Development of a novel nomogram for patients with SCLC and comparison with other models.

BACKGROUND: Though several nomograms have been established to predict the survival probability of patients with small-cell lung cancer (SCLC), none involved enough variables. This study aimed to construct a novel prognostic nomogram and compare its performance with other models. METHODS: Seven hundred twenty-two patients were pathologically diagnosed with SCLC in Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Cancer Hospital Affiliated to Shanxi Medical University from January 2016 to December 2018. We input Forty-one factors by reviewing the medical records. The nomogram was constructed based on the variables identified by univariate and multivariate analyses in the training set and validated in the validation set. Then we compared the performance of the models in terms of discrimination, calibration, and clinical net benefit. RESULTS: There were eight variables involved in the nomogram: gender, monocyte (MON), neuron-specific enolase (NSE), cytokeratin 19 fragments (Cyfra211), M stage, radiotherapy (RT), chemotherapy cycles (CT cycles), and prophylactic cranial irradiation (PCI). The calibration curve showed a good correlation between the nomogram prediction and actual observation for overall survival (OS). The area under the curve (AUC) of the nomogram was higher, and the Integrated Brier score (IBS) was lower than other models, indicating a more accurate prediction. Decision curve analysis (DCA) showed a significant improvement in the clinical net benefit compared to the other models. CONCLUSIONS: We constructed a novel nomogram to predict OS for patients with SCLC using more comprehensive and objective variables. It performed better than existing models and would assist clinicians in individually estimating risk and making a therapeutic regimen.

Value of the lung immune prognostic index in patients with advanced small cell lung cancer treated with programmed death-ligand 1 and programmed death-1 inhibitors in the Chinese alpine region.

Purpose: To assess the potential added value of the lung immune prognostic index (LIPI) in patients with small cell lung cancer (SCLC), treated with programmed death-ligand 1 (PD-L1)/programmed death-1 (PD-1) inhibitors, who lived in the Chinese alpine region. Methods: 120 SCLC patients treated with PD-L1/PD-1 inhibitors were divided into three LIPI groups, from July 2018 to April 2021. Cox regression models were used to evaluate the prognostic effect of three LIPI groups on overall survival (OS) and progression-free survival (PFS). Logistic regression analysis was conducted to explore the association between immune-related adverse events (irAEs) and the pretreatment of neutrophil-to-lymphocyte ratio (dNLR), lactate dehydrogenase (LDH), and LIPI. Results: The median OS was 4.5, 6.3, and 10.0 months (p=0.001) and the median PFS was 2.5, 4.3, and 5.3 months (p=0.049) for Poor, Intermediate, and Good LIPI, respectively. The disease control rate (DCR) was also higher in the Good LIPI group (p=0.003). Moreover, multivariate analysis confirmed that worse LIPI was correlated with shorter OS and PFS. dNLR was associated with the onset of irAEs, not LIPI. Conclusion: The LIPI might be a promising predictive and prognostic biomarker in SCLC patients treated with PD-L1/PD-1 inhibitors in the Chinese Alpine region.

Case report: Emerging therapies for transformed small cell lung cancer: efficacy of serplulimab and a comprehensive case report.

This research reports a case of histological transformation from non-small cell lung cancer (NSCLC) to transformed small cell lung cancer (T-SCLC) in a patient undergoing EGFR-tyrosine kinase inhibitors (TKIs). The aggressive characteristics of the tumor diverged significantly from those commonly associated with lung adenocarcinomas, leading to further histological analysis. The subsequent histological examination confirmed the transformation to SCLC, consistent with established mechanisms of acquired resistance in NSCLC. Given the limited therapeutic options, the patient was administered a serplulimab-based immunochemotherapy regimen, achieving a progression-free survival (PFS) of 6 months post-transformation. The study underscores the potential of PD-1 inhibitors, particularly serplulimab, in the treatment landscape for T-SCLC and highlights the need for future comprehensive research.

Tarlatamab-dlle: A New Hope for Patients with Extensive-Stage Small-Cell Lung Cancer.

