Outcomes of responders to PD-1/PD-L1 inhibitors who discontinue therapy after sustained disease control.

BACKGROUND: PD-1/PD-L1 immune checkpoint inhibitors (ICIs) are widely used in the treatment of metastatic malignancies. Judiciously balancing disease control (DC) against development of immune-related adverse events (irAE) remains a crucial aspect of treatment. The effect of treatment discontinuation after sustained disease control (SDC) is unknown. The purpose of this analysis was to evaluate outcomes of responders to ICI who discontinue treatment after a minimum of 12 months (SDC). METHODS: We retrospectively reviewed the database of the University of New Mexico Comprehensive Cancer Center (UNMCCC) between 2014 and 2021 and identified patients who had received ICI. Patients with metastatic solid tumors who had stopped ICI therapy after achieving SDC [stable disease, partial response, complete response (SD, PR, CR)] were selected and outcomes reviewed from their electronic health records. RESULTS: We identified 204 patients who were treated with ICI for various solid cancers. Forty-four patients (21.6%) met the criteria, of whom 35 with follow-up data were included in the final analysis; including 11 melanoma, 5 non-small cell lung, 4 head & neck, 8 renal, 4 urothelial, 1 anal, 1 Merkel cell carcinoma, and 1 liposarcoma. Patients were divided into two groups: those who stopped ICI due to an irAE [irAE group, n = 14, median treatment time (MTT), 16.6 mo] and those who stopped due to other reasons (eg completion of 2 years of therapy, n = 20, non-cancer related surgery, n = 1) (non-irAE group, n = 21, MTT, 23.7 mo). Among the irAE group, the most common irAE included pneumonitis, rash, transaminitis, and fatigue. As of data cutoff date, 9 of 14 (64%) patients continued to show SDC. Only 5 of 14 (36%) patients in this group experienced progression of disease (PD), with 1 of 2 patients achieving DC (median follow-up of 19.2 mo after last dose of treatment, range 3-50.2 mo). Among the non-irAE group, 13 of 21 (62%) continued to have SDC. Eight of 21 (38%) experienced PD after stopping treatment, 7 of whom received ICI rechallenge, with 2 of 7 achieving DC (median follow-up of 22.2 mo, range 3.6-54.8 mo). At a median follow-up of 21.3 mo from stopping ICI therapy (range, 3-54.8 mo), 10 patients (71%) from the irAE group and 13 (61.9%) from the non-irAE group are in DC and have not experienced PD. CONCLUSIONS: We demonstrate that 22 (66%) patients experienced SDC, regardless of cancer type or development of irAE. After including patients who were re-challenged with ICI due to PD, 25 (71%) remain in DC. Future prospective malignancy-specific trials are warranted to evaluate optimal treatment duration.

Time to treatment initiation and its impact on real-world survival in metastatic colorectal cancer and pancreatic cancer.

BACKGROUND: Given the dearth of data regarding the time to treatment initiation (TTI) in the palliative setting, and its impact on survival outcomes, we sought to determine TTI in a real-world cohort of metastatic colorectal cancer (mCRC) and metastatic pancreatic cancer (mPC) patients and evaluate the impact of TTI on real-world survival outcomes. METHODS: We collected survival and treatment data for mCRC and mPC from the Flatiron Health electronic health records (EHR) derived database. We divided TTI into 3 categories: < 2 weeks, 2-< 4 weeks, and 4-8 weeks, from diagnosis to first-line therapy. Outcome measures were median TTI, real-world overall survival (RW-OS) based on TTI categories by Kaplan-Meier method, and impact of TTI on survival using cox proportional hazard models. RESULTS: Among 7108 and 3231 patients with mCRC and mPC treated within 8 weeks of diagnosis, the median TTI were 28 days and 20 days. Median RW-OS for mCRC was 24 months; 26.9 months versus 22.6 and 18.05 months in the 4-8-week, 2-< 4 week (control) and < 2-week groups, respectively (p < 0.0001). For mPC, median RW-OS was 8 months, without significant difference in RW-OS among the groups (p = 0.05). The 4-8-week group was associated with lower hazard of death (HR 0.782, 95% CI 0.73-0.84, p < 0.0001) and the < 2-week group was associated with a higher hazard of death (HR 1.26, 95% CI 1.15-1.38, p < 0.0001) in mCRC. The 4-8-week group was associated with lower hazard of death for mPC (HR 0.88, 95% CI 0.8-0.97, p = 0.0094). CONCLUSION: In a real-world cohort of patients treated within 8 weeks of diagnosis, and with the limitations of a retrospective study, later TTI did not have a negative impact on survival outcomes in mCRC and mPC.

