Pituitary immune-related adverse events induced by programmed cell death protein 1 inhibitors in advanced lung cancer patients: A report of 3 cases / 北京大学学报(医学版)

Pituitary immune-related adverse events induced by programmed cell death protein 1 inhibitors in advanced lung cancer patients: A report of 3 cases SUMMARY Programmed cell death protein 1 (PD-1) and its ligand 1 (PD-L1) have been widely used in lung cancer treatment, but their immune-related adverse events (irAEs) require intensive attention. Pituitary irAEs, including hypophysitis and hypopituitarism, are commonly induced by cytotoxic T lymphocyte antigen 4 inhibitors, but rarely by PD-1/PD-L1 inhibitors. Isolated adrenocorticotropic hormone(ACTH) deficiency (IAD) is a special subtype of pituitary irAEs, without any other pituitary hormone dysfunction, and with no enlargement of pituitary gland, either. Here, we described three patients with advanced lung cancer who developed IAD and other irAEs, after PD-1 inhibitor treatment. Case 1 was a 68-year-old male diagnosed with metastatic lung adenocarcinoma with high expression of PD-L1. He was treated with pembrolizumab monotherapy, and developed immune-related hepatitis, which was cured by high-dose methylprednisolone [0.5-1.0 mg/(kg·d)]. Eleven months later, the patient was diagnosed with primary gastric adenocarcinoma, and was treated with apatinib, in addition to pembrolizumab. After 17 doses of pembrolizumab, he developed severe nausea and asthenia, when methylprednisolone had been stopped for 10 months. His blood tests showed severe hyponatremia (121 mmol/L, reference 137-147 mmol/L, the same below), low levels of 8:00 a.m. cortisol (< 1 μg/dL, reference 5-25 μg/dL, the same below) and ACTH (2.2 ng/L, reference 7.2-63.3 ng/L, the same below), and normal thyroid function, sex hormone and prolactin. Meanwhile, both his lung cancer and gastric cancer remained under good control. Case 2 was a 66-year-old male with metastatic lung adenocarcinoma, who was treated with a new PD-1 inhibitor, HX008, combined with chemotherapy (clinical trial number: CTR20202387). After 5 months of treatment (7 doses in total), his cancer exhibited partial response, but his nausea and vomiting suddenly exacerbated, with mild dyspnea and weakness in his lower limbs. His blood tests showed mild hyponatremia (135 mmol/L), low levels of 8:00 a.m. cortisol (4.3 μg/dL) and ACTH (1.5 ng/L), and normal thyroid function. His thoracic computed tomography revealed moderate immune-related pneumonitis simultaneously. Case 3 was a 63-year-old male with locally advanced squamous cell carcinoma. He was treated with first-line sintilimab combined with chemotherapy, which resulted in partial response, with mild immune-related rash. His cancer progressed after 5 cycles of treatment, and sintilimab was discontinued. Six months later, he developed asymptomatic hypoadrenocorticism, with low level of cortisol (1.5 μg/dL) at 8:00 a.m. and unresponsive ACTH (8.0 ng/L). After being rechallenged with another PD-1 inhibitor, teslelizumab, combined with chemotherapy, he had pulmonary infection, persistent low-grade fever, moderate asthenia, and severe hyponatremia (116 mmol/L). Meanwhile, his blood levels of 8:00 a.m. cortisol and ACTH were 3.1 μg/dL and 7.2 ng/L, respectively, with normal thyroid function, sex hormone and prolactin. All of the three patients had no headache or visual disturbance. Their pituitary magnetic resonance image showed no pituitary enlargement or stalk thickening, and no dynamic changes. They were all on hormone replacement therapy (HRT) with prednisone (2.5-5.0 mg/d), and resumed the PD-1 inhibitor treatment when symptoms relieved. In particular, Case 2 started with high-dose prednisone [1 mg/(kg·d)] because of simultaneous immune-related pneumonitis, and then tapered it to the HRT dose. His cortisol and ACTH levels returned to and stayed normal. However, the other two patients' hypopituitarism did not recover. In summary, these cases demonstrated that the pituitary irAEs induced by PD-1 inhibitors could present as IAD, with a large time span of onset, non-specific clinical presentation, and different recovery patterns. Clinicians should monitor patients' pituitary hormone regularly, during and at least 6 months after PD-1 inhibitor treatment, especially in patients with good oncological response to the treatment.