OPINION STATEMENT: Lung cancer is expected to contribute to about 0.234 million new cases and about 0.125 million mortalities in the United States in the year 2024. Small cell lung cancer (SCLC), a neuroendocrine carcinoma, has lesser prevalence but is more aggressive at an extensive stage where the tumor is not only confined to hemithorax, mediastinum, and supraclavicular region but spread beyond the supraclavicular region. The prognosis of SCLC, irrespective of the limited or extensive stage, is very poor. Only a 5-10% overall survival rate in five years is expected and with extensive-stage SCLC, long-term disease-free survival is rare. In May 2024, the USFDA approved Tarlatamab-dlle, a DLL3 targeted bi-specific T-cell engager, for treating extensive-stage SCLC in adult patients, on or after platinum-based chemotherapy or on progression. Before the approval of Tarlatamab-dlle, only a few drugs, such as Atezolizumab and Durvalumab, received FDA approval for treating extensive-stage SCLC. It might be possible that Tarlatamab-dlle received accelerated FDA approval for extensive-stage SCLC, leaving some questions unanswered at this stage. This manuscript is focused on clinical, pre-clinical, and other pharmacological aspects of Tarlatamab-dlle for extensive-stage SCLC.

Aberrant positivity for BCOR immunohistochemistry in merkel cell carcinoma - a potential diagnostic pitfall.

BACKRGOUND: Merkel cell carcinoma (MCC) is a rare, aggressive primary cutaneous neuroendocrine carcinoma, frequently associated with clonal Merkel cell polyomavirus integration. MCC can pose significant diagnostic challenges due to its diverse clinical presentation and its broad histological differential diagnosis. Histologically, MCC presents as a small-round-blue cell neoplasm, where the differential diagnosis includes basal cell carcinoma, melanoma, hematologic malignancies, round cell sarcoma and metastatic small cell carcinoma of any site. We here report strong aberrant immunoreactivity for BCOR in MCC, a marker commonly used to identify round cell sarcomas and other neoplasms with BCOR alterations. METHODS: Based on strong BCOR expression in three index cases of MCC, clinically mistaken as sarcoma, a retrospective analysis of three patient cohorts, comprising 31 MCC, 19 small cell lung carcinoma (SCLC) and 5 cases of neoplasms with molecularly confirmed BCOR alteration was conducted. Immunohistochemical staining intensity and localization for BCOR was semi-quantitatively analyzed. RESULTS: Three cases, clinically and radiologically mimicking a sarcoma were analyzed in our soft tissue and bone pathology service. Histologically, the cases showed sheets of a small round blue cell neoplasm. A broad panel of immunohistochemistry was used for lineage classification. Positivity for synaptophysin, CK20 and Merkel cell polyoma virus large T-antigen lead to the diagnosis of a MCC. Interestingly, all cases showed strong positive nuclear staining for BCOR, which was included for the initial work-up with the clinical differential of a round cell sarcoma. We analyzed a larger retrospective MCC cohort and found aberrant weak to strong BCOR positivity (nuclear and/or cytoplasmic) in up to 90% of the cases. As a positive control, we compared the expression to a small group of BCOR-altered neoplasms. Furthermore, we investigated a cohort of SCLC as another neuroendocrine neoplasm and found in all cases a diffuse moderate to strong BCOR positivity. CONCLUSIONS: This study demonstrates that neuroendocrine neoplasms, such as MCC and SCLC can express strong aberrant BCOR. This might represent a diagnostic challenge or pitfall, in particular when MCC is clinically mistaken as a soft tissue or a bone sarcoma.

A Rare Cause of Cauda Equina Syndrome: Neuroendocrine Carcinoma of the Lung.

Cauda equina syndrome (CES) is a rare condition describing the constellation of symptoms resulting from the compression of the cauda equina. Metastatic lesions are a common cause of CES, with lung lesions often implicated as the primary source. A particularly rare cause of CES is leptomeningeal metastasis (LM) from primary solid tumors. In this case, a 63-year-old male presented with urinary and fecal retention, as well as altered sensation in the genitalia. The clinical diagnosis of CES was based on the constellation of symptoms. Computed tomography (CT) imaging demonstrated a metastatic lesion in the S2 and S3 sacral vertebral bodies, with extension into the right piriformis muscle. Magnetic resonance imaging (MRI) revealed an intramedullary lesion at L2 and leptomeningeal enhancement, indicative of metastasis. Further imaging identified a primary lesion in the right lower lobe of the lung, with additional metastases to the brain and liver. A pathological diagnosis of metastatic neuroendocrine carcinoma (NEC) was confirmed following a supraclavicular lymph node biopsy. The patient received steroid therapy, chemotherapy, and radiation to the pelvis. This case provides an important perspective on CES evaluation due to the scarcity of literature highlighting spinal metastases as the primary presentation in patients with NEC of the lung. The clinical diagnosis of CES should raise suspicion for metastasis and warrant further investigation.

