Rechallenge of immune checkpoint inhibitors in advanced non-small cell lung cancer.

Immune checkpoint inhibitor (ICI) rechallenge in non-small cell lung cancer (NSCLC) is a promising therapeutic strategy. The situation for ICI rechallenge can be divided into three categories: adverse events (AEs); resistance to ICIs, and rechallenge becomes compulsive because of tumor relapse while the patients had completed a 2 year course of immunotherapy. However, these categories are still controversial and should be explored further. Through voting at the 6th Straits Summit Forum on Lung Cancer, in this study we summarize the consensus of 147 experts in ICI rechallenges. A total of 97.74% experts agreed to rechallenge; 48.87% experts rechallenge with the original drug, and the others rechallenge with a different drug; 40.3% agreed to rechallenge directly after progression; 88.06% experts agreed to ICI rechallenge with a combination regimen; and factors such as previous performance status score, PD-1 expression, and age should also be considered. Understanding the the clinical studies in ICI rechallenge could bring us one step closer to understanding the consensus. In patients with advanced NSCLC who have suffered recurrent or distant metastasis after immunotherapy, the option of rechallenge with ICIs is a promising treatment option.

[The efficacy of chemotherapy re-challenge in third-line setting for metastatic colorectal cancer patients: a real-world study].

Objective: To explore the efficacy of chemotherapy re-challenge in the third-line setting for patients with metastatic colorectal cancer (mCRC) in the real world. Methods: The clinicopathological data, treatment information, recent treatment efficacy, adverse events and survival data of mCRC patients who had disease progression after treatment with oxaliplatin-based and/or irinotecan-based chemotherapy and received third-line chemotherapy re-challenge from January 2013 to December 2020 at Tianjin Medical University Cancer Institute and Hospital were retrospectively collected. Survival curves were plotted with the Kaplan-Meier method, and the Cox proportional hazard model was used to analyze the prognostic factors. Results: A total of 95 mCRC patients were included. Among them, 32 patients (33.7%) received chemotherapy alone and 63 patients (66.3%) received chemotherapy combined with targeted drugs. Eighty-three patients were treated with dual-drug chemotherapy (87.4%), including oxaliplatin re-challenge in 35 patients and irinotecan re-challenge in 48 patients. The remaining 12 patients were treated with triplet chemotherapy regimens (12.6%). Among them, as 5 patients had sequential application of oxaliplatin and irinotecan in front-line treatments, their third-line therapy re-challenged both oxaliplatin and irinotecan; 7 patients only had oxaliplatin prescription before, and these patients re-challenged oxaliplatin in the third-line treatment. The overall response rate (ORR) and disease control rate (DCR) reached 8.6% (8/93) and 61.3% (57/93), respectively. The median progression free survival (mPFS) and median overall survival (mOS) were 4.9 months and 13.0 months, respectively. The most common adverse events were leukopenia (34.7%) and neutropenia (34.7%), followed by gastrointestinal adverse reactions such as nausea (32.6%) and vomiting (31.6%). Grade 3-4 adverse events were mostly hematological toxicity. Cox multivariate analysis showed that gender (HR=1.609, 95% CI: 1.016-2.548) and the PFS of front-line treatments (HR=0.598, 95% CI: 0.378-0.947) were independent prognostic factors. Conclusion: The results suggested that it is safe and effective for mCRC patients to choose third-line chemotherapy re-challenge, especially for patients with a PFS of more than one year in front-line treatments.

Second to none: rationale, timing, and clinical management of clozapine use in schizophrenia.

Despite its enduring relevance as the single most effective and important evidence-based treatment for schizophrenia, underutilization of clozapine remains considerable. To a substantial degree, this is attributable to a reluctance of psychiatrists to offer clozapine due to its relatively large side-effect burden and the complexity of its use. This underscores the necessity for continued education regarding both the vital nature and the intricacies of clozapine treatment. This narrative review summarizes all clinically relevant areas of evidence, which support clozapine's wide-ranging superior efficacy - for treatment-resistant schizophrenia (TRS) and beyond - and make its safe use eminently feasible. Converging evidence indicates that TRS constitutes a distinct albeit heterogeneous subgroup of schizophrenias primarily responsive to clozapine. Most importantly, the predominantly early onset of treatment resistance and the considerable decline in response rates associated with its delayed initiation make clozapine an essential treatment option throughout the course of illness, beginning with the first psychotic episode. To maximize patients' benefits, systematic early recognition efforts based on stringent use of TRS criteria, a timely offer of clozapine, thorough side-effect screening and management as well as consistent use of therapeutic drug monitoring and established augmentation strategies for suboptimal responders are crucial. To minimize permanent all-cause discontinuation, re-challenges after neutropenia or myocarditis should be considered. Owing to clozapine's unique efficacy, comorbid conditions including substance use and most somatic disorders should not dissuade but rather encourage clinicians to consider clozapine. Moreover, treatment decisions need to be informed by the late onset of clozapine's full effects, which for reduced suicidality and mortality rates may not even be readily apparent. Overall, the singular extent of its efficacy combined with the high level of patient satisfaction continues to distinguish clozapine from all other available antipsychotics.

