A Case of Peritoneal Carcinomatosis After Hyperprogression in Human Papillomavirus-Positive (HPV+) Oropharyngeal Squamous Cell Carcinoma.

Immunotherapy has been shown to provide clinical benefit in selected patients with head and neck squamous cell carcinoma (HNSCC), regardless of human papillomavirus (HPV) infection, and including recurrent/metastatic (R/M) platinum refractory tumors. Hyperprogression is an uncommon negative outcome of treatment with immunotherapy. We present the case of a patient with HPV+ HNSCC who presented hyperprogression after immunotherapy and a rare metastasis location with peritoneal carcinomatosis and subcutaneous nodules. HPV+ HNSCC is related to distant recurrence after a longer interval of time and more diverse metastasis sites compared with HPV- disease. However, the literature on peritoneal metastasis in HNSCC remains limited, with few documented cases. To the best of our knowledge, this is the first case reporting peritoneal carcinomatosis after hyperprogression in HNSCC.

Noninvasive radiomic biomarkers for predicting pseudoprogression and hyperprogression in patients with non-small cell lung cancer treated with immune checkpoint inhibition.

This study aimed to develop a computed tomography (CT)-based radiomics model capable of precisely predicting hyperprogression and pseudoprogression (PP) in patients with non-small cell lung cancer (NSCLC) treated with immunotherapy. We retrospectively analyzed 105 patients with NSCLC, from three institutions, treated with immune checkpoint inhibitors (ICIs) and categorized them into training and independent testing set. Subsequently, we processed CT scans with a series of image-preprocessing techniques, and 6008 radiomic features capturing intra- and peritumoral texture patterns were extracted. We used the least absolute shrinkage and selection operator logistic regression model to select radiomic features and construct machine learning models. To further differentiate between progressive disease (PD) and hyperprogressive disease (HPD), we developed a new radiomics model. The logistic regression (LR) model showed optimal performance in distinguishing PP from HPD, with areas under the receiver operating characteristic curve (AUC) of 0.95 (95% confidence interval [CI]: 0.91-0.99) and 0.88 (95% CI: 0.66-1) in the training and testing sets, respectively. Additionally, the support vector machine model showed optimal performance in distinguishing PD from HPD, with AUC of 0.97 (95% CI: 0.93-1) and 0.87 (95% CI: 0.72-1) in the training and testing sets, respectively. Kaplan‒Meier survival curves showed clear stratification between PP predicted by the radiomics model and true progression (HPD and PD) (hazard ratio = 0.337, 95% CI: 0.200-0.568, p < 0.01) in overall survival. Our study demonstrates that radiomic features extracted from baseline CT scans are effective in predicting PP and HPD in patients with NSCLC treated with ICIs.

Targeting T regulatory (Treg) cells in immunotherapy-resistant cancers.

Primary or secondary (i.e., acquired) resistance is a common occurrence in cancer patients and is often associated with high numbers of T regulatory (Treg) cells (CD4+CD25+FOXP3+). The approval of ipilimumab and the development of similar pharmacological agents targeting cell surface proteins on Treg cells demonstrates that such intervention may overcome resistance in cancer patients. Hence, the clinical development and subsequent approval of Cytotoxic T Lymphocyte Antigen-4 (CTLA-4) targeting agents can serve as a prototype for similar agents. Such new agents aspire to be highly specific and have a reduced toxicity profile while increasing effector T cell function or effector T/T regulatory (Teff/Treg) ratio. While clinical development with large molecules has shown the greatest advancement, small molecule inhibitors that target immunomodulation are increasingly entering early clinical investigation. These new small molecule inhibitors often target specific intracellular signaling pathways [e.g., phosphoinositide-3-kinase delta (PI3K-δ)] that play an important role in regulating the function of Treg cells. This review will summarize the lessons currently applied to develop novel clinical agents that target Treg cells.

Progress in the research of immunotherapy­related hyperprogression (Review).