Combination of Cytologic Findings and Circulating Tumor DNA From Cerebrospinal Fluid Revealed SCLC Transformation in Patients With Leptomeningeal Metastases of Lung Adenocarcinoma.

Introduction: Transformation to SCLC is a resistance mechanism to tyrosine kinase inhibitor in EGFR-mutated lung adenocarcinoma (LUAD). Nevertheless, the clinical and molecular features of SCLC transformation in LUAD with leptomeningeal metastases (LM) are scarce. Methods: We retrospectively collected 237 patients with NSCLC who underwent lumbar puncture owing to suggestion of LM. All SCLC transformation in cerebrospinal fluid (CSF) was confirmed by two experienced pathologists using cytologic evaluation. CSF circulating tumor DNA (ctDNA) was tested by next-generation sequencing. Results: Tumor cells in CSF samples were found in 111 patients (111 of 237, 46.8%), and eight cases (eight of 111, 7.2%) were identified as having SCLC cells in CSF. Seven patients carried the EGFR mutation, including four patients with EGFR exon 19 deletion and three patients with EGFR exon 21 L858R mutation. Another patient harbored ERBB2 insertion. Seven of these patients were resistant to targeted therapy. CSF ctDNA analysis reported that TP53 and RB1 mutations were common. The median time from the diagnosis of advanced NSCLC to SCLC transformation found in CSF was 9.7 months (95% confidence interval [CI]: 4.0-17.5 mo). The median overall survival since the initial diagnosis of metastatic NSCLC was 15.3 months (95% CI: 1.2-29.4 mo). The median overall survival after SCLC transformation detected in CSF was 5.0 months (95% CI: 4.0-5.9 mo). Conclusions: SCLC transformation may be revealed in CSF by both cytologic evaluation and ctDNA, not just in tissue that underwent rebiopsy. SCLC transformation of CSF is informative for resistance mechanism in patients with LUAD with LM on tyrosine kinase inhibitor progression, which was associated with poor survival.

A comparative study of ProGRP and CEA as serological markers in small cell lung cancer treatment.

BACKGROUND: Small Cell Lung Cancer (SCLC) presents a significant clinical challenge due to its aggressive nature and the need for effective biomarkers for treatment monitoring. This study aimed to compare ProGRP and CEA as serological markers in the monitoring of SCLC treatment. METHODS: We retrospectively analyzed data from 80 SCLC patients and 80 matched controls. ProGRP and CEA levels were measured, and their associations with clinical parameters, including tumor stage and treatment response, were assessed using Spearman's rank correlation coefficient. Multivariate logistic regression models were employed to identify independent predictors of treatment response and disease progression. RESULTS: ProGRP and CEA levels were considerably higher in cases than controls, with median ProGRP levels at 198.5 pg/mL versus 48.7 pg/mL and median CEA levels at 5.2 ng/mL versus 2.9 ng/mL (both p < 0.001). ProGRP levels correlated positively with tumor stage (ρ = 0.58, p < 0.001) and negatively with treatment response (ρ = - 0.45, p = 0.001). CEA levels also showed positive correlation with tumor stage (ρ = 0.48, p = 0.002) and negative correlation with treatment response (ρ = - 0.35, p = 0.005). Multivariate analysis revealed that ProGRP was an independent predictor for treatment response (OR 1.25 per 100 pg/mL increase, p = 0.001) and disease progression (OR 1.25 per 50 pg/mL increase, p = 0.012), while CEA was a marginal predictor for treatment response (OR 0.95 per 1 ng/mL increase, p = 0.045). CONCLUSION: Both ProGRP and CEA are significant serological markers in SCLC patients, with ProGRP showing a stronger correlation with tumor stage and treatment response. ProGRP may serve as a superior independent predictor of treatment response and disease progression compared to CEA. These findings support the incorporation of ProGRP in SCLC treatment monitoring protocols.

Metabolomic Profiling of Pulmonary Neuroendocrine Neoplasms.