Re-challenge of immune checkpoint inhibitor pembrolizumab with concurrent tocilizumab after prior grade 3 pneumonitis.

Immune checkpoint inhibitors (ICIs) are associated with specific immune-related adverse events (irAEs) which are unique compared to cytotoxic chemotherapy. For life-threatening adverse events including grade 3 or more, permanent discontinuation of the ICIs is recommended, albeit without much robust evidence. Safe re-challenge of ICIs with concurrent immunosuppression has been reported with irAEs like gastrointestinal toxicity and arthritis. Here we present a case of a lady with undifferentiated pleomorphic sarcoma with programmed death ligand1 expression, who showed a complete response to pembrolizumab used as third-line therapy. However, it had to be stopped after 22 doses when the patient developed grade 3 pneumonitis. In view of progression off pembrolizumab, and lack of other effective alternatives, pembrolizumab was re-challenged with concurrent interleukin-6 (IL-6) blockade using tocilizumab. This was based on preliminary evidence on the role of IL-6 in mediating the irAEs, especially pneumonitis. The patient re-attained a complete response with pembrolizumab. There was no recurrence of the pneumonitis after rechallenging, and there was partial radiographic resolution of the ICI-interstitial lung disease after the combination therapy.

Long-term survival in extensive-stage small-cell lung cancer treated with different immune checkpoint inhibitors in multiple-line therapies: A case report and literature review.

Background: Extensive-stage small-cell lung cancer (ES-SCLC) is highly malignant, is highly prone to recurrence, and has a short survival period. It is very difficult to achieve long-term survival in ES-SCLC, which has not been significantly improved in the last 20 years. For a long time, platinum-based chemotherapy has occupied the core position in the treatment of small-cell lung cancer (SCLC), but there are few options for treatment drugs or regimens, and if disease progression occurs, the options for follow-up regimens are obviously limited. The advent of immunotherapy has changed this situation to some extent, and immunotherapy has shown some effects in improving efficiency and prolonging survival, whether in first- or third-line therapy, but it is still unsatisfactory. Case presentation: A 57-year-old patient with ES-SCLC experienced disease progression after four lines of treatment including synchronous radiotherapy, chemotherapy, and antiangiogenesis. However, the patient still benefited when switching to the programmed cell death receptor-1 (PD-1) inhibitor toripalimab in combination with chemotherapy in the fifth line. Even after the development of immune resistance, the patient still benefited after switching to tislelizumab in combination with different chemotherapy regimens or alone in the sixth and seventh lines. Following the progression of tislelizumab in combination with chemotherapy, the patient again profited after switching to durvalumab in combination with anlotinib and again achieved a progressive-free survival (PFS) of 11 months. Overall, the patient achieved a total of 45 months of PFS and 50 months of overall survival (OS), with a shocking and exciting 30 months of PFS achieved in the immune combination phase alone. Conclusion: We report a patient with ES-SCLC who achieved long-term survival after at least eight lines of therapy including chemotherapy, antiangiogenesis, and different immune checkpoint inhibitors (ICIs). This suggests that long-term survival in SCLC is possible with aggressive, combined, and standardized treatment. Otherwise, immunotherapy postline enablement can still benefit patients, rechallenge after immune resistance is also possible in SCLC, and combination with chemotherapy or antiangiogenic therapy can improve the efficacy and prolong the survival. This will provide new ideas and options for the selection of treatment options for SCLC.

Spectrum of anti tubercular therapy induced cutaneous adverse drug reactions and its management through rechallenge: A prospective study at a Tertiary Care Centre.