Immunotherapy has become an effective method for the treatment of a variety of malignant tumors. However, with the development of immunotherapy, the phenomenon of hyperprogression in patients with cancer has gradually attracted attention. Hyperprogression refers to a condition in which the progression of a disease during treatment of a patient with cancer is suddenly accelerated. To date, no reliable marker has been found to predict accelerated tumor growth during immune checkpoint inhibitor (ICI) treatment. The aim the present study was to summarize the definition of hyperprogression and the difference between hyperprogression and pseudocytosis, and investigate the potential mechanisms of hyperprogression including clinical characteristics, potential molecular markers and the immune microenvironment. The effect of macrophage-related different types and factors on tumors in the immune microenvironment was analyzed, and the findings may be used to determine the future directions of research in hyperprogression.

Formation of Hyperprogression of Immunotherapy from Perspective of "Yang Deficiency and Toxin Knot" and Role of "Five Views on Differentiation and Treatment" Intervention / 中国实验方剂学杂志

Immune checkpoint inhibitors （ICIs） have shown good efficacy in tumor treatment and have changed the landscape of tumor treatment. However， some patients treated with ICIs have not only failed to achieve the desired therapeutic effect， but also developed an atypical response pattern of abnormally accelerated tumor growth， namely hyperprogressive disease （HPD）. The pathogenesis of HPD is still unclear and it is difficult to diagnose， which poses a challenge for clinical identification and treatment decisions. Exploring the underlying mechanism of HPD is important to improve the effect of immunotherapy. Based on the theory of "Yang deficiency and toxic knot"， this paper discussed the mechanism of HPD in immunotherapy from the perspective of "spleen and kidney Yang deficiency and hefty toxic pathogens". It was concluded that the inactivation of p53 oncogene and immunosuppressive microenvironment were the manifestations of the deficiency of healthy qi in the body and declined yang in the spleen and kidney， serving as an important basis for the occurrence of HPD. Adverse reactions caused by ICIs belong to the category of "drug toxicity". The occurrence and development of murine double minute 2 （MDM2）/murine double minute 4 （MDM4） activation， epidermal growth factor receptor （EGFR） mutation， and tumor inflammatory microenvironment are the manifestations of the hyperactivity of pathogenic Qi， conflict of cancer toxicity and drug toxicity， and being hefty by virtue of deficiency， which can promote the abnormal proliferation of tumor cells， and they are the core pathogenic elements of HPD and are closely related to disease prognosis. In terms of treatment， under the guidance of the theory of "five views on differentiation and treatment" （time-space view， core view， symptom view， precision view， and disease-before-onset view）， which was summarized according to the clinical practice of this research team， this paper， taking the prevention and treatment of HPD as the entry point， formulated traditional Chinese medicine （TCM） compounds to reinforce healthy Qi and warm Yang and realize the dynamic management of the whole spatiotemporal cycle， and removed toxins and resisted cancer to realize the all-round systemic intervention of the specimen. Additionally， targets were enriched in the macro-clinical manifestations and microscopic pathological changes of HPD to improve the targeting of drug selection and the precision of prevention and treatment， giving full play to the unique therapeutic advantages of TCM， and providing new ideas for the clinical application of TCM in the prevention and treatment of HPD.

Stem Cell Origin of Cancer: Clinical Implications for Cancer Immunity and Immunotherapy.

A simple way to understand the immune system is to separate the self from non-self. If it is self, the immune system tolerates and spares. If it is non-self, the immune system attacks and destroys. Consequently, if cancer has a stem cell origin and is a stem cell disease, we have a serious problem and a major dilemma with immunotherapy. Because many refractory cancers are more self than non-self, immunotherapy may become an uphill battle and pyrrhic victory in cancer care. In this article, we elucidate cancer immunity. We demonstrate for whom, with what, as well as when and how to apply immunotherapy in cancer care. We illustrate that a stem cell theory of cancer affects our perspectives and narratives of cancer. Without a pertinent theory about cancer's origin and nature, we may unwittingly perform misdirected cancer research and prescribe misguided cancer treatments. In the ongoing saga of immunotherapy, we are at a critical juncture. Because of the allure and promises of immunotherapy, we will be treating more patients not immediately threatened by their cancer. They may have more to lose than to gain, if we have a misconception and if we are on a wrong mission with immunotherapy. According to the stem cell theory of cancer, we should be careful with immunotherapy. When we do not know or realize that cancer originates from a stem cell and has stem-ness capabilities, we may cause more harm than good in some patients and fail to separate the truth from the myth about immunotherapy in cancer care.