BACKGROUND/OBJECTIVES: Pulmonary neuroendocrine neoplasms (NENs) account for 20% of malignant lung tumors. Their management is challenging due to their diverse clinical features and aggressive nature. Currently, metabolomics offers a range of potential cancer biomarkers for diagnosis, monitoring tumor progression, and assessing therapeutic response. However, a specific metabolomic profile for early diagnosis of lung NENs has yet to be identified. This study aims to identify specific metabolomic profiles that can serve as biomarkers for early diagnosis of lung NENs. METHODS: We measured 153 metabolites using liquid chromatography combined with mass spectrometry (LC-MS) in the plasma of 120 NEN patients and compared them with those of 71 healthy individuals. Additionally, we compared these profiles with those of 466 patients with non-small-cell lung cancers (NSCLCs) to ensure clinical relevance. RESULTS: We identified 21 metabolites with consistently altered plasma concentrations in NENs. Compared to healthy controls, 18 metabolites were specific to carcinoid tumors, 5 to small-cell lung carcinomas (SCLCs), and 10 to large-cell neuroendocrine carcinomas (LCNECs). These findings revealed alterations in various metabolic pathways, such as fatty acid biosynthesis and beta-oxidation, the Warburg effect, and the citric acid cycle. CONCLUSIONS: Our study identified biomarker metabolites in the plasma of patients with each subtype of lung NENs and demonstrated significant alterations in several metabolic pathways. These metabolomic profiles could potentially serve as biomarkers for early diagnosis and better management of lung NENs.

Theranostics with somatostatin receptor antagonists in SCLC: Correlation of 68Ga-SSO120 PET with immunohistochemistry and survival.

Rationale: Positron Emission Tomography (PET) using the somatostatin receptor 2 (SSTR2)-antagonist satoreotide trizoxetan (68Ga-SSO120) is a novel, promising imaging modality for small-cell lung cancer (SCLC), which holds potential for theranostic applications. This study aims to correlate uptake in PET imaging with SSTR2 expression in immunohistochemistry (IHC) and to assess the prognostic value of 68Ga-SSO120 PET at initial staging of patients with SCLC. Methods: We analyzed patients who underwent 68Ga-SSO120 PET/CT during initial diagnostic workup of SCLC as part of institutional standard-of-care. SSTR2 expression in IHC was evaluated on a 4-level scale and correlated with normalized standardized uptake values and tumor-to-liver ratios (SUVmax and TLRpeak) in 68Ga-SSO120 PET on a lesion level. Highest lesion SUVmax/TLRpeak per patient, SSTR2 score in IHC, M status according to TNM classification, and other parameters were analyzed for association with overall survival (OS) and time to treatment failure (TTF) by univariate, multivariate (cut-off values were identified on data for best separation), and stratified Cox regression. Results: We included 54 patients (24 men/30 women, median age 65 years, 21 M0/33 M1 according to TNM classification). In 43 patients with available surplus tumor tissue samples, hottest lesion SUVmax/TLRpeak showed a significant correlation with the level of SSTR2-expression by tumor cells in IHC (Spearman's rho 0.86/0.81, both p < 0.001; ANOVA p < 0.001). High SSTR2 expression in IHC, 68Ga-SSO120 SUVmax and TLRpeak of the hottest lesion per patient, whole-body TLRmean, MTV, TLG, M status, and serum LDH showed a significant association with inferior TTF/OS in univariate analysis. In separate multivariate Cox regression (including sex, age, M stage, and LDH) higher hottest-lesion TLRpeak showed a significant association with shorter OS (HR = 0.26, 95%CI: 0.08-0.84, p = 0.02) and SSTR2 expression in IHC with significantly shorter TTF (HR = 0.24, 95%CI: 0.08-0.71, p = 0.001) and OS (HR = 0.22, 95%CI: 0.06-0.84, p = 0.03). In total, 12 patients (22.2%) showed low (< 1), 21 (38.9%) intermediate (≥ 1 but < 2), 14 (25.9%) high (≥ 2 but < 5), and 7 (13.0%) very high (≥ 5) whole-body mean TLRmean. Conclusion: In patients with SCLC, SSTR2 expression assessed by 68Ga-SSO120 PET and by IHC were closely correlated and associated with shorter survival. More than 75% of patients showed higher whole-body 68Ga-SSO120 tumor uptake than liver uptake and almost 40% high or very high uptake, possibly paving the way towards theranostic applications.

Unique Ovarian Metastasis of Small-Cell Lung Cancer and Complete Response After Chemo-Immunotherapy: An Unusual Spread as a Predictor Factor.