Nephrotoxicity in the Age of Immune Checkpoint Inhibitors: Mechanisms, Diagnosis, and Management.

Immune checkpoint inhibitors (ICI) revolutionized cancer therapy by augmenting anti-tumor immunity via cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death-1/programmed death-ligand 1 (PD-1/PD-L1). However, this breakthrough is accompanied by immune-related adverse effects (irAEs), including renal complications. ICI-related nephritis involves complex mechanisms like auto-reactive T cells, auto-antibodies, reactivation of drug-specific T cells, and cytokine-driven inflammation culminating in AKI. ICI-AKI typically manifests weeks to months into treatment, often with other irAEs. Timely detection relies on monitoring creatinine levels and urine characteristics. Biomarkers, like soluble interleukin-2 receptor (sIL-2R) and urine cytokine levels, provide non-invasive insights, while renal biopsy remains the gold standard for confirmation. Management of ICI-AKI requires a balance between discontinuing ICI therapy and prompt immunosuppressive intervention, typically with corticosteroids. Some cases permit ICI therapy resumption, but varying renal recovery rates highlight the importance of vigilant monitoring and effective therapy. Beyond its clinical implications, the potential of irAEs to predict positive treatment responses in certain cancers raises intriguing questions. Data on nephritis-treatment response links are limited, and ongoing research explores this complex interaction. In summary, ICI therapy's transformative impact on cancer treatment is counterbalanced by irAEs, including nephritis. Early recognition and management are vital, with ongoing research refining diagnostic and treatment strategies.

Improving Outpatient Infusion Clinic Wait Times at a Comprehensive Cancer Center.

PURPOSE: Many factors contribute to long wait times for patients on the day of their chemotherapy infusion appointments. Longer wait time leads to nonoptimal care, increased costs, and decreased patient satisfaction. We conducted a quality improvement project to reduce the infusion wait times at a Comprehensive Cancer Center. METHODS: A multidisciplinary working group of physicians, infusion center nurses, pharmacists, information technology analysts, the Chief Medical Officer, and patient advocates formed a working group. Wait times were analyzed, and the contributing factors to long wait time were identified. Plan-Do-Study-Act cycles were implemented and included labeling patients ready to treat earlier, loading premedications into the medication dispensing system, increasing the number of pharmacy staff, and improving communication using a secure messaging system. The outcome measure was time from patient appointment to initiation of first drug at the infusion center. The secondary outcome measure was patient wait time satisfaction on the basis of Press Ganey score. RESULTS: Postintervention, the mean time from appointment to initiation of first drug decreased 17.6 minutes (P < .001; 95% CI, 16.3 to 18.9), from 58.1 minutes to 40.5 minutes (43.5% decrease). Patient wait time satisfaction score increased 8.9 points (P < .001; 95% CI, 6.0 to 11.82), from 76.2 to 85.1 (11.7% increase). CONCLUSION: Exploring real-time data and using a classic quality improvement methodology allowed a Comprehensive Cancer Center to identify deficiencies and prevent delays in chemotherapy initiation. This significantly improved patient wait time and patient satisfaction.

Prolonged Response to Anti-PD-1 Antibody Therapy in Chemotherapy-Refractory Cholangiocarcinoma With High Tumor Mutational Burden.

Management of advanced intrahepatic cholangiocarcinoma (iCCA) is challenging and overall survival is poor. Progress in the development of new therapeutic options for metastatic cholangiocarcinoma (CCA) has been slow; hence, to date, there are no approved second-line agents in this setting. Although the development of immune checkpoint inhibitors has significantly improved overall survival in a variety of malignancies, there has not been a clinically important impact in CCA. This report presents a 66-year-old patient with chemotherapy-refractory iCCA who experienced a prolonged response to immunotherapy. Tumor genome profiling revealed a high tumor mutation burden of 17 mutations per megabase in the absence of microsatellite instability. He was started on immunotherapy with nivolumab and has experienced an ongoing response for 16 months without clinical symptoms and only minimal radiologic disease.

Plasmacytoid/diffuse urothelial carcinoma: a single-institution immunohistochemical and molecular study of 69 patients.