Integrating [18F]-Fluorodeoxyglucose Positron Emission Tomography with Computed Tomography with Radiation Therapy and Immunomodulation in Precision Therapy for Solid Tumors.

[18F]-FDG positron emission tomography with computed tomography (PET/CT) imaging is widely used to enhance the quality of care in patients diagnosed with cancer. Furthermore, it holds the potential to offer insight into the synergic effect of combining radiation therapy (RT) with immuno-oncological (IO) agents. This is achieved by evaluating treatment responses both at the RT and distant tumor sites, thereby encompassing the phenomenon known as the abscopal effect. In this context, PET/CT can play an important role in establishing timelines for RT/IO administration and monitoring responses, including novel patterns such as hyperprogression, oligoprogression, and pseudoprogression, as well as immune-related adverse events. In this commentary, we explore the incremental value of PET/CT to enhance the combination of RT with IO in precision therapy for solid tumors, by offering supplementary insights to recently released joint guidelines.

Enteral lorlatinib after immune hyperprogression as a treatment option for anaplastic lymphoma kinase­positive non­small cell lung cancer: A case report.

Fusion of the anaplastic lymphoma kinase (ALK) gene is a rare driver in non-small cell lung cancer (NSCLC). Lorlatinib is a third-generation ALK inhibitor approved for the treatment of locally advanced or metastatic ALK+ NSCLC. The traditional administration method of lorlatinib is whole tablet ingestion, while the efficacy effect of gastric tube injection after water dissolution remains unclear. In the present report, a marked response to lorlatinib in a 49-year-old patient with ALK+ NSCLC who was administered lorlatinib through a gastric tube, was described. The patient had received chemotherapy combined with immune checkpoint inhibitors prior to targeted drug therapy and developed hyperprogression, which was mainly manifested as rapid enlargement of the primary lesion with multiple new systemic metastases, accompanied by poor performance status score, esophageal compression and difficulty eating. The patient was injected with pre-dissolved lorlatinib through the nasogastric tube. After 6 days, related symptoms, such as dyspnea and dysphagia, were relieved. After 18 days, the esophageal stenosis was significantly alleviated, and the gastric tube was removed. In conclusion, gastric tube injection be used as a means of lorlatinib administration in patients with ALK+ NSCLC with dysphagia, regardless of previous immunotherapy-associated hyperprogression.

Hyperprogressive Disease (HPD) in Solid Tumours Receiving Immune Checkpoint Inhibitors in a Real-World Setting.

Introduction: Hyperprogressive disease (HPD) is a state of accelerated tumor growth from cancer immunotherapy, associated with poor outcome. The reported incidence is 6% to 29% among studies using varying definitions of HPD, with no predictive biomarkers. Tumor infiltrating lymphocytes (TILs) are prognostic and predictive for immunotherapy benefit in various tumor types, but have only been tested for correlation with HPD in one study. Objectives: The objective of the study was to determine the prevalence of HPD in solid tumor patients treated with immune checkpoint inhibitor therapy in a real-world setting, and to assess clinicopathological features as potential biomarkers for HPD. Methods: We conducted a retrospective analysis of solid tumor patients treated with immune checkpoint inhibitors at a single institution. Imaging pre-immunotherapy and postimmunotherapy were assessed for HPD, and correlated against clinicopathological factors, including TILs and programmed death-ligand 1 (PD-L1) status through archival tumor assessment. HPD was defined per Matos et al as response evaluation criteria in solid tumors (RECIST) progressive disease, minimum increase in measurable lesions of 10 mm, plus increase of ≥40% in sum of target lesions compared with baseline and/or increase of ≥20% in sum of target lesions compared with baseline plus new lesions in at least 2 different organs. Results: HPD occurred in 11 of 87 patients (13%), and associated with inferior overall survival (median 5.5 months vs 18.3 months, P = .002). However, on multivariate analysis, only liver metastases (hazard ratio [HR] 4.66, 95% confidence interval [CI] 2.27-9.56, P < .001) and PD-L1 status (HR 0.53, 95% CI 0.30-0.95, P = .03) were significantly associated with survival. Presence of liver metastases correlated with occurence of HPD (P = .01). Age, sex, and monotherapy versus combination immunotherapy were not predictive for HPD. PD-L1 status and TILs were not associated with HPD. Conclusions: We found 13% HPD among solid tumor patients treated with immunotherapy, consistent with the range reported in prior series. Assessment for HPD is feasible outside of a clinical trials setting, using modified criteria that require comparison of 2 imaging studies. Liver metastases were associated with risk of HPD, while TILs and PD-L1 status were not predictive for HPD.