A 41-year-old woman, never-smoker, accessed the emergency room for an episode of hemoptysis in September 2019. CT scan showed a defect of opacification in the left pulmonary artery and a solid mass of 12 cm in the left annex. PET confirmed high metabolic activity in the ovarian mass and, surprisingly, in the left hilar lung. The patient underwent a left annessiectomy and the histological examination showed a metastasis of small-cell lung cancer (SCLC) that mimicked a primary ovarian cancer. Fibrobronchoscopy and echo-guided biopsy confirmed the diagnosis of pulmonary SCLC. From January 2020, we started systemic therapy with carboplatin, etoposide, and atezolizumab. After six cycles of induction therapy with a complete response, thoracic and prophylactic cranial radiotherapy was done and maintenance therapy with atezolizumab was administered. After 53 months, the patient is still under treatment with a complete radiological response. This case report describes a rare instance of ovarian metastasis from SCLC that responded exceptionally well to immunotherapy. By reviewing literature from 1950 to the present, we identified other cases of ovarian metastases from SCLC, highlighting shared clinical and pathological traits and distinguishing them from primary ovarian tumors. We also examined the potential mechanisms behind the prolonged immunotherapy response observed in this case. As research on SCLC and immunotherapy evolves, this case may offer valuable insights into prognostic and predictive factors for this typically fatal cancer.

Effect of FDG PET-CT for Staging and Radiotherapy Planning - A Comparison of Cohorts From Two Randomized Trials of Thoracic Radiotherapy in Limited-Stage SCLC.

Introduction: 18F-fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) is recommended for staging and defining target volume in limited-stage SCLC, though the impact on outcomes compared with CT staging and elective nodal irradiation (ENI) is not well documented. We analyzed patients receiving 45 Gy/30 fractions in two randomized trials of thoracic radiotherapy (TRT) in limited-stage SCLC (HAST and THORA trials) to evaluate whether PET-CT for staging and radiotherapy planning reduces radiotoxicity and improves survival. Methods: Patients in HAST were staged with CT of the thorax and upper abdomen and brain magnetic resonance imaging of the brain. Patients in THORA were staged with PET-CT in addition. All patients were to receive four courses of platinum/etoposide chemotherapy and concurrent TRT starting three to four weeks after the first chemotherapy course. In HAST, target volumes included pathological lesions on CT plus ENI of lymph node stations 4-7 (bilateral). In THORA, target volumes were limited to PET-CT-positive lesions (selective nodal irradiation [SNI]). Results: A total of 149 patients were included (PET-CT/SNI: n = 76, CT/ENI: n=73); the median age was 64 years, 56% were women, 85% had PS 0 to 1, and 81% had stage III disease. The PET-CT/SNI group experienced less grade 3-4 esophagitis (18% versus 33%, p = 0.043), less grade >=1 pneumonitis (5% versus 16%, p = 0.028), and less dysphagia after TRT (mean scores on European Organisation for Research and Treatment of Cancer 13-item lung cancer module: 45 versus 72). There was no difference in median overall survival (24 versus 25 mo, p = 0.59) or progression-free survival (11 versus 11 mo, p = 0.23). Conclusions: Using PET-CT for staging and target volume definition of TRT reduces acute radiotoxicity but does not improve overall or progression-free survival in limited-stage SCLC.

Efficacy and safety of immune checkpoint inhibitors plus platinum-etoposide vs. platinum-etoposide in the first-line treatment of extensive-stage small cell lung cancer: a systematic review and a meta-analysis.

Background: Currently, immune checkpoint inhibitors (ICIs) combined with platinum-etoposide (EP) are gradually becoming the first-line standard treatment for extensive-stage small cell lung cancer (ES-SCLC). This meta-analysis aims to compare the efficacy and safety of ICIs combined with EP vs. EP alone in the first-line treatment of ES-SCLC. Methods: We searched PubMed, Embase, and Cochrane Library databases for phase II/III randomized controlled trials (RCTs) that met inclusion criteria from January 2016 to November 2023. Outcome measures included progression-free survival (PFS), overall survival (OS), objective response rate (ORR), treatment-related adverse events (TRAEs), treatment-related serious adverse events (TRSAEs), and immune-related adverse events (IRAEs). The effect analysis statistics of the outcome indicators were expressed with hazard ratio (HR) and odds ratio (OR) and their 95% confidence interval (CI). Results: This study included nine RCTs with a total of 4,711 patients. Compared to EP, ICIs plus EP improved patients' PFS (HR =0.71; 95% CI: 0.64-0.79; P<0.001), OS (HR =0.79; 95% CI: 0.74-0.84; P<0.001), and ORR (OR =1.27; 95% CI: 1.12-1.44; P=0.001), but increased the incidence of adverse events (AEs): TRAEs (OR =1.45; 95% CI: 1.20-1.76; P<0.001), IRAEs (OR =3.97; 95% CI: 2.49-6.32; P<0.001), and grade 3-4 IRAEs (OR =6.17; 95% CI: 2.36-16.15; P<0.001). However, there was no significant difference in the incidence of grade 3-4 TRAEs (OR =1.05; P=0.54), TRSAEs (OR =1.40; P=0.13), and grade 3-4 TRSAEs (OR =1.17; P=0.72). Subgroup analysis found that patients with brain metastasis did not benefit from ICIs combined with EP therapy, and patients with programmed cell death ligand 1 (PD-L1) expression ≥1% had poorer survival benefits compared to patients with PD-L1 expression <1%. Conclusions: In the first-line treatment of ES-SCLC, compared to EP chemotherapy, ICIs with EP can benefit patients in terms of PFS, OS, and ORR, but it will increase the occurrence of AEs.

