Nivolumab rechallenge after severe immune hepatitis in a metastatic renal cell cancer patient with hepatitis B and no detectable primary

Renal cell carcinoma (RCC) is an aggressive tumor with high metastatic potential and most of cases are determined incidentally on radiologic imaging. Metastatic RCC (mRCC) without a primary is very rare, and only a small number of cases have been reported in the literature. In recent years, immune checkpoint inhibitors have been used to treat mRCC, but they are associated with immune-related adverse events. Immune hepatitis is rare and usually observed within three months of initiation of therapy. Patients with hepatitis B virus (HBV) infection have generally been excluded from immunotherapy trials, although a small number of reports and retrospective studies exist on the use of immunotherapy in patients with HBV infection. A 59-year-old man was diagnosed with mRCC with adrenal and liver metastases and vena cava inferior thrombosis but without evidence of a primary. Second-line therapy with nivolumab achieved a good clinical response, but grade IV immune-related hepatitis was observed after one year. He also had an occult HBV infection. However, HBV reactivation did not occur with continuous entecavir prophylaxis. The hepatitis gradually resolved within two months without any management, and the patient was rechallenged with nivolumab. Metastatic RCC rarely presents without a primary mass in the kidney. In such cases, histologic and immunohistochemical characteristics are critical. Nivolumab-induced immune hepatitis may occur as late as one year after initiation of therapy. Rechallenge of immunotherapy may be considered in selected patients. HBV infection is not a contraindication for immunotherapy, these patients can be treated safely with frequent monitoring and antiviral prophylaxis

Clinical analysis of immunotherapy rechallenge in advanced gastric cancer / 中华肿瘤杂志

Objective: To evaluate the efficacy and influencing factors of programmed death protein 1 (PD-1) monoclonal antibody rechallenge therapy in advanced gastric cancer (GC). Methods: The clinical data of patients with advanced GC who were treated with anti-PD-1 rechallenge in Henan Cancer Hospital from January 2020 to December 2021 were collected retrospectively. The progression-free survival (PFS) was defined as the time from the first or second used of anti-PD-1 treatment to the date of disease progression or the last follow-up, named PFS(1) and PFS(2), respectively. Kaplan-Meier method and Log rank test were used for survival analysis, Cox proportional hazard model was used to analyze the influencing factors. Results: A total of 60 patients with anti-PD-1 rechallenge therapy were collected, the median follow-up time was 12.2 months. The median progression-free survival (PFS(2)) of anti-PD-1 rechallenge therapy was 2.9 months, the objective response rate (ORR) was 16.7%, and the disease control rate (DCR) was 55.0%. The median PFS(2) of the first and second anti-PD-1 identical and different rechallenge treatment was 3.5 months and 1.9 months (P=0.007) respectively. The median PFS(2) of positive PD-L1 expression in rechallenge therapy was 3.4 months, ORR was 22.7%, and DCR was 63.6%; the median PFS(2) was 4.5 months, ORR was 27.3%, and DCR was 54.5% in patients with median PFS(1)≥6 months. Multivariate analysis showed that peritoneal metastasis was independently associated with anti-PD-1 rechallenge therapy with PFS(2) (HR=2.327, 95% CI, 1.066-5.082, P=0.034). The incidence of adverse reactions in grade 1-2 and grade 3-4 of anti-PD-1 rechallenge therapy was 83.3%, and 35.0%, respectively, and the safety was controllable. Conclusion: Rechallenge therapy with anti-PD-1 is a feasible treatment in advanced GC, but the screening of suitable population for rechallenge therapy still needs prospective data analysis and verification.