INTRODUCTION: The use of multi-drug regimens including 1st and 2nd line anti tubercular drugs in management of tuberculosis (TB) has been associated with undesirable adverse drug reactions including cutaneous one. Re-challenge remains the only option to restart the safe therapy and combat the tuberculous infection simultaneously. MATERIALS AND METHODOLOGY: This cross-sectional study was conducted via prospective review of outpatients as well as indoor patients who presented with cutaneous adverse drug reactions to ATT between March 2020 and March 2021. Data were analysed regarding demographic profile, site of TB, ATT regimen, pattern of cutaneous lesions, offending drugs, past history of drug allergy, and reinstitution of ATT after re-challenge. RESULTS: Out of total 56 registered tubercular patients presented with cutaneous adverse drug reaction 30 were females (53.57%). The most common site of TB was pulmonary followed by cervical lymph node TB. The three most common adverse drug reaction detected were maculopapular rash 32 (57.1%) followed by lichenoid drug eruptions in 6 (10.7%) and urticaria in 2 (3.6%). Ethambutol was found to be common offending drug followed by other first line anti-tubercular drugs. 5 patients developed multiple drug hypersensitivity on re-challenging and have to introduce steroids along with ATT. CONCLUSION: Adverse cutaneous drug reactions to ATT is like a double-edged sword as stopping ATT and starting treatment with systemic steroids can further flare up the infection with increased risk of disseminated and multidrug resistant tuberculosis. Re-challenge was found out to be safest way in identifying culprit drug and hence to restart a safer alternate ATT regimen for better management.

Case report: A successful re-challenge report of GLS-010 (Zimberelimab), a novel fully humanized mAb to PD-1, in a case of recurrent endometrial cancer.

With the widespread use of immune checkpoint inhibitors (ICI), there is growing concern about reports of immune-related adverse events (irAE). In clinical practice, patients who experience severe toxicities by ICI-based therapies would require utmost caution in resuming ICI therapy because of the potential risk of serious irAEs caused by the reintroduction of immunotherapy. In this study, we report a case of recurrent endometrial cancer patient with PD-L1 positive as well as dMMR suffering from immunotherapy-associated myocarditis after first-line treatment with ICI combined with a multi-targeted anti-angiogenic agent. After symptomatic treatment, the patient was in complete remission from treatment toxicities. Subsequently, through MDT discussions, we selected a new PD-1 agent, zimberelimab, for rechallenge therapy, and the patient achieved a sustained disease remission without any treatment-related toxicities. To date, the manner and timing of the ICI re-challenge has been a subject of iterative deliberation. We believe that our experience could shed some light on ICI rechallenge therapy, and we look forward to more literatures to refine the ICI rechallenge scenarios.

Successful re-challenge of dabrafenib-trametinib combination therapy in advanced BRAF V600E-mutant non-small cell lung cancer after previous cytotoxic chemotherapy, targeted therapy, and immunotherapy: a case report.

Background: Patients with v-raf murine sarcoma viral oncogene homolog B1 (BRAF)V600E-mutant non-small cell lung cancer (NSCLC) benefit from treatment with a combination of BRAF and mitogen-activated protein kinase (MEK) inhibitors, but resistance and disease progression develop in most patients. Pre-clinical studies and case studies of melanoma indicate that acquired resistance to BRAF inhibition may be reversible. However, studies on the effects of dabrafenib-trametinib (D/T) re-challenge for relapse in NSCLC are limited. Case Description: A 58-year-old Chinese woman with a history of smoking and hypertension was diagnosed with stage IV B lung adenocarcinoma with metastasis. The targeted next-generation sequencing (NGS) of the patient's lung tumor biopsy tissues revealed the presence of a BRAF V600E mutation with an allele frequency (AF) of 30.54%. The patient was treated with cytotoxic chemotherapy (the 1st line), D/T targeted therapy (the 2nd line), and immune checkpoint inhibitor monotherapy (pembrolizumab, the 3rd line), all of which achieved a partial response (PR) that lasted for a total of 8 months. The 2nd NGS analysis of the lung tissue specimens revealed the presence of a BRAF V600E mutation (AF =18.41%) without mutations, which was potentially involved in the resistance to BRAF/MEK inhibition. At the 4th line, she subsequently re-challenged D/T, and achieved a 4th PR, lasting for 5 months. The 3rd NGS analysis revealed the retention of the BRAF V600E mutation (AF =0.39%). Her treatment was switched to pembrolizumab (the 5th line), and the disease remained stable for another 6 months as of the last follow-up in November 2021. She didn't experience any adverse events throughout the treatment. Conclusions: Our findings suggest that the re-challenge of D/T and immune checkpoint blockage therapies offer another therapeutic option for NSCLC patients with the BRAF V600E-mutant who have received extensive prior treatments. In addition, our advanced NSCLC patient with the BRAF V600E-mutant also derived long-term clinical benefits from initial chemotherapy, molecular-targeted therapy, and immunotherapy.