Redefining YAP1 in small cell lung cancer: shifting from a dominant subtype marker to a favorable prognostic indicator.

Background: Molecular and transcription factor subtyping were recently introduced to identify patients with unique clinical features in small cell lung cancer (SCLC). However, its prognostic relevance is yet to be established. This study aims to investigate the clinical implications and prognostic significance of transcription factor subtyping in SCLC using immunohistochemistry. Methods: One hundred and ninety consecutive SCLC patients treated with platinum-based chemotherapy at a single institution were retrospectively reviewed. Expression of ASCL1, NeuroD1, POU2F3, and YAP1 was assessed by immunohistochemical staining and applied to determine the transcription factor subtype of each case. Results: The association among transcription factors was not entirely mutually exclusive. YAP1 expression was the most significant prognostic indicator compared with other transcription factors or their related subtypes. Among patients with limited-stage disease (LD), complete response (CR) rates were 46.2% and 22.4% in the YAP1-positive and YAP1-negative groups, respectively. The median duration of response among patients who achieved CR was 64.8 and 36.4 months in the YAP1-positive and YAP1-negative groups, respectively (P=0.06). Median overall survival (OS) in LD was 35.6 and 16.9 months in the YAP1-positive and YAP1-negative groups, respectively (P=0.03). In extensive-stage disease (ED), the median OS was 11.3 months for the YAP1-positive group and 11 months for the YAP1-negative group (P=0.03). Conclusions: Positive expression of YAP1 can be associated with durable CR and favorable survival outcomes in patients with SCLC, especially in LD.

Immune-related osteoblastic bone alterations mimicking bone metastasis in a small-cell lung cancer patient treated with durvalumab: a case report.

Background: Chemotherapy combined with immunotherapy is currently the standard first-line treatment for advanced small-cell lung cancer (SCLC). Immunotherapy can induce specific adverse events, called immune-related adverse events (irAEs). IrAEs of bones have rarely been reported. However, identifying bone irAEs could be important in avoiding misdiagnosis and ensuring appropriate patient management. This is the first report describing the diagnosis of irAEs of osteoblastic bone changes mimicking bone metastasis in a SCLC patient treated with durvalumab. Case Description: In this report, we describe a unique and challenging case in which a 54-year-old female patient with SCLC treated with durvalumab, an immunotherapy drug, exhibited osteoblastic bone changes that appeared similar to bone metastasis on imaging but were actually a side effect of immunotherapy. Before treatment, imaging revealed no bone metastasis. In the third month after treatment with durvalumab, computed tomography (CT) revealed multiple bone alterations, predominantly osteoblastic lesions with minor osteolytic changes. Various imaging tests suggested bone metastasis, but she had no symptoms related to bone disease. Notably, the lesions in the chest had achieved a partial response. Based on a comprehensive analysis of the CT-guided pathological biopsy results, the patient's symptoms, and the biological characteristics of SCLC, we determined that these bone changes were irAEs occurring in the skeletal system. The patient was followed up for 10 months, during which time the bone lesions remained stable. Conclusions: IrAEs of bones are rare, and their manifestations vary. Sometimes, the imaging manifestations of bone irAEs are difficult to distinguish from bone metastasis. If patients show variable treatment responses between different lesions, careful evaluation (including a pathological biopsy) is necessary.

Adebrelimab plus chemotherapy and sequential thoracic radiotherapy as first-line therapy for extensive-stage small-cell lung cancer (ES-SCLC): a phase II trial.

