centrifuge tube and plastic bad filled with argon, oxygen partial pressure of hypoxia UW solution was stable, about 88±13 mmHg at 72 h. It was concluded that oxygen of UW solution could be purged by argon efficiently. Sealed up by the centrifuge tube and plastic bag filled with argon, oxygen partial pressure of UW solution could be stabilized.

Watch and wait approach in rectal cancer:Current controversies and future directions

According to the main international clinical guidelines,the recommended treatment for locally-advanced rectal cancer is neoadjuvant chemoradiotherapy followed by surgery.However,doubts have been raised about the appropriate definition of clinical complete response(cCR)after neoadjuvant therapy and the role of surgery in patients who achieve a cCR.Surgical resection is associated with significant morbidity and decreased quality of life(QoL),which is especially relevant given the favourable prognosis in this patient subset. Accordingly, therehas been a growing interest in alternative approaches with less morbidity,including the organ-preserving watch and wait strategy, in which surgery isomitted in patients who have achieved a cCR. These patients are managed with aspecific follow-up protocol to ensure adequate cancer control, including the earlyidentification of recurrent disease. However, there are several open questionsabout this strategy, including patient selection, the clinical and radiologicalcriteria to accurately determine cCR, the duration of neoadjuvant treatment, therole of dose intensification (chemotherapy and/or radiotherapy), optimal followupprotocols, and the future perspectives of this approach. In the present review,we summarize the available evidence on the watch and wait strategy in thisclinical scenario, including ongoing clinical trials, QoL in these patients, and thecontroversies surrounding this treatment approach.

Warm HTK donor pretreatment reduces liver injury during static cold storage in experimental rat liver transplantation

BACKGROUND： Organ shortage has led to an increased number of transplantations from extended criteria donors. These organs are more vulnerable to ischemia-reperfusion injury. Thus, improvement of organ preservation is needed. HTK is a widely used preservation solution for static cold storage in liver transplantation. The present study was to investigate the beneficial effect of warm HTK donor pretreatment on liver preservation.

Therapeutics administered during ex vivo liver machine perfusion:An overview

Although the use of extended criteria donors has increased the pool of available livers for transplant,it has also introduced the need to develop improved methods of protection against ischemia-reperfusion injury(IRI),as these"marginal"organs are particularly vulnerable to IRI during the process of procurement,preservation,surgery,and post-transplantation.In this review,we explore the current basic science research investigating therapeutics administered during ex vivo liver machine perfusion aimed at mitigating the effects of IRI in the liver transplantation process.These various categories of therapeutics are utilized during the perfusion process and include invoking the RNA interference pathway,utilizing defatting cocktails,and administering classes of agents such as vasodilators,anti-inflammatory drugs,human liver stem cell-derived extracellular vesicles,and δ-opioid agonists in order to reduce the damage of IRI.Ex vivo machine perfusion is an attractive alternative to static cold storage due to its ability to continuously perfuse the organ,effectively deliver substrates and oxygen required for cellular metabolism,therapeutically administer pharmacological or cytoprotective agents,and continuously monitor organ viability during perfusion.The use of administered therapeutics during machine liver perfusion has demonstrated promising results in basic science studies.While novel therapeutic approaches to combat IRI are being developed through basic science research,their use in clinical medicine and treatment in patients for liver transplantation has yet to be explored.

Concise review of machine perfusion in liver transplantation

With the advances and clinical growth in liver transplantation over the last four decades the focus on expanding deceased donor organs has been in need of scientific research.In the past ten years several researchers have looked at the domain of machine perfusion as it applies to deceased donor livers.The following review focuses on the clinical trials and recent advances that will likely have the earliest entrance into the clinical arena.

Watch and wait in locally advance rectal cancer:Past,present and future

In rectal cancer,a complete pathological response after neoadjuvant therapy means better rates survival and better rates of local recurrence.Nevertheless,these patients suffer from complications following surgery such as low anterior resection syndrome,sexual dysfunction or colostomy for the rest of their lives.Due to this,several groups are working in an organ preservation strategy when a clinical response is diagnosed.This strategy is known as watch and wait.In this editorial,we review the past,present and future perspectives for this conservative management.