Pulmonary lesions following inoculation with the SARS-CoV-2 Omicron BA.1 (B.1.1.529) variant in Syrian golden hamsters.

The Omicron BA.1 (B.1.1.529) SARS-CoV-2 variant is characterized by a high number of mutations in the viral genome, associated with immune escape and increased viral spread. It remains unclear whether milder COVID-19 disease progression observed after infection with Omicron BA.1 in humans is due to reduced pathogenicity of the virus or due to pre-existing immunity from vaccination or previous infection. Here, we inoculated hamsters with Omicron BA.1 to evaluate pathogenicity and kinetics of viral shedding, compared to Delta (B.1.617.2) and to animals re-challenged with Omicron BA.1 after previous SARS-CoV-2 614G infection. Omicron BA.1 infected animals showed reduced clinical signs, pathological changes, and viral shedding, compared to Delta-infected animals, but still showed gross- and histopathological evidence of pneumonia. Pre-existing immunity reduced viral shedding and protected against pneumonia. Our data indicate that the observed decrease of disease severity is in part due to intrinsic properties of the Omicron BA.1 variant.

Honey bee venom re-challenge during specific immunotherapy: prolonged cardio-pulmonary resuscitation allowed survival in a case of near fatal anaphylaxis.

BACKGROUND: Specific immunotherapy for patients with honey bee hypersensitivity is commonly applied. Re-challenge with venom is performed to prove protection in individual cases. CASE PRESENATION: We report a case of near fatal anaphylaxis with asystole for 24 min in a 35-years-old patient with mastocytosis after honey bee sting challenge, despite 5-years of specific immunotherapy. Successful cardio-pulmonary resuscitation was applied for 32 min. CONCLUSION: This intervention demonstrates, that in anaphylaxis with cardio-vascular arrest, prolonged cardio-pulmonary resuscitation for up to 40 min may be appropriate to overcome the half-life of massively released histamine. Failure of specific immunotherapy was possibly due to sensitization to the allergen Api m10, potentially underrepresented in commercial honey bee venom extracts. Molecular analyses may provide additional clues to the potentially unsuccessful outcome of venom specific immunotherapy, especially in high-risk patients such as mastocytosis.

Changes in Neutrophil to Lymphocyte Ratio, Lymphocyte to Monocyte Ratio, and Platelet to Lymphocyte Ratio During Palliative Radiotherapy May Predict Efficacy of Immune Checkpoint Inhibitor as Re-Challenge Treatment in Advanced Gastric Cancer: A Case Report.

Introduction: Immunotherapy with programmed death-1 (PD-1) inhibitors has emerged as frontline option in patients with advanced or metastatic gastric cancer. However, two-thirds of patients who received PD-1 inhibitors treatment still had disease progression in 1 year. Subsequent treatment strategies as salvage options always lead to limited efficacy. Case Description: Herein, we presented a case of recurrent metastatic gastric adenocarcinoma that had progressed on first-line treatment with nivolumab, in which systematic inflammation parameters with neutrophil to lymphocyte ratio (NLR), lymphocyte to monocyte ratio (LMR), and platelet to lymphocyte ratio (PLR) were significantly changed by palliative radiotherapy on metastatic lymph nodes. The patient achieved persistent response to the re-challenge of immune checkpoint inhibitor, which resulted in survival time reaching 52 months, and is still in extension. Conclusions: We supposed that the palliative radiotherapy may lead to the correction of NLR, LMR, and PLR and finally contribute to the efficacy of the re-challenge treatment by PD-1 inhibitor.

Transition of the PD-1 occupancy of nivolumab on T cells after discontinuation and response of nivolumab re-challenge.