Background: This phase II prospective trial aimed to investigate the efficacy and safety of adebrelimab (PD-L1 antibody) plus first-line chemotherapy followed by sequential thoracic radiotherapy (TRT) combined with adebrelimab in extensive-stage small-cell lung cancer (ES-SCLC). Biomarkers associated with potential therapeutic effects were also explored. Methods: Patients with previously untreated ES-SCLC were enrolled at Shandong Cancer Hospital and Institute (Jinan, China). Patients received 4-6 cycles of adebrelimab (20 mg/kg, D1, Q3W) combined with EP/EC (etoposide, 100 mg/m2, D1-3, Q3W and cisplatin, 75 mg/m2, D1, Q3W or carboplatin, AUC = 5, D1, Q3W). Then patients with response sequentially underwent consolidative TRT (≥30 Gy in 10 fractions or ≥50 Gy in 25 fractions, involved-field irradiation), and maintenance adebrelimab until disease progression or intolerable adverse events (AEs). The primary endpoint was overall survival (OS). Genomic and circulating tumour DNA (ctDNA) profiling were also analyzed with tumour tissues and peripheral blood. This trial was registered with ClinicalTrials.gov, NCT04562337. Findings: From October 2020 to April 2023, 67 patients diagnosed with ES-SCLC were enrolled and received at least one dose of study treatment. All patients were included in the efficacy and safety analyses. 45 patients received sequential TRT as planned. The median OS and progression-free survival (PFS) was 21.4 months (95% CI: 17.2-not reached months) and 10.1 months (95% CI: 6.9-15.5 months), respectively. The confirmed objective response rate was 71.6% (48/67, 95% CI: 59.3-82.0%) and disease control rate was 89.6% (60/67, 95% CI: 79.7-95.7%). There were no treatment-related deaths. The most common grade 3 or higher treatment-related adverse events (TRAEs) were hematological toxicities. The incidence of any grade and G3+ pneumonitis was 25% (17/67) and 6% (4/67), respectively. No unexpected adverse events were observed. Patients without co-mutations of TP53/RB1 in both tissue and peripheral blood displayed longer PFS (tissue, P = 0.071; ctDNA, P = 0.060) and OS (tissue, P = 0.032; ctDNA, P = 0.031). Interpretation: Adebrelimab plus chemotherapy and sequential TRT as first-line therapy for ES-SCLC showed promising efficacy and acceptable safety. Funding: This study was funded by the National Natural Science Foundation of China (82172865), Jiangsu Hengrui Pharmaceuticals Co., Ltd. and Amoy Diagnostics Co., Ltd.

Potential therapeutic option for EGFR-mutant small cell lung cancer transformation: a case report and literature review.

Transformation from non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is rare and is associated with poor prognosis. However, the standard treatment protocols for patients with SCLC transformation remain unknown. Here, we report the case of a patient with advanced EGFR exon 19 deletion (19del) NSCLC who underwent SCLC transformation during targeted therapy. Biopsies and genetic testing were performed to adjust treatment regimens accordingly. The patient responded favorably to a combined treatment regimen comprising etoposide plus cisplatin chemotherapy and adebrelimab plus osimertinib. This case highlights the critical importance of acknowledging tumor heterogeneity in clinical decision-making and identifying potentially effective treatment options for patients with SCLC transformation. Additionally, we reviewed cases of the transformation of NSCLC to SCLC from 2017 to 2023.

Prognostic value of baseline clinicopathological characteristics in first-line chemotherapy ± immunotherapy for extensive-stage small cell lung cancer: a retrospective cohort study.