Abiraterone acetate rechallenge for mCRPC patients with AR mutant / 中华泌尿外科杂志

A 75-year-old patient was admitted with "progressive dysuria for more than 2 months" in January 2017. The tPSA level was 498 ng/ml and then diagnosed as metastatic prostate cancer (cT 3bN xM 1). For the resistance of abiraterone, gene mutation was detected during the endocrine therapy. After 5 months of endocrine therapy, the serum tPSA was decreased to a minimum of 12.5 ng/ml. Since July, the serum PSA level gradually rebounded, and the endocrine therapy was altered to androgen deprivation therapy (ADT). The level of tPSA was maintained at 104 ng/ml in October 2017, and ADT was discontinued. After 1 year of discontinuation, the re-examination of PSA was 3 205 ng/ml. As the first-line regimen for mCRPC, abiratone and prednisone combined with goserelin was used. After 5 months of treatment, the level of tPSA still showed progression. The drug resistance of abiraterone was considered, so the treatment was discontinued. Next-generation sequencing technology (NGS) revealed the presence of AR, FGFR3 and RIT1 mutations, while no HRR germline mutation was detected. Docetaxel combined with ADT was performed. It was changed to comprehensive treatment of goserelin + docetaxel in March 2019. During chemotherapy CT images indicated significant reduction of pelvic lymph nodes and left inguinal lymph nodes, while bone metastasis showed stable condition. In April 2020, the chemotherapy was terminated for the lower extremity edema, joint pain and other related discomfort. The level of tPSA was 289 ng/ml after the last chemotherapy. DNA sequencing testing were performed again, and the mutation of AR and AR-V7 was negative. According to the results of genetic testing, the tPSA continued to decrease to 23 ng/ml after 6 months of abiraterone rechallenge, the imagings suggested that no disease progression. After AR mutation turns negative after chemotherapy, patients with refractory CRPC can still obtain a good PSA response such as tumor control and other clinical benefits from abiraterone. Abiraterone rechallenge is probably a new attempt for AR mutant patients with refractory CRPC.

Management and outcome of hypersensitivity reactions to oxaliplatin: A real-word study in a single center / 中国肿瘤临床

Objective: To review the clinical characteristics of patients with hypersensitivity to oxaliplatin, symptom management, and treatment outcomes to guide further treatment. Methods: From January 2015 to December 2017, 62 cases of hypersensitivity reactions to oxaliplatin were reported to the National Center for Adverse Drug Reaction(ADR) Monitoring in the Daycare Center of Peking University Cancer Hospital & Institute. The hypersensitivity reactions were classified into standard infusion-related reactions and anaphylaxis in accordance with international standards. The clinical data, treatment information, and outcomes of these patients were retrospectively collected and analyzed. Results: The mean age of the 62 patients was (52.9±11.3) years, the male-to-female radio was 1.07:1, and 59.7% (37/62) of patients received premedication with glucocorticoids before oxaliplatin. The median onset time was 6 (interquartile range 4-7.25) cycles with a median cumulative dose of 456.9 (263.5-651.0) mg/m2. Of the 62 patients, 19 (30.6%) patients had an oxaliplatin-free interval, 41 (66.1%) patients were diagnosed with a standard infusion-related reaction, and 21 (33.9%) patients were diagnosed with anaphylaxis based on clinical criteria. The medication was suspended for all patients and the infusion set was replaced. No patient received epinephrine for symptom management. All patients recovered completely; no deaths were reported. In addition, 58.6% (17/29) of patients with grade 2 standard infusion-related reactions who need further treatment were subsequently rechallenged with oxaliplatin, 70.6% (12/17) showed no symptoms of hypersensitivity. Conclusions: Premedication before oxaliplatin was not sufficient and the management of hypersensitivity was not standardized; therefore, the first-line usage of epinephrine should be performed with caution. Most cases of moderate hypersensitivity for soxaliplatin can be rechallenged successfully.

A prospective study on treatment of recurrent epithelial ovarian cancer with gemcitabine and pegylated liposomal doxorubicin

Background: Rechallenge of a platinum-based chemotherapy is the most common approach for a recurrent platinumsensitive epithelial carcinoma ovary. However, this carries a substantial risk of cumulative neurotoxicity. Objectives: In the present study, we tried to compare the efficacy and toxicities of gemcitabine pegylated liposomal doxorubicin combination regimen to rechallenge of paclitaxel-carboplatin in this setting. Materials and Methods: A total of 30 patients were included in the study. The patients were randomized into two groups each containing 15 patients. The study group received injection gemcitabine at the dose of 1 g/m2 injection intravenously on day 1 and day 8 and liposomal doxorubicin 30 mg/m2 on day 1 in a 3 weekly cycle up to a total of six cycles in absence of disease progression or unacceptable toxicities. The control group patients were treated with injection paclitaxel at a dose of 175 mg/m2 I/V infusion and injection carboplatin at a dose considering area under the curve 6 in a 3 weekly for six cycles. Results: In the study arm, out of 14 patients, 4 (28.57%) patients had complete response, 6 (42.85%) had partial response, 3 (21.42%) had stable disease, and 1 (7.14%) showed disease progression. In the control arm, 6 (40%) patients out of 15 showed complete response, and 4 (26.66%) partial response. Disease progression was noted in 1 (6.66%) patient. There was less incidence of neurotoxicity compared to the control arm. Conclusion: Chemotherapy with a combination of gemcitabine and pegylated liposomal doxorubicin shows equivalent efficacy in platinum-sensitive recurrent ovarian cancer when compared to rechallenge of platinum-based chemotherapy. The regimen has an acceptable toxicity profile with lesser incidence of neuropathy than rechallenge of paclitaxel-carboplatin combination.

