As the first one to evaluate the prognostic value of serum α-HBDH in UTUC patients after RNU, the present study found that preoperative serum α-HBDH value was an independent predictor for survival outcomes in localized UTUC patients.
α-HBDH, which played a role in catalyzing the oxidation of α-hydroxybutyrate to α-ketobutyric acid, was one of the enzymes that contributed to the formation of the myocardial enzyme spectrum and reflected hemolysis and heart injury when the level increased12,13. The increase of the α-HBDH in serum was not only the result of myocardial injury, but also associated with the damage to the renal, hematologic system and so on, which reflected the abnormity of multiple systems and might be a predictive factor for adverse prognosis of patients with systemic disease, such as viral infection and malignant carcinomas.
In 2021, Liu et al reported their findings that the in-hospital mortality and disease severity of patients infected by SARS-Cov‐2 was significantly associated with the α-HBDH level14,15. But such findings were confounded by the coexisting factors (age, white blood cell count, IL‐6, D‐dimer, LDH, lymphocyte count, and albumin levels) and more further researches about the specific mechanism were needed. In the present study, age, albumin level and LDH were also included. Although UTUC patients in α-HBDH-high group had advanced age and lower albumin level, these two factors did not have a significant impact on oncological outcomes. Our data showed that α-HBDH, which was an isoenzyme of LDH and could represent LDH1 and LDH2, has a similar or parallel expression with LDH in serum16. However, further cox analysis indicated that there was a significant association between the serum LDH value and MFS in the localized UTUC and even the whole group, while such association was not found in α-HBDH. Interestingly, a study, conducted by our center about 5 years ago, investigated the effect of LDH on the prognosis of UTUC8. In that previous study, using the LDH cutoff level of 220 U/L for the upper limit of normal, LDH-high group did not reach a statistical difference on MFS with the comparison of LDH-low group for patients with localized UTUC or without any restriction. The nature of continuous variable of LDH in the present study or the inappropriate cutoff value might be the reasons for such a difference. More future studies were needed to validate the conclusion and further explore the relationship with UTUC prognosis by combining LDH and α-HBDH.
The previous studies about the α-HBDH had mostly focused on myocardial infarction, atherothrombotic and liver injury and only a few on cancers13,17,18. The phenomena concerning the elevation of serum α-HBDH in malignant carcinomas has been observed in several specific cancers. In children, the simultaneous presence of high α-HBDH value with musculoskeletal symptoms suggested the necessity of screening for the occult tumors, such as acute lymphocytic leukemia, lymphoma, neuroblastoma and so on9. After comparing 51 cases of testicular germ tell tumors with 40 healthy controls, Khanolkar et al proposed that serum LDH and α-HBDH could both be used as tumor markers in the diagnosis of testicular germ cell tumors as well as prognostic indicators in monitoring therapy. What’s more, α-HBDH was more specific in monitoring therapy than serum LDH10. Recently, Yuan et al launched a study about the prognostic value of α-HBDH in lung cancer patients, and found that α-HBDH was an independent risk factor for OS, which was also found in our study, and the sensitivity of α-HBDH was higher than LDH11. Benefit from a relatively lager sample size, in the present study, we further performed subgroup analysis by tumor stage and found a more precise conclusion, which might represent a broader applicability. Therefore, the application of α-HBDH on oncological outcomes prediction is only in its infancy and whether the ability of α-HBDH to predict survival is effective for other tumors remains to be witnessed.
In addition to the tumor size, stage and grade, which were level C evidence recommended by EAU guideline, another independent risk factor, that cannot be ignored, for OS, CSS and MFS is the lymph node status19. In our study, patients with LNM tended to be associated with worse OS, CSS and MFS, which was consistent with a systematic review20. However, there were several adverse conditions that might affect the conclusion. In our center, lymphadenectomy was not performed routinely (72.3% patients were not staged with a lymph node dissection in our study) and only for patients with abnormal examination about lymph nodes preoperatively or palpable lymph nodes intraoperatively, which meant the positive rate of lymph node might be overestimated. What’s more, we regarded patients who were lymph node-negative and unevaluated as negative group, which would reduce the proportion of patients in the lymph node-positive group and thus rendered the inauthentic effect of node-positivity on prognosis.
For the whole group, the level of hemoglobin, which represented the basic physical condition, was also an independent risk factor for OS and CSS, but albumin failed. Hypoalbuminemia was previously proved to be strongly associated with cancer patients’ worsened OS and PFS, but the clinical practice of the single factor was limited because it could be easily affected by liver function, fluid volume and systemic inflammatory21–23. It might be the reason of the above phenomenon. Recently, based on the level of albumin, the novel nutrition assessment tools, named Prognostic Nutrition Index (PNI) and Naples prognostic score (NPS), are gaining increasing popularity in predicting the prognosis of patients with different cancers24,25. Data from our center showed that NPS is an easy and effective tool in predicting the OS in UTUC patients after RNU especially in locally advanced patients and PNI was significantly related to the OS in total patients, which laid emphasis on the importance of nutrition status of patients with malignant carcinomas and advocated paying more attention to manage nutrition status throughout cancer treatment.
Nonetheless, our study had some limitations. Firstly, it was performed in a retrospective, single-center designed study, which might lead to selection bias and be different from other studies’ findings. Secondly, the information about comorbidity of UTUC patients before or at the time of RNU was not recorded, and the co-existing disease, such as myocardial infarction, atherothrombotic and liver injury, might affect the α-HBDH level and further had an impact on conclusion. Third, despite the potential relationship between α-HBDH and survival outcomes identified in this study, little has been done to explore the underlying mechanisms. We are conducting a prospective, multi-center study with more improved baseline data to address these limitations and establish the predictive value of preoperative α-HBDH level.