Hyperprogression after anti-programmed death-1 therapy in a patient with urothelial bladder carcinoma: A case report.

BACKGROUND: Immune checkpoint inhibitors, including programmed death-ligand 1 (PD-L1) and programmed death-1 (PD-1) have recently been approved to treat locally advanced and metastatic urothelial carcinoma (UC). However, some patients experience rapid tumor progression rather than any clinical benefit from anti-PD-L1/PD-1 therapy. CASE SUMMARY: A 73-year-old woman with bladder UC showed the progression of multiple metastases after surgery and chemotherapy for over 12 mo. The patient could not tolerate further chemotherapy. Next-generation sequencing was performed, and the results indicated that the tumor mutational burden was 6.4 mutations/Mb. The patient received the anti-PD-L1 agent toripalimab combined with albumin-bound paclitaxel. Compared with the baseline staging before immunotherapy, the patient had a treatment failure time of < 2 mo, an increase in tumor burden of > 50%, and a > 2-fold increase in progression, indicating hyperprogression. CONCLUSION: Selecting patients most likely to respond to treatment with immunotherapeutic agents remains challenging. For older patients with advanced UC who have already exhausted multi-line chemotherapy options, immunotherapy should be used prudently if no effective biomarker is available. Further studies are required to clarify the causes and mechanisms of hyperprogression.

Rapid T-cell lymphoma progression associated with immune checkpoint inhibitors.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) are widely used for multiple types of malignancies and are considered the fourth pillar in cancer treatment. Anti-programmed death-1 (PD-1) antibodies pembrolizumab and nivolumab are approved for relapsed/refractory classical Hodgkin lymphoma. Nonetheless, two phase 2 trials for T-cell lymphoma were terminated because of hyperprogression after a single dose in some patients. AREAS COVERED: In this review, we summarize available information on the rapid progression of peripheral T-cell lymphoma including adult T-cell leukemia/lymphoma (ATLL). EXPERT OPINION: In the abovementioned two trials, disease subtypes in patients who experienced hyperprogression were mostly ATLL or angioimmunoblastic T-cell lymphoma. Possible hyperprogression mechanisms induced by PD-1 blockade are the compensatory upregulation of the expression of other checkpoints, altered expression of lymphoma-promoting growth factors, functional blockade of stromal PD-ligand 1 acting as a tumor suppressor, and unique immune environment in indolent ATLL. The differentiation between hyperprogression and pseudoprogression is practically essential. There are no established methods to predict hyperprogression before administration of an ICI. In the future, the progress of novel diagnostic modalities such as positron emission tomography with computed tomography and circulating tumor DNA is expected to facilitate early cancer detection.

Radiomics-guided checkpoint inhibitor immunotherapy for precision medicine in cancer: A review for clinicians.

Immunotherapy using immune checkpoint inhibitors (ICIs) is a breakthrough in oncology development and has been applied to multiple solid tumors. However, unlike traditional cancer treatment approaches, immune checkpoint inhibitors (ICIs) initiate indirect cytotoxicity by generating inflammation, which causes enlargement of the lesion in some cases. Therefore, rather than declaring progressive disease (PD) immediately, confirmation upon follow-up radiological evaluation after four-eight weeks is suggested according to immune-related Response Evaluation Criteria in Solid Tumors (ir-RECIST). Given the difficulty for clinicians to immediately distinguish pseudoprogression from true disease progression, we need novel tools to assist in this field. Radiomics, an innovative data analysis technique that quantifies tumor characteristics through high-throughput extraction of quantitative features from images, can enable the detection of additional information from early imaging. This review will summarize the recent advances in radiomics concerning immunotherapy. Notably, we will discuss the potential of applying radiomics to differentiate pseudoprogression from PD to avoid condition exacerbation during confirmatory periods. We also review the applications of radiomics in hyperprogression, immune-related biomarkers, efficacy, and immune-related adverse events (irAEs). We found that radiomics has shown promising results in precision cancer immunotherapy with early detection in noninvasive ways.