Accurate diagnosis of plasmacytoid urothelial carcinoma (PUC) is important given its poor prognosis and frequent presentation at high stage. We aim to assess the clinicopathological features, molecular aberrations, and follow-up data in a series of PUC cases from a single tertiary cancer center. Seventy-two urinary bladder, ureteral, and renal pelvic specimens with urothelial carcinoma with plasmacytoid differentiation were identified. Immunohistochemical stains were performed on 48 cases. Among urinary bladder origin markers, GATA3 was most sensitive (96%). Breast carcinoma markers (estrogen receptor, mammaglobin) were usually negative, but progesterone receptor stained 1 case (4%). Neuroendocrine markers CD56 and TTF-1 were each positive in 1 case (4% and 4%, respectively). Gastrointestinal adenocarcinoma marker CDX2 was positive in 4 cases (15%), but nuclear ß-catenin was negative in all cases. CD138 was positive in 83% and E-cadherin expression was lost in 57% of cases. Fluorescence in situ hybridization using the UroVysion Bladder Cancer Kit and FGFR3 mutational analysis using polymerase chain reaction were performed on 15 cases; deletion of chromosome 9p21 was common (60%), and FGFR3 mutations were detected in 60% of cases (5 cases had both deletion 9p21 and FGFR3 mutations). Cases were divided into 3 morphologic groups: classic (29%), desmoplastic (35%), and pleomorphic (36%). The 3 morphologic subtypes had distinct survival outcomes (P = .083), with median survival for all patients 18 being months versus 10 months for the desmoplastic group.

Clinical Characteristics of Patients Experiencing Pathologic Complete Response Following Neoadjuvant Therapy for Borderline Resectable/Locally Advanced Pancreatic Adenocarcinoma.

OBJECTIVES: The purpose of this study is to describe clinical characteristics and outcomes of patients with borderline resectable pancreatic cancer (BRPC) or locally advanced pancreatic cancer (LAPC) who achieved pathologic complete response (pCR) following neoadjuvant therapy. MATERIALS AND METHODS: A single institution clinical database for patients with pancreatic ductal adenocarcinoma was queried. Between 2008 and 2014 patients were identified with BRPC and LAPC, who underwent surgical resection after receiving neoadjuvant treatment. Clinical and pathologic features of the patients who achieved pCR were acquired retrospectively. RESULTS: Six patients were identified to have pCR on pathology of the postoperative specimen. On the basis of pretreatment clinical staging, 2 patients were considered to have BRPC and 4 LAPC. Four patients received gemcitabine-based chemotherapy and 2 patients received FOLFIRINOX (5-fluorouracil, oxaliplatin, irinotecan, and leucovorin). Five of 6 patients received radiation therapy before operative resection. Operative procedures included distal pancreatectomy (n=3) and pancreatoduodenectomy (n=3). Pancreatic intraepithelial neoplasia 1 to 2 was present in 3 cases, and pancreatic intraepithelial neoplasia 3 in 1 case. During a median follow-up of 21.3 months, 2 patients died, with a median survival of 11.0 months (range, 10.4 to 11.6 mo). Four patients are alive and continue to follow-up with median survival of 28.7 months (range, 20.1 to 42.4 mo). CONCLUSIONS: Multimodality neoadjuvant therapy may lead to complete pathologic response in a small number of patients with borderline resectable/locally advanced pancreatic adenocarcinoma. pCR to neoadjuvant therapy does not lead to cure in most cases, and the majority of patients appear to relapse locally or systemically.

Targeting FGFR in Squamous Cell Carcinoma of the Lung.

Unlike for adenocarcinomas of the lung, no molecular targeted therapies have yet been developed for squamous cell lung cancers, because targetable oncogenic aberrations are scarce in this tumor type. Recent discoveries have established that the fibroblast growth factor (FGF) signaling pathway plays a fundamental role in cancer development by supporting tumor angiogenesis and cancer cell proliferation via different mechanisms. Through comprehensive genomic studies, aberrations in the FGF pathway have been identified in various tumor types, including squamous cell lung cancer, making FGF receptor (FGFR) a potentially druggable target in this malignancy. Several multi-targeted tyrosine kinase inhibitors include FGFR in their target spectrum and a number of these compounds have been approved for clinical use in different cancers. Novel agents selectively targeting FGFRs have been developed and are currently under investigation in clinical trials, showing promising results. This article reviews FGFR aberrations and the clinical data involving selective and multikinase FGFR inhibitors in squamous cell lung cancer.

Do Nonseminomatous Germ Cell Tumors of the Testis With Lymphovascular Invasion of the Spermatic Cord Merit Staging as pT3?