Although nivolumab is administered every two or four weeks, high programmed cell death-1 (PD-1) binding of nivolumab on T cells lasting for several months has been reported. A relationship between the PD-1 occupancy rate on T-cells and the efficacy of nivolumab is not yet fully understood. The present study used flow cytometric analyses to determine the time-dependence of PD-1 occupancy in five patients who discontinued nivolumab. The relationship between PD-1 occupancy at relapse and the efficacy of re-challenge was also studied. Occupancies after discontinuation were measured at a total of 32 points. The data indicated that it took 32.4 and 48.9 weeks to decrease occupancy by 50 and 70%, respectively. Subsequently, two patients had recurrence and were re-challenged with nivolumab. At that time, one patient had 70.8% occupancy while the other had 6.6%. Treatment was effective only for the patient with lower occupancy. Overall, the present study suggests that re-challenge with nivolumab may be efficacious in patients with low occupancy at recurrence.

The Price of Success: Immune-Related Adverse Events from Immunotherapy in Lung Cancer.

Cancer immunotherapy has the goal of enhancing a patient's intrinsic immune processes in order to mount a successful immune response against tumor cells. Cancer cells actively employ tactics to evade, delay, alter, or attenuate the anti-tumor immune response. Immune checkpoint inhibitors (ICIs) modulate endogenous regulatory immune mechanisms to enhance immune system activation, and have become the mainstay of therapy in many cancer types. This activation occurs broadly and as a result, activation is supraphysiologic and relatively non-specific, which can lead to immune-related adverse events (irAEs), the frequency of which depends on the patient, the cancer type, and the specific ICI antibody. Careful assessment of patients for irAEs through history taking, physical exam, and routine laboratory assessments are key to identifying irAEs at early stages, when they can potentially be managed more easily and before progressing to higher grades or more serious effects. Generally, most patients with low grade irAEs are eligible for re-challenge with ICIs, and the use of corticosteroids to address an irAE is not associated with poorer patient outcomes. This paper reviews immune checkpoint inhibitors (ICIs) including their mechanisms of action, usage, associated irAEs, and their management.

Successful treatment of metastatic bladder cancer by gemcitabine-cisplatin re-challenge after pembrolizumab.

INTRODUCTION: The advent of pembrolizumab has contributed to improved treatment outcomes for metastatic urothelial carcinoma, but the outcomes of treatments after second-line treatment have not been established. CASE PRESENTATION: A 72-year-old man was referred to our hospital with gross hematuria and diagnosed with suspicion of bladder cancer cT1N0M0. Transurethral resection of the bladder tumor was performed, but local recurrence and multiple lung metastases appeared 5 months after surgery. Although gemcitabine-cisplatin was performed as first-line chemotherapy, the local lesion increased, and pembrolizumab was used as a second-line treatment. Pembrolizumab was also ineffective; however, re-challenge with gemcitabine-cisplatin as third-line treatment produced a good therapeutic effect. CONCLUSION: We report a successful case in which gemcitabine-cisplatin re-challenge after pembrolizumab therapy was effective in metastatic bladder cancer. Re-administration of chemotherapy after immune checkpoint inhibitors may be a broadly effective treatment option.

A phase IIA extension study evaluating the effect of booster vaccination with a fractional dose of RTS,S/AS01E in a controlled human malaria infection challenge.

BACKGROUND: We previously demonstrated that RTS,S/AS01B and RTS,S/AS01E vaccination regimens including at least one delayed fractional dose can protect against Plasmodium falciparum malaria in a controlled human malaria infection (CHMI) model, and showed inferiority of a two-dose versus three-dose regimen. In this follow-on trial, we evaluated whether fractional booster vaccination extended or induced protection in previously protected (P-Fx) or non-protected (NP-Fx) participants. METHODS: 49 participants (P-Fx: 25; NP-Fx: 24) received a fractional (1/5th dose-volume) RTS,S/AS01E booster 12 months post-primary regimen. They underwent P. falciparum CHMI three weeks later and were then followed for six months for safety and immunogenicity. RESULTS: Overall vaccine efficacy against re-challenge was 53% (95% CI: 37-65%), and similar for P-Fx (52% [95% CI: 28-68%]) and NP-Fx (54% [95% CI: 29-70%]). Efficacy appeared unaffected by primary regimen or previous protection status. Anti-CS (repeat region) antibody geometric mean concentrations (GMCs) increased post-booster vaccination. GMCs were maintained over time in primary three-dose groups but declined in the two-dose group. Protection after re-challenge was associated with higher anti-CS antibody responses. The booster was well-tolerated. CONCLUSIONS: A fractional RTS,S/AS01E booster given one year after completion of a primary two- or three-dose RTS,S/AS01 delayed fractional dose regimen can extend or induce protection against CHMI. CLINICAL TRIAL REGISTRATION: NCT03824236. linked to this article can be found on the Research Data as well as Figshare https://figshare.com/s/ee025150f9d1ac739361.