Low Risk of Hyperprogression with First-Line Chemoimmunotherapy for Advanced Non-Small Cell Lung Cancer: Pooled Analysis of 7 Clinical Trials.

BACKGROUND: Monotherapy immune checkpoint inhibitor (ICI) used in second- or later-line settings has been reported to induce hyperprogression. This study evaluated hyperprogression risk with ICI (atezolizumab) in the first-, second-, or later-line treatment of advanced non-small cell lung cancer (NSCLC), and provides insights into hyperprogression risk with contemporary first-line ICI treatment. METHODS: Hyperprogression was identified using Response Evaluation Criteria in Solid Tumours (RECIST)-based criteria in a dataset of pooled individual-participant level data from BIRCH, FIR, IMpower130, IMpower131, IMpower150, OAK, and POPLAR trials. Odds ratios were computed to compare hyperprogression risks between groups. Landmark Cox proportional-hazard regression was used to evaluate the association between hyperprogression and progression-free survival/overall survival. Secondarily, putative risk factors for hyperprogression among second- or later-line atezolizumab-treated patients were evaluated using univariate logistic regression models. RESULTS: Of the included 4644 patients, 119 of the atezolizumab-treated patients (n = 3129) experienced hyperprogression. Hyperprogression risk was markedly lower with first-line atezolizumab-either chemoimmunotherapy or monotherapy-compared to second/later-line atezolizumab monotherapy (0.7% vs. 8.8%, OR = 0.07, 95% CI, 0.04-0.13). Further, there was no statistically significant difference in hyperprogression risk with first-line atezolizumab-chemoimmunotherapy versus chemotherapy alone (0.6% vs. 1.0%, OR = 0.55, 95% CI, 0.22-1.36). Sensitivity analyses using an extended RECIST-based criteria including early death supported these findings. Hyperprogression was associated with worsened overall survival (HR = 3.4, 95% CI, 2.7-4.2, P < .001); elevated neutrophil-to-lymphocyte ratio was the strongest risk factor for hyperprogression (C-statistic = 0.62, P < .001). CONCLUSIONS: This study presents first evidence for a markedly lower hyperprogression risk in advanced NSCLC patients treated with first-line ICI, particularly with chemoimmunotherapy, as compared to second- or later-line ICI treatment.

Life-threatening "hyper-progression" on immunotherapy revealed as pseudo-progression in DNA mismatch repair deficiency: a case report.

Background: Distinguishing pseudo-progression from true progression on immunotherapy remains a clinical challenge. Clinical tools to aid in this task are currently lacking. DNA mismatch repair (MMR) status is a known predictive marker for anti-programmed death (PD)-1 therapy, but its role in helping to address this situation is not well-defined. Case Description: We report the first case, to our knowledge, of life-threatening hyper-progression which was later revealed to be pseudo-progression in a patient with a deficient MMR (dMMR) tumor. We describe a 62-year-old man with advanced dMMR gastric cancer who was being treated with pembrolizumab monotherapy. After three doses of pembrolizumab he exhibited signs and symptoms that met all applicable definitions of hyper-progression in the setting of acute life-threatening gastrointestinal hemorrhage, extensive radiographic progression of metastases, and increasing carcinoembryonic antigen (CEA). Comfort measures were considered given the appearance of hyper-progression. But partly given the patient's request, aggressive support was provided, including blood products, vasopressors, and splenic artery embolization. His condition improved, and subsequent scans revealed regression of his metastases and decreased CEA, confirming pseudo-progression. Pembrolizumab was restarted. The patient remains on pembrolizumab with minimal tumor burden more than one year later. Conclusions: This case demonstrates that life-threatening hyper-progression can represent pseudo-progression and suggests that MMR status could be important to consider in determining the aggressiveness of clinical management during apparent hyper-progression.

Advances in the Study of Hyperprogression of Different Tumors Treated with PD-1/PD-L1 Antibody and the Mechanisms of Its Occurrence.

Immune checkpoint inhibitors (ICIs) including PD-1/PD-L1 antibodies, have demonstrated significant clinical benefits in the treatment of individuals with many types of cancer. However, as more and more patients use such therapies, the side effects of immune checkpoint inhibitors have also been discovered. These include accelerated tumor growth in some patients, creating new lesions, and even life-threatening ones. These side effects are known as hyperprogression disease (HPD), and different types of tumors have different HPD conditions after ICIs treatment. Therefore, understanding the pathogenesis of HPD and predicting its occurrence is critical for patients using ICIs therapy. Here, we will briefly review the current status of PD-1/PD-L1 antibody therapy, HPD occurrence in various types of tumors, and the underlying mechanism.