Immune checkpoint inhibitors induced pituitary immune-related adverse events: diagnosis and management / 中华肿瘤杂志

Immune checkpoint inhibitors (ICIs) have been used in treating a wide variety of cancers, but they challenge clinicians with a series of special immune related adverse events (irAEs) resulting from activated immune system. Since June 2018, when the first programmed cell death 1 (PD-1) inhibitor, nivolumab, was approved by the National Medical Products Administration (NMPA), abundant experience has been accumulated in coping with irAEs from PD-1 and PD-1 ligand 1 (PD-L1) blockade therapies. In October 2021, the first CTLA-4 inhibitor, ipilimumab, which has a different spectrum of irAEs was also approved by NMPA. The discrepancy in clinical features of pituitary irAEs is obvious between these two types of ICIs. Pituitary irAEs include hypophysitis and hypopituitarism. In this review of latest literature, we have summarized the incidence, possible mechanisms, time of onset, clinical presentations, hormone test, pituitary imaging, treatment strategies and recovery patterns of pituitary irAEs. By referring to domestic and foreign clinical guidelines, we have proposed practical suggestions for screening, diagnosing and treating pituitary irAEs.

The role of expression of Nrf2 in predicting chemoresistance and prognosis in advanced non-small cell lung cancer receiving platinum-based first-line chemotherapy / 肿瘤

Objective: To examine the expression of Nrf2 (nuclear factor erythroid 2-related factor 2) protein in patients with NSCLC (advanced non-small cell lung cancer), and to elucidate the correlation of the expression level of Nrf2 with response to platinum-based first-line chemotherapy and the prognosis of NSCLC patients. Methods: This retrospective study enrolled 50 patients with chemotherapynaïve advanced NSCLC. All patients received platinum-based regimens as first-line chemotherapy. The expression level of Nrf2 protein in tumor specimens was detected by immunohistochemical analysis. The associations between Nrf2 expression with response to chemotherapy and the prognosis were analyzed by SPSS 17.0 statistical software. Results: The Nrf2 protein expression level in NSCLC patients exhibited interindividual differences and the positive rate was 34% (17/50). The positive-expression rate of Nrf2 was higher in patients with age ≥ 70 years (58.3%, 7/12) than that in patients with age < 70 years (26.3%, 10/38) (P = 0.041), which was also higher in patients with distant metastasis (46.7%, 14/30) than that in patients without metastasis (15.0%, 3/20) (P = 0.021). The expression of Nrf2 was correlated with age (r = 0.370, P = 0.020), distant metastasis (r = 0.289, P = 0.042), response to platinum-based chemotherapy (r = 0.315 P = 0.026), progression-free survival (r = -0.393, P = 0.006) and overall survival (r = -0.309, P = 0.029). Furthermore, the expression of Nrf2 was an independent predictive factor for response to platinum-based first-line chemotherapy and progression-free survival (P < 0.05). Conclusion: Nrf2 expression is an independent predictor of response to platinum-based first-line chemotherapy and the prognosis of patients with advanced NSCLC, and it may be helpful to select the appropriate chemotherapy regimen for advanced NSCLC. Copyright © 2012 by TUMOR.

Association analysis of the expression level of Nrf2 mRNA in peripheral blood nucleated cells and the severity of chemotherapy-induced myelosuppression / 肿瘤

Objective: To investigate the interindividual variation of nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA expression level in the peripheral blood nucleated cells and its correlation with the severity of chemotherapy-induced myelosuppression. Methods: The expression level of Nrf2 mRNA in the peripheral blood nucleated cells from 30 cases of cancer was detected by semi-quantitative RT-PCR before chemotherapy, and the association between the Nrf2 mRNA expression and the chemotherapyinduced myelosuppression was analyzed. Results: The Nrf2 mRNA expression level in the peripheral blood mononuclear cells exhibited significant interindividual differences. The Nrf2 mRNA expression level was significantly higher in the patients with grades 0-1 leukopenia or neutropenia than that in the patients with grades 2-4 (P <0.05), but it was not associated with the age, gender, chemotherapeutic regimen and the type of tumor. The association analysis showed that the Nrf2 mRNA expression level in the peripheral blood mononuclear cells was negatively associated with leukopenia and neutropenia (r = -0.448, P = 0.013; r = -0.493, P = 0.006). Conclusion: The expression level of Nrf2 mRNA in the peripheral blood mononuclear cells is significantly correlated with chemotherapy-induced myelosuppression. It may be employed as an ideal marker to predict the severity of chemotherapy-induced myelosuppression and helpful for clinical decision-making and early prevention and treatment of myelosuppression. Copyright © 2012 by TUMOR.