The Outcome and Safety of Re-challenge Lutetium-177 PSMA (177Lu-PSMA) Therapy with Low-Dose Docetaxel as a Radiosensitizer-a Promising Combination in Metastatic Castrate-Resistant Prostate Cancer (mCRPC): a Case Report.

Prostate-specific membrane antigen (PSMA)-directed radioligand therapy (PSMA-RLT) with lutetium-177 (177Lu-PSMA) has been used in metastatic castrate-resistant prostate cancer (mCRPC), and retrospective data have shown this therapy to be favourably safe with attractive clinical responses. Re-challenge 177Lu-PSMA therapy in early responders has been shown to be safe and effective. We report the use of low-dose Taxol-based chemotherapy (modified dose 25 mg/m2 weekly × 6 weeks) as a radiosensitizer with re-challenge 177Lu-PSMA therapy (4 cycles). In a period of 3 years, the patient underwent a total of 8 cycles of 177Lu-PSMA with a cumulative dose of 51.8 GBq. All therapies were uneventful and well tolerated. There was a good response to re-challenge 177Lu-PSMA therapy and low-dose docetaxel (Taxol-177Lu-PSMA) with no recorded tumour resistance.

Platinum-doublet chemotherapy as second-line treatment for relapsed patients with small-cell lung cancer: A systematic review and meta-analysis.

OBJECTIVE: Optimal second-line chemotherapy for patients with relapsed small-cell lung cancer remains debatable. In addition to topotecan or amrubicin monotherapy, re-challenge with first-line platinum-doublets have been commonly used. In this study, we investigated whether platinum-doublets are suitable as second-line treatment for relapsed small-cell lung cancer. MATERIALS AND METHODS: Studies that enrolled relapsed small-cell lung cancer and compared platinum-doublets with non-platinum-based regimens for second-line treatment were identified using PubMed and EMBASE. A meta-analysis was conducted to calculate the relative risk of objective response rate and disease control rate of the second-line chemotherapy. Subgroup analyses were conducted to focus on comparison with standard second-line regimens and sensitive relapse. Progression-free and overall survival, and adverse events were systematically reviewed. RESULTS: Ten studies published between 2011 and 2020 were included in our analysis with a total of 1222 patients: 438 treated with platinum-doublets and 784 with non-platinum-based regimens. The objective response rates for second-line platinum-doublet and non-platinum regimens were 47.3 % [95 % CI: 40.5-54.0] and 31.5 % [95 % CI: 22.2-40.8], respectively.　Patients treated with platinum-doublets had a significantly higher objective response rate than patients with non-platinum-based regimens (RR [95 % CI]: 1.527 [1.100-2.121], p = 0.011), as well as disease control rate (RR [95 % CI]: 1.152 [1.052-1.262], p = 0.002). In a subgroup analysis comparing platinum-doublets with topotecan or amrubicin, patients treated with platinum-doublets had significantly higher objective response rate and disease control rate (RR [95 % CI]: 1.663 [1.055-2.619], p = 0.028 and 1.170 [1.021-1.340], p = 0.023 respectively). Progression-free and overall survival appeared consistent with the tumor responses. Adverse events associated with platinum-doublets appeared acceptable compared with the monotherapies. CONCLUSION: Platinum-doublet chemotherapy as second-line treatment for patients with relapsed small-cell lung cancer can be considered as a reasonable option in comparison with non-platinum regimens.

Exploring chemotherapy holiday and drugs re-challenge in advanced pancreatic cancer patients.