The debatable role of immune checkpoint blockade therapy in lung adenocarcinoma-oriented liver metastatic malignant lesions.

BACKGROUND: The use of anti-PD-1 or PD-L1 inhibitors in combination with other anti-cancer agents was a priority for treating advanced non-small cell lung cancer (NSCLC) patients with considerable PD-L1 expression. However, studies seldom show the progression of liver metastases after using immune checkpoint inhibitors (ICIs). METHODS: Data were obtained from the Department of Pulmonary and Critical Care of Medicine, the First Affiliated Hospital of the Air Force Military Medical University. In the present study, we analyzed five non-small cell lung cancer (NSCLC) patients who had liver metastases after they were treated with pembrolizumab between 2019 and 2021. All of them had both stable primary lesions and liver progression with pembrolizumab intervention. Blood laboratory tests and imaging examinations were performed regularly during the treatment to assess the tumor responses of patients. RESULTS: All patients displayed reduction or stability in the initial lesions as a result, but they also experienced the emergence of metastatic liver locations, which were regularly detected throughout immunotherapy. Additionally, the appearance of liver metastasis weakened their liver function gradually with the escalation of carcinoembryonic antigen, regarded as a predictor for evaluating the progression of tumors. These individuals were highly distinctive with hyper-progressive diseases associated with immunotherapy. We drew individualized intervention schemes for metastatic lesions in each patient and found that their life expectancy shared no significance given the restricting subjected population. CONCLUSIONS: Our study indicated a clinical phenomenon after using immune checkpoint inhibitors and presented a necessity for implementing large scales clinical studies to manage NSCLC-oriented liver metastasis.

Hyperprogressive disease in non-small cell lung cancer treated with immune checkpoint inhibitor therapy, fact or myth?

The therapeutic landscape for patients with non-small cell lung cancer (NSCLC) has dramatically evolved with the development and adoption of immune checkpoint inhibitors (ICI) as front-line therapy. These novel antibodies target the interactions in immunoregulatory pathways, between programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1), or cytotoxic T-lymphocyte antigen 4 (CTLA-4) and B7, resulting in the activation of T cells and cytotoxic response to induce an immunologic response. ICIs have demonstrated significant survival benefits and sustained responses in the treatment of NSCLC leading to the long-term survival of up to 5 year. One unusual response to ICI is a phenomenon termed Hyperprogressive Disease (HYD), which occurs in a subset of patients for whom ICI therapy can induce rapid disease growth, which ultimately leads to poorer outcomes with an incidence rate ranging from 5 to 37% in NSCLC patients. Prior reviews demonstrated that HYD can be defined by rapid tumor progression, deterioration of patient's symptoms or new onset of disease. The mechanism of HYD could be related to genomic and tumor microenvironment changes and altered immune response. It will be important to establish a common definition of HYD for future research and clinical care.

PET/CT radiomics for prediction of hyperprogression in metastatic melanoma patients treated with immune checkpoint inhibitors.