A Case Report on Successful Third Challenge to the Pemetrexed-based Regimen for Advanced Non-small Cell Lung Cancer / 中国肺癌杂志

Non-small cell lung cancer (NSCLC) accounts for about 85% of lung cancer, with a 5-year survival rate of less than 15%-19%, and more than 80% of the patients with lung cancer have progressed to advanced stage (Stage IIIb-IV) when they are clearly diagnosed. The comprehensive treatment mainly based on chemotherapy as the primary form is now considered as the major therapy method for advanced NSCLC without actionable driver gene mutations. Pemetrexed plus platinum doublet as well as single-agent pemetrexed are respectively the first-line major regimens recommended by guidelines and the second-line optional regimens. Yet the third-line treatment or beyond in advanced NSCLC is not evidence-based but conducted based on patients' previous medications, which is one of the most commonly used clinical methods. As pemetrexed is a multi-target chemotherapy drug with high efficiency but low toxicity, pemetrexed re-challenge strategy in advanced NSCLC is also a reasonable choice. We report one effective individual case that adopted pemetrexed re-challenge strategy in advanced NSCLC for three times, and at the same time conduct the relevant literature review.

Nocebo effect in dermatology.

Nocebo effect, originally denoting the negative counterpart of the placebo phenomenon, is now better defined as the occurrence of adverse effects to a therapeutic intervention because the patient expects them to develop. More commonly encountered in patients with a past negative experience, this effect stems from highly active processes in the central nervous system, mediated by specifi c neurotransmitters and modulated by psychological mechanisms such as expectation and conditioning. The magnitude of nocebo effect in clinical medicine is being increasingly appreciated and its relevance encompasses clinical trials as well as clinical practice. Although there is hardly any reference to the term nocebo in dermatology articles, the phenomenon is encountered routinely by dermatologists. Dermatology patients are more susceptible to nocebo responses owing to the psychological concern from visibility of skin lesions and the chronicity, unpredictable course, lack of ‘permanent cure’ and frequent relapses of skin disorders. While fi nasteride remains the prototypical drug that displays a prominent nocebo effect in dermatologic therapeutics, other drugs such as isotretinoin are also likely inducers. This peculiar phenomenon has recently been appreciated in the modulation of itch perception and in controlled drug provocation tests in patients with a history of adverse drug reactions. Considering the confl ict between patients’ right to information about treatment related adverse effects and the likelihood of nocebo effect stemming from information disclosure, the prospect of ethically minimizing nocebo effect remains daunting. In this article, we review the concept of nocebo effect, its postulated mechanism, relevance in clinical dermatology and techniques to prevent it from becoming a barrier to effective patient management.

Clozapine Re-Challenge With Lithium Supplementation Following Clozapine-Induced Neutropenia

Objectives: This paper aims to report on a case in which re-challenging with clozapine in combination with lithium in a patient who developed neutropenia was carried out. Methods: The patient was treated with clozapine for treatmentresistant schizophrenia. After five weeks he showed much improvement but developed neutropenia. Withdrawal of clozapine brought on a relapse of psychotic symptoms. Subsequently, clozapine was reintroduced along with Lithium. The neutrophil count was monitored closely. Results: The neutrophil and white blood cell count were noted to return to normal upon re-challenging, and the patient’s clinical condition also improved. Conclusion: Simultaneous administration of lithium and clozapine to patients experiencing neutropenia on clozapine is a possible strategy. However, very close monitoring of the white count is needed.

Adverse Effects of Antituberculosis Drugs and the Solutions

The principle of antituberculosis therapy is to apply a combination regimen of at least two bactericidal drugs to which the bacteria are susceptible for sufficient duration, thus improving the efficacy of the therapy and preventing the development of resistant strains. If a certain side effect develops during the therapeutic trial, the next step includes identifying the causative drug, estimating the type and magnitude of the side effect, and finally deciding whether the regimen should be discontinued. In a clinical setting, however, these decisions cannot be made easily. Many antituberculosis drugs causes similar side effects, and even if the causative drug is identified, the decision to discontinue the drug must be based on its relative importance in the current antituberculosis regimen. Effective application of antituberculosis medication requires the physician to fully understand what adverse effects each drug is associated with, which side effect necessitates withdrawal of the drug, and how to rechallenge the drug with side effects when it is absolutely required in the regimen.