PURPOSE: We aimed to explore the role of drugs re-challenge at the disease progression after a chemotherapy-free interval for pancreatic adenocarcinoma (PDAC) patients. METHODS: We retrospectively analyzed the outcome of re-treatments at the progression in two cohorts of advanced PDAC patients who had disease control (DC) and a treatment holiday ≥ 3 months after upfront chemotherapy. RESULTS: Between 2015 and 2019, 66 advanced PDAC patients (cohort A) had DC with nab-paclitaxel-based chemotherapy (i.e. AG or PAXG = cisplatin, nab-paclitaxel, gemcitabine, capecitabine). At the time of progressive disease (PD), 34 patients were re-treated with AG (A1) and 32 were treated with other regimens (A2). The median (m) duration of chemotherapy holiday was 6.1 and 5.9 months in A1 and A2, respectively. Partial response (PR) and stable disease (SD) were found in 14 (41%) and 12 (35%) of patients in A1 and in 8 (25%) and 6 (19%) patients in A2. CA19-9 response was recorded in 23/33 evaluable patients (70%) in A1 and in 5/20 (25%) in A2. mPFS2 and mOS2, defined as the time between the second line of treatment start and the disease progression or death, were 4.8 and 12.2 months in A1 and 3.9 and 8.4 months in A2, respectively. Similarly, between 2006 and 2013, 64 patients (cohort B) had DC with upfront PEFG/PEXG/PDXG regimens (epirubicin or docetaxel, cisplatin, gemcitabine, capecitabine or 5-fluorouracil) and were re-treated at PD with either 4-drug (B1; N = 30) or other regimens (B2; N = 34), yielding a mOS2 of 10.9 and 7.2 months, respectively. CONCLUSION: Our data endorse the strategy of resuming prior drugs after a chemotherapy holiday ≥ 3 months in advanced PDAC patients who achieved a  durable disease control after upfront treatments.

Clinical characteristics and management of immune checkpoint inhibitor-related pneumonitis: A single-institution retrospective study.

INTRODUCTION: The increasing application of immune checkpoint inhibitors (ICIs) will cause more checkpoint inhibitor-related pneumonitis (CIP), which is a common cause of ICI-related death. The clinical management of CIP needs further optimization. METHODS: Patients who were managed at Peking Union Medical College Hospital (PUMCH) between February 2017 and December 2019 with a diagnosis of CIP were retrospectively analyzed. Clinical data including clinical manifestations, radiologic data, laboratory and bronchoscopy results, treatments, and outcomes were collected and analyzed. The Mann-Whitney test was used to compare patients with and without co-infections. RESULTS: In total, 48 CIP cases in 42 patients were analyzed. The median time from the first dose of ICI to the onset of CIP was 1.9 months (range: 0.1-13.7). Grade 3-4 (G3-4) accounted for 30 cases (71.4%). The most common symptoms were cough (88.1%) and dyspnea (78.6%). The median starting dose of equivalent prednisone (EP) was 55 mg (range: 30-200) for all patients. The median total duration of glucocorticosteroids (GCS) treatment was 42.5 days (range: 15-89). Three patients (7.14%) died because of infection. A higher starting dose and longer duration of GCS (≥30 mg/day; p = 0.001) were associated with opportunistic infection. Chest computed tomography (CT) showed diverse and asymmetrical lesions. Twelve patients were re-challenged, and six patients developed recurrent CIP. CONCLUSIONS: The clinical and imaging manifestations of CIP are various, and differential diagnosis of exclusion is essential. GCS at 1-2 mg/kg is feasible to treat CIP, but the duration of GCS ≥30 mg/day should be used with caution, given the high risk of acquired infections. Re-challenges of ICI are feasible, but the recurrence of CIP needs to be closely monitored.

Recurrent acute pancreatitis induced by 5-ASA and azathioprine in ulcerative colitis.

Drug-induced acute pancreatitis (DIAP) is an often-neglected entity where the disorder is the consequence of the toxic effects of various agents applied to treat potentially life-threatening conditions, such as inflammatory bowel disease. Here, we present the case of a male patient with ulcerative colitis with a history of two episodes of recurrent acute pancreatitis. After excluding other potential causes, we suspected DIAP since the patient received 5-aminosalycilate (5-ASA) prior to the first episode and, one year later, azathioprine (AZA) prior to the second episode. The causative effect of AZA was confirmed by performing a re-challenge with a reduced dose. While both episodes of DIAP had a mild disease course, they were associated with acute relapse of ulcerative colitis. Last seen, the patient was asymptomatic. With this case, we would like to highlight the importance and diagnostic difficulties of DIAP in the background of recurrent cases when common etiological factors of acute pancreatitis are excluded.