Purpose: This study evaluated pretreatment 2[18F]fluoro-2-deoxy-D-glucose (FDG)-PET/CT-based radiomic signatures for prediction of hyperprogression in metastatic melanoma patients treated with immune checkpoint inhibition (ICI). Material and method: Fifty-six consecutive metastatic melanoma patients treated with ICI and available imaging were included in the study and 330 metastatic lesions were individually, fully segmented on pre-treatment CT and FDG-PET imaging. Lesion hyperprogression (HPL) was defined as lesion progression according to RECIST 1.1 and doubling of tumor growth rate. Patient hyperprogression (PD-HPD) was defined as progressive disease (PD) according to RECIST 1.1 and presence of at least one HPL. Patient survival was evaluated with Kaplan-Meier curves. Mortality risk of PD-HPD status was assessed by estimation of hazard ratio (HR). Furthermore, we assessed with Fisher test and Mann-Whitney U test if demographic or treatment parameters were different between PD-HPD and the remaining patients. Pre-treatment PET/CT-based radiomic signatures were used to build models predicting HPL at three months after start of treatment. The models were internally validated with nested cross-validation. The performance metric was the area under receiver operating characteristic curve (AUC). Results: PD-HPD patients constituted 57.1% of all PD patients. PD-HPD was negatively related to patient overall survival with HR=8.52 (95%CI 3.47-20.94). Sixty-nine lesions (20.9%) were identified as progressing at 3 months. Twenty-nine of these lesions were classified as hyperprogressive, thereby showing a HPL rate of 8.8%. CT-based, PET-based, and PET/CT-based models predicting HPL at three months after the start of treatment achieved testing AUC of 0.703 +/- 0.054, 0.516 +/- 0.061, and 0.704 +/- 0.070, respectively. The best performing models relied mostly on CT-based histogram features. Conclusions: FDG-PET/CT-based radiomic signatures yield potential for pretreatment prediction of lesion hyperprogression, which may contribute to reducing the risk of delayed treatment adaptation in metastatic melanoma patients treated with ICI.

High serum LDH and liver metastases are the dominant predictors of primary cancer resistance to anti-PD(L)1 immunotherapy.

AIM: Anti-PD-(L)1 immunotherapies improve survival in multiple cancers but remain ineffective for most patients. We applied machine-learning algorithms and multivariate analyses on baseline medical data to estimate their relative impact on overall survival (OS) upon anti-PD-(L)1 monotherapies. METHOD: This prognostic/predictive study retrospectively analysed 33 baseline routine medical variables derived from computed tomography (CT) images, clinical and biological meta-data. 695 patients with a diagnosis of advanced cancer were treated in prospective clinical trials in a single tertiary cancer centre in 3 cohorts including systemic anti-PD-(L)1 (251, 235 patients) versus other systemic therapies (209 patients). A random forest model combined variables to identify the combination (signature) which best estimated OS in patients treated with immunotherapy. The performance for estimating OS [95%CI] was measured using Kaplan-Meier Analysis and Log-Rank test. RESULTS: Elevated serum lactate dehydrogenase (LDHhi) and presence of liver metastases (LM+) were dominant and independent predictors of short OS in independent cohorts of melanoma and non-melanoma solid tumours. Overall, LDHhiLM+ patients treated with anti-PD-(L)1 monotherapy had a poorer outcome (median OS: 3.1[2.4-7.8] months]) compared to LDHlowLM-patients (median OS: 15.3[8.9-NA] months; P < 0.0001). The OS of LDHlowLM-patients treated with immunotherapy was 28.8[17.9-NA] months (vs 13.1[10.8-18.5], P = 0.02) in the overall population and 30.3[19.93-NA] months (vs 14.1[8.69-NA], P = 0.0013) in patients with melanoma. CONCLUSION: LDHhiLM+ status identifies patients who shall not benefit from anti-PD-(L)1 monotherapy. It could be used in clinical trials to stratify patients and eventually address this specific medical need.

Hyperprogressive Disease In a Metastatic Renal Cell Carcinoma Patient After Receiving Immune Checkpoint Inhibitors: A Case Report.

Owing to their survival benefits, immune checkpoint inhibitors (ICIs) have emerged as the mainstay treatment for several types of malignant tumors including renal cell carcinoma (RCC). However, the usage of ICIs such as nivolumab, ipilimumab, and atezolizumab can be complicated by unexpected rapid clinical deterioration and acceleration of tumor growth. This adverse event is called hyperprogressive disease (HPD) with an incidence rate of 10-20%. Since its first description in 2016, efforts have been made to identify and predict this phenomenon. We report a case of a 34-year-old female patient diagnosed with metastatic renal cell carcinoma (mRCC) with sarcomatoid features. She underwent a left radical nephrectomy followed by combination ICIs (nivolumab/ipilimumab) therapy. However, she presented with a rapid clinical deterioration shortly after receiving her second cycle of ICIs. The radiological assessment showed new multiple bilateral lung nodules, new multiple mediastinal and left hilar lymph node involvement, and two focal areas of new appearance involving the left aspect of L3 lumbar vertebrae and left ischial bone. The diagnosis of HPD was made. Unfortunately, the patient died soon following her second infusion of the nivolumab/ipilimumab combination.