Background: The integration of chemotherapy and immunotherapy as a first-line treatment for extensive-stage small cell lung cancer (ES-SCLC) has been adopted in clinical practice, yet the response to immune checkpoint inhibitors (ICIs) is variable, benefiting only a fraction of patients. The current absence of reliable biomarkers for predicting treatment response and prognosis represents a significant gap in knowledge, hindering the optimization of patient stratification and treatment planning. This retrospective cohort study aims to assess the potential predictive and prognostic significance of clinicopathological baseline features in ES-SCLC patients. Methods: Our study retrospectively analyzed the data of consecutive patients with ES-SCLC treated with first-line etoposide plus platinum chemotherapy ± immunotherapy at The Affiliated Lihuili Hospital of Ningbo University from April 2017 to April 2023. Data on clinical information, serum laboratory indicators, pathological immunohistochemical markers, and progression-free survival (PFS) times were collected. Univariate and multivariate Cox regression analyses were employed to determine whether these indicators could serve as independent prognostic factors for PFS. Further, potential predictive markers for treatment efficacy were identified using a Cox regression model that incorporated an interaction term between treatment modality and the indicator. Results: A total of 121 patients with ES-SCLC were enrolled in the study, of whom 62 received chemotherapy alone, and 59 received chemotherapy in combination with immunotherapy. Compared to chemotherapy alone, the addition of immunotherapy to first-line chemotherapy significantly extended the PFS time [P<0.001; hazard ratio (HR) =0.42; 95% confidence interval (CI): 0.28, 0.64] of the ES-SCLC patients. The multivariate analysis revealed that an immunochemotherapy regimen (P<0.001, HR =0.40; 95% CI: 0.24, 0.68), a low-density lipoprotein (LDL) level of >1.8 mmol/L (P=0.02; HR =0.41; 95% CI: 0.20, 0.85) were independent prognostic factors of favorable PFS in the first-line treatment of all ES-SCLC, while a lactate dehydrogenase (LDH) level of >273 U/L (P=0.04; HR =1.78; 95% CI: 1.03, 3.07), a neuron-specific enolase (NSE) concentration of >102.6 ng/mL (P=0.009; HR =6.49; 95% CI: 1.60, 26.32), an apolipoprotein A1 (ApoA1) concentration of >0.9 g/L (P<0.001; HR =4.15; 95% CI: 1.98, 8.71), and an apolipoprotein B (ApoB) concentration of >0.8 g/L (P=0.002; HR =2.24; 95% CI: 1.34, 3.75) were independent prognostic factors of poorer PFS. Further, the interaction effect analysis demonstrated that an LDL level of >1.8 mmol/L and the absence of bone metastasis were potential predictors of an improved response to ICI therapy compared to chemotherapy alone. Conclusions: This study showed the survival benefit of receiving a chemoimmunotherapy regimen as the first-line treatment in a real-world scenario. It also suggests the prognostic significance of pre-treatment LDL, LDH, NSE, ApoA1, and ApoB with optimal cut-off values in the first-line treatment of all ES-SCLC, and the potential utility of baseline LDL level or the presence of bone metastasis in guiding first-line treatment strategies.

DB-1314, a novel DLL3-targeting ADC with DNA topoisomerase I inhibitor, exhibits promising safety profile and therapeutic efficacy in preclinical small cell lung cancer models.

BACKGROUND: Delta-like ligand 3 (DLL3) is highly expressed on the cell surface of small cell lung cancer (SCLC), one of the most lethal malignancies, but minimally or not in normal tissues, making it an attractive target for SCLC. However, none of the DLL3-targeting antibody-drug conjugates (ADCs) have been approved for SCLC therapy yet. We developed DB-1314, the new anti-DLL3 ADC composed of a novel humanized anti-DLL3 monoclonal antibody (DB131401) conjugated with eight molecules of P1021 (topoisomerase I inhibitor), and described its preclinical profiles. METHODS: The binding epitope for DB131401 and Rovalpituzumab was tested by biolayer interferometry. The binding affinity and specificity of DB-1314 to DLL3 and other homologous proteins were respectively measured by surface plasmon resonance and enzyme-linked immunosorbent assay. Internalization, bystander effects, and antibody-dependent cell-mediated cytotoxicity (ADCC) were assessed by respective assay. DLL3 was quantified by antibodies bound per cell assay and immunohistochemistry. In vitro and in vivo growth inhibition studies were evaluated in SCLC cell lines, and cell line/patient-derived xenograft models. The safety profile was measured in cynomolgus monkeys. RESULTS: DB-1314 induces potent, durable, and dose-dependent antitumor effects in cells in vitro and in cell/patient-derived xenograft models in vivo. The killing activity of DB-1314 mechanically arises from P1021-induced DNA damage, whereby P1021 is delivered and released within tumor cells through DLL3-specific binding and efficient internalization. Bystander effects and ADCC also contribute to the antitumor activity of DB-1314. DB-1314 displays favorable pharmacokinetic and toxicokinetic profiles in rats and cynomolgus monkeys; besides, DB-1314 is well-tolerated at a dose of up to 60 mg/kg in monkeys. CONCLUSIONS: These results suggest that DB-1314 may be a candidate ADC targeting DLL3 for the treatment of DLL3-positive SCLC, supporting further evaluation in the clinical setting.