Remission After Hydrogen InhalationCercetare Științifică
A Gallbladder Carcinoma Patient With Pseudo-Progressive Remission After Hydrogen Inhalation
Abstract
Background
Hydrogen therapy has been reported to convert exhausted programmed cell death receptor (PD-1)+CD8+ T cells to PD-1-CD8+ T cells, in advanced colorectal cancer patients, which is associated with significantly prolonged survival.
Case presentation
A 72-year-old female patient presented with metastatic gallbladder cancer and underwent symptomatic treatment combined with hydrogen therapy. The tumors were initially enlarged and displayed increased tumor marker expression following hydrogen inhalation therapy, after which they continued to remit, similar to the pseudo-progression that occurs after anti-PD-1 treatment. During one month of hydrogen therapy, the patient’s gallbladder and liver tumors continued to progress, and intestinal obstruction occurred. The intestinal obstruction was gradually relieved after symptomatic treatment, and the metastases in the abdominal cavity gradually decreased in size, anemia and hypoalbuminemia were corrected, and both the lymphocyte and tumor marker levels returned to normal. The patient was able to resume normal life two and a half months after hydrogen inhalation and survived over 10 months.
Conclusion
This is the first report of pseudo-progression followed by sustained remission after hydrogen inhalation. This phenomenon is similar to the pseudo-progression-remission pattern that occurs following PD-1 antibody treatment. These findings suggest that hydrogen may have an inhibitory effect on PD-1 expression.
Discussion
The treatment for gallbladder cancer is difficult, primarily due to the development of early intrahepatic and hepatic metastases.8 There is no evidence that minimally invasive ablation and chemotherapy can be used to obtain survival gains.9 In this patient, intrahepatic and hepatic portal metastases were present at the time of diagnosis. Although irreversible electroporation ablation and chemotherapy were performed, the lesion progressed further after nine months, invading the duodenum and appearing around the head of the pancreas. Multiple lymph node metastases involving the inferior vena cava was indicative of metastatic cancer (T4N1aM0). In addition to the patient’s original rheumatic heart disease with mitral valve replacement, the patient was 72 years old with diabetes (fasting blood glucose up to 22 mmol/L) and severe anemia (hemoglobin only 37 g/L), making it impossible for her to receive routine anti-tumor treatments.
The patient’s disease status changed following hydrogen inhalation. One month after hydrogen therapy, the patient’s general condition and blood parameters (including total protein, albumin, red blood cell count, and hemoglobin levels) gradually improved. After two and a half months of therapy, her duodenal obstruction was relieved and subsequently disappeared, the gastric tube was removed, the level of tumor marker expression began to decline, the CT examination showed that the tumors in the gallbladder and liver had gradually reduced, and the PS score was significantly improved. The patient has undergone hydrogen treatment for 10 months to date, and her condition has further improved. However, in this case, although the symptoms and systemic conditions improved within one month of hydrogen inhalation, the tumor size and tumor marker expression increased and subsequently decreased following continued treatment. Clearly, the initial changes observed regarding the tumors and associated markers are false indicators of progression. Moreover, these findings are highly similar to the pseudo-remission-response patterns that occur during immunotherapy with PD-1 inhibitors.10,11
Pseudo-progression refers to an increase in the original lesions at the beginning of treatment or the emergence of new lesions, which is reduced following continued treatment. This response appears to be “exclusive” to anti-PD-1/PD-L1 immunotherapy, first observed in melanoma patients,12,13 and has subsequently been reported in other cancers.14,15 The mechanism for this phenomenon may be that during immunotherapy, immunocytes (i.e., cytotoxic T cells) infiltrate the tumor, causing edema and necrosis.16
PD-1 is a typical marker of senescent apoptotic CD8+ T cells.17,18 Recent studies have shown that hydrogen can inhibit the expression of PD-1 on T cells in vivo. Moreover, Akagi et al.7 reported that after the hydrogen treatment of 55 patients with stage IV colorectal cancer, PD-1+CD8+ T cells decreased and PD-1−CD8+ T cells increased in the peripheral blood. As the hydrogen inhalation time increases, the ratio of the two cells is further reduced. Additionally, the greater the reduction in PD-1+CD8+ T cells, the longer the progression-free survival and overall survival of the patients. Indeed, this study showed that hydrogen therapy restored exhausted CD8+ T cell activity by inhibiting PD-1 expression. We observed a similar phenomenon in this case, which supports the evidence that hydrogen therapy may exhibit an effect similar to the pseudo-progression phenomenon observed following anti-PD-1 treatment.
It has been found that an increased number of CD8+ T cells expressing PD-1 in the peripheral blood of cancer patients represents a serious prognostic marker.19 In addition, PD-1+CD8+ T cells are functionally exhausted and have lost their anti-tumor functionality.20,21 Further studies have found that mitochondrial dysfunction results in an insufficient energy supply to such T cells, which leads to functional impairment.22 Hydrogen can stimulate peroxisome proliferator-activated receptor gamma cofactor 1 alpha (PGC1α),23,24 which positively regulates several metabolic processes, including mitochondrial biosynthesis, respiration, adaptive caloric production, and gluconeogenesis,25 thereby enhancing and improving mitochondrial activity and exerting immunomodulatory effects.
Conclusion
Here, we reported a case of progressive gallbladder cancer that received only hydrogen inhalation therapy in addition to symptomatic treatment. Pseudo-progression and subsequent remission after hydrogen inhalation exhibited a similar response pattern following anti-PD-1 immunotherapy. We found a significant decrease in the proportion of exhausted CD8+PD-1+ T cells by immunological function tests before and after hydrogen inhalation, which suggests that hydrogen can revitalize senescent apoptotic CD8+ T cells through mitochondrial rescue. However, the process of tumor killing and shrinking may induce pseudo-progression. The potential clinical use of this therapy still needs validation with additional large-scale trials.
Published online 2019 Oct 18. doi: 10.2147/OTT.S227217PMCID: PMC6804672PMID: 31695424A Gallbladder Carcinoma Patient With Pseudo-Progressive Remission After Hydrogen Inhalation