Zinc is a potent heat shock protein inducer during liver cold preservation in rats

OBJECTIVE: A simple liver cold preservation model was established to study the synthesis of heat shock protein 70 (HSP70) induced by zinc (ZnSO(4), i.p.) and its protection during liver cold preservation in rat. METHODS: Male Wistar rats were divided into 5 groups (n = 6). In control group rat received no pretreatment; in Zn-1 group, Zn-2 group, and Zn-3 group rats were pretreated with zinc sulfate at a dose of 5 mg/kg, 10 mg/kg, 15 mg/kg respectively; and in H group rat received heat shock preconditioning (42.5 degrees C x 15 min). Livers were preserved in UW solution for 6, 12 and 24 h, respectively. HSP70 was analyzed by Western blot. Aspartate transaminase (AST) and lactate dehydrogenase (LDH) values of the perfusion solution and the histology of the liver were evaluated. RESULTS: HSP70 expression was markedly elevated after pretreatment with zinc and heat shock. AST and LDH values in the Zn-1, Zn-2 and H groups were significantly lower than those in the control group, respectively (P 0.05), whereas the AST and LDH values in the Zn-3 group were much higher than those in the control group. Histology results showed that liver injury in the Zn-1, Zn-2 and H groups were minimal, while it was severe in the Zn-3 group. CONCLUSIONS: Zn(2+) is a potent and feasible inducer of HSP expression and is able to protect liver from cold preservation injury. The proper inducing dosage of Zn(2+) ranged from 5 mg/kg to 10 mg/kg. The dosage of 15 mg/kg for Zn(2+) as a HSP inducer is not indicated for its severe toxicity to the liver.

A study on continuous low-flow perfusion with low-potassium dextran for donor isolated lung preservation

OBJECTIVE: To test the validity of continuous low-flow perfusion with low-potassium dextran (LPD) to preserve rabbit lung. METHODS: Isolated rabbit lungs were preserved for eight hours either in Ringer's solution by simple storage (Group I) or in continuous low-flow perfusion with LPD (Group II). After preservation, lung functions were assessed to compare these two methods. RESULTS: The water gain in Group I was higher than that in Group II. During reperfusion, the functional test values for the immersed lungs were lower than those for the perfused lungs. The lipid peroxidation product (MDA) was significantly decreased in perfused lungs during reperfusion. CONCLUSIONS: Low-flow perfusion with LPD is better than immersion for the lung preservation.

Addition of ulinastatin to preservation solution promotes protection against ischemia-reperfusion injury in rabbit lung

Background The composition of the lung preservation solution used in lung graft procurement has been considered the key to minimize lung injury during the period of ischemia. Low-potassium dextran glucose （LPDG）, an extracellular-type solution, has been adopted by most lung transplantation centers, due to the experimental and clinical evidences that LPDG is superior to intracellular-type solutions. Ulinastatin has been shown to attenuate ischemia-reperfusion （I/R） injury in various organs in animals. We supposed that the addition of ulinastatin to LPDG as a flushing solution, would further ameliorate I/R lung injury than LPDG solution alone.Methods Twelve male New Zealand white rabbits were randomly divided into 2 groups. Using an alternative in situ lung I/R model, the left lung in the control group was supplied and preserved with LPDG solution for 120 minutes. In the study group 50 000 U/kg of ulinastatin was added to the LPDG solution for lung preservation. Then re-ventilation and reperfusion of the left lung were performed for 90 minutes. Blood gas analysis （PaO2, PaCO2）, mean pulmonary artery pressure （MPAP） and serum TNF-α level were measured intermittently. The pulmonary water index （D/W）, tissue myeloperoxidase （MPO） activity, tissue malondialdehyde （MDA） content and morphologic changes were analyzed.Results The study group showed significantly higher PaO2 and lower MPAP at the end of reperfusion. Serum TNF-α level, left lung tissue MPO and MDA in the study group were significantly lower than those in the control group. D/W and pathologic evaluation were also remarkably different between the two groups.Conclusions This study indicated that better lung preservation could be achieved with the use of an ulinastatin modified LPDG solution. Ulinastatin further attenuated lung I/R injury, at least partly by reducing oxidative reactions,inhibiting the release of inflammatory factors and neutrophils immigration.