A clinical study on multi-disciplinary team and surgery for resectable colorectal cancer with liver metastases / 中华外科杂志

<p><b>OBJECTIVES</b>To analyze the survival outcomes of the surgery for colorectal cancer with liver metastases (CRCLM), and study the mode of multi-disciplinary team (MDT) for CRCLM.</p><p><b>METHODS</b>The retrospective analysis was conducted for 38 patients with CRCLM received MDT management and surgical treatment from January 2009 to August 2011. The peri-operative and survival outcomes of MDT and surgery were evaluated.</p><p><b>RESULTS</b>All the cases met the present criteria of resetability for CRCLM, but only 4 cases (10.5%) met the previous one. Coloproctectomy and hepatectomy were performed in all cases, with 39 colorectal neoplasms and 155 liver lesions removed. One case died of postoperative septic shock. Colorectal and hepatic specific complications were absent in the others patients except one case of biliary leak which was treated with conservative management. Neoadjuvant chemotherapy was arranged in 13 cases. Adjuvant chemotherapy was administered for every patient. After a mean follow-up of (22 ± 10) months according to the finding time of liver metastases, recurrence and metastases were observed in 16 cases and 6 cases died of late-stage cachexia. The 1-, 2- and 3-overall survival rate were 94.4%, 85.3% and 75.8% respectively, and the 1-, 2- and 3-disease-free survival rate were 70.1%, 54.2% and 54.2% respectively.</p><p><b>CONCLUSIONS</b>MDT mode for resectable CRCLM is recommendable. Surgical resection of CRCLM is feasible and safe, which seems to achieve favourable short-middle oncologic outcomes. And long-term survival is expected.</p>

Observation and clinical significance of adjuvant chemotherapy-induced amenorrhea in premenopausal breast cancer patients / 中华肿瘤杂志

<p><b>OBJECTIVE</b>A retrospective analysis of 160 pre-menopausal breast cancer patients was carried out to elucidate the the menstrual outcome in those cases who had undergone adjuvant chemotherapy after surgery, and evaluate the relationship between chemotherapy-induced amenorrhea (CIA) and recurrence of the disease.</p><p><b>METHODS</b>160 pre-menopausal breast cancer patients were collected, 62/159 (39.0%) of them were node positive, 91/158 (57.6%) were ER positive, and 95/155 (61.3%) were PR positive. 111 cases had infiltrative ductal carcinoma, 26 cases had infiltrative lobular carcinoma, and 22 cases with others. In 152 cases data were collected by face-to-face interview and 8 cases by phone conversation. Types and cycles of chemotherapy regimen as well as menstrual abnormalities were recorded before, during, and after chemotherapy completion. Follow up duration was 12-72 months after chemotherapy completion for all patients.</p><p><b>RESULTS</b>107 (66.9%) developed CIA, 24 cases returned to normal menses (22.4%), 83 cases continued CIA during more than 12-month follow up (77.6%). The rate of CIA increased with age (P < 0.01). During the follow up, disease free survival (DFS) rate was 85.9% in CIA group and 79.2% in non-CIA group, with no statistically significant difference. But in hormonal receptor positive patients, DFS was 80.0% in non-CIA and 90.1% in CIA, respectively (P = 0.04), showing a significant difference. Because of the small number of died cases, no analysis of the overall outcome was carried out.</p><p><b>CONCLUSION</b>Adjuvant chemotherapy causes ovarian function suppression, and may further leading to amenorrhoea. Women who experienced amenorrhoea after chemotherapy had a significantly better disease-free survival (DFS) rate showed by univariate analysis than women who continued normal menstruation. Chemotherapy is insufficient therapy for very young patients who are in high risk with hormone responsive disease, particularly when chemotherapy fails to induce amenorrhea. Further research is needed to evaluate interventional chemotherapy to improve the quality of life in women with early stage breast cancer who experienced ovarian toxicity. The post-chemotherapy menstruation status is a clinically valuable, objective and salient marker for sufficient endocrine effect of chemotherapy in ER/PR-positive premenopausal patients.</p>