A modified CZ-1 preserving solution for organ transplantation： comparative study with UW preserving solution

Background The University of Wisconsin colloid based preserving solution （UW solution） is the most efficient preserving solution for multiorgan transplantation. Unfortunately, unavailability of delayed organ preserving solutions hindered further progression of cardinal organ transplantation in China. In this study, we validated an organ preserving Changzheng Organ Preserving Solution （CZ-1 solution） and compared it with UW solution. Methods A series of studies were conducted on how and how long CZ-1 solution could preserve the kidneys, livers, hearts, lungs and pancreas of New Zealand rabbits and SD rats. Morphology of transplanted organs was studied by visible microscopy and electron microscopy; biochemical and physiological functions and the survival rate of the organs during prolonged cold storage were studied. Results There was no significant difference between CZ-1 and UW solutions in preserving the kidneys, livers, hearts or lungs of rabbits; kidneys, livers, intestinal mucosa or pancreases of SD rats or five deceased donors＇ testicles. In some aspects, such as preserving rabbits＇ hearts, rats＇ intestinal mucosa and pancreases, the effect of CZ-1 solution was superior to UW solution. CZ-1 could safely preserve kidneys for 72 hours, livers for 24 hours, hearts for 18 hours and lungs for 8 hours for SD rats. Twelve kidneys preserved in cold CZ-1 solution for 22-31 hours were transplanted successfully and the mean renal function recovery time was （3.83±1.68） days. Conclusions CZ-1 solution is as effective as UW solution for organ preservation. The development of CZ-1 solution not only reduces costs and improves preservation of organs, but also promotes future development of organ transplantation in China.

Paleoproductivity and Paleoredox Condition of the Huai Hin Lat Formation in Northeastern Thailand

The petroleum exploration has been conducted in the Khorat Plateau since 1962 and two gas fields have been discovered and commercially produced. The lacustrine facies of the Huai Hin Lat Formation is believed to be one of the main source rocks of the gas. Therefore, investigation and analysis of the Huai Hin Lat shale for understanding the paleoenvironment and petroleum source rock are carried out in this study. Petrographical study and geochemical analysis of shale samples were performed to explain the paleoproductivity and past redox condition. The palynofacies assemblage comprises abundant AOM, acritarchs, phytoclasts, and very small amount of spores and pollen. Geochemical analysis was used to determine the total organic carbon（TOC） and the concentration of major, trace, and rare earth elements. The paleoproductivity proxies are composed of palynofacies, TOC, excess SiO2, Ba/Al, and P/Al. They reflect a high paleoproductivity except the middle of the lower part（bed 3） and the lower bed 13 of the upper part. Bed 3 shows the highest peak of TOC and the lower bed 13 exhibits a relatively lower TOC, which can be explained by the excellent and the poorer preservation condition, respectively. The paleoredox proxies consist of U/Th, V/Cr, Ni Co,（Cu＋Mo）/Zn, Ni/V, and Ce anomaly. They are used to establish the depositional environments, to characterize the organic matter content, and to assess the source rock potential. They reflect many high peaks and predominantly high values of paleoredox proxies except the middle part and the lower bed（lower bed 13） of the upper part. They indicate that the section was mainly under anoxic or reducing condition, which is supported by the high Ce/Ce＊（〉0.8） and V/Cr（〉2.0） values. The middle of the lower part（bed 3） shows lower productivity but it contains the highest peak of TOC, which is conformed to be the excellent preservation of organic matters in the strong reducing condition. The middle part, which shows high productivity, contains relatively lower TOC as it possesses a less reducing condition compared to the more reducing intervals. The lower bed 13 of the upper part shows a less reducing condition and a lower TOC, which conforms to a lower productivity. The organic matters of the Huai Hin Lat Formation consist mainly of AOM and acritarchs and possess good to excellent TOC（2%–7%）. They belong mainly to type I and type II kerogens with some mixture of type III as indicated by the presence of phytoclasts, spores, and pollen. The organic matters of the Huai Hin Lat Formation, based on the kerogen type and the thermal history, have already generated significant amount of oil and some gas to the Sap Phlu Basin.