The staging of testicular nonseminomatous germ cell tumors (NSGCTs) with lymphovascular invasion (LVI) of the spermatic cord in the absence of cord parenchymal involvement remains controversial. Our previous study showed that tumors with spermatic cord LVI present at a higher clinical stage than tumors with LVI confined to the testis (pT2). We compared NSGCTs with LVI of the spermatic cord without direct involvement of the spermatic cord soft tissues to pT3 tumors to help clarify the appropriate staging of this histologic finding. A retrospective, multi-institutional review was performed to identify cases of NSGCTs with LVI in the spermatic cord without soft tissue invasion of the cord. The clinical-pathologic findings were compared with NSGCTs with spermatic cord soft tissue invasion (pT3). We identified 38 pT2 NSGCTs with LVI in the spermatic cord without soft tissue invasion of the cord and 89 pT3 tumors. There were no significant differences in patient age, tumor size, or clinical stage at presentation between the 2 groups. There were no significant differences in dominant histologic subtype, rete testis invasion, hilar soft tissue invasion, or margin status. There were no significant differences in disease recurrence/progression (P=0.63), recurrence/progression after chemotherapy (P=0.35), or death (P=0.51) between patients with only spermatic cord LVI versus patients with cord soft tissue invasion. In patients with pT2 NSGCTs according to the current staging, LVI in the spermatic cord without cord soft tissue invasion is comparable with pT3 tumors in terms of clinical stage at presentation as well as disease recurrence and survival.

The Significance of Lymphovascular Invasion of the Spermatic Cord in the Absence of Cord Soft Tissue Invasion.

CONTEXT: - Testicular germ cell tumors with lymphovascular invasion (LVI) are staged pT2, and those with spermatic cord involvement are staged pT3. OBJECTIVE: - To study the clinical significance of LVI within the spermatic cord without direct involvement of the cord soft tissues. DESIGN: - A retrospective, multi-institutional review was performed on testicular GCTs with spermatic cord LVI in the absence of cord soft tissue invasion. RESULTS: - Forty-four germ cell tumors had LVI in the spermatic cord without soft tissue invasion; 37 of 44 patients (84%) had nonseminomatous germ cell tumors (NSGCT), and 7 (16%) had pure seminomas. Patients with NSGCTs and spermatic cord LVI had worse clinical outcomes compared with patients with pure seminoma and spermatic cord LVI (P = .008). We then compared patients with NSGCTs and spermatic cord LVI (n = 37) to patients with NSGCTs and LVI limited to the testis (n = 32). A significantly greater percentage of patients with LVI in the spermatic cord presented with advanced clinical stage (76% versus 50%; P = .01). There was no statistically significant difference in disease recurrence/progression or death between patients with spermatic cord LVI and patients with LVI limited to the testis (P = .40; P = .50). There was no significant difference in the presence of embryonal dominant histology (P = .30) or rete testis invasion (P = .50) between the 2 groups. More hilar soft tissue invasion was seen in patients with LVI present in the spermatic cord (P = .004). CONCLUSIONS: - In patients with NSGCTs, LVI in the spermatic cord, without soft tissue invasion, is associated with worse clinical stage at presentation compared with patients with LVI confined to the testis.

Epstein-barr virus-related hemophagocytic lymphohistiocytosis: hematologic emergency in the critical care setting.

Hemophagocytic lymphohistiocytosis (HLH) is a rare and potential life-threatening clinical syndrome that results from uncontrolled activation of the immune system. Secondary HLH, more commonly observed in adult patients, is seen in the context of underlying triggering conditions. Epstein-Barr virus (EBV) has been recognized as the leading infectious cause and is associated with a poor outcome. As clinical and laboratory features of HLH could overlap with septic shock syndrome in most patients, the diagnosis of HLH, especially in adults, is the most challenging aspect of the disease that results in delayed recognition and treatment of rapidly progressive multiorgan system failure. We report a case of Hemophagocytic lymphohistiocytosis in a patient who presented with signs of septic shock syndrome and we review the literature on the topic.

Bilateral Acromioclavicular Septic Arthritis as an Initial Presentation of Streptococcus pneumoniae Endocarditis.

Infective endocarditis (IE) is infrequently associated with septic arthritis. Moreover, septic arthritis of the acromioclavicular (AC) joint is rarely reported in the literature. We report a case of Streptococcus pneumoniae IE in a patient who presented with bilateral AC joint septic arthritis and we review the literature on the topic.

Bevacizumab in high-grade gliomas: a review of its uses, toxicity assessment, and future treatment challenges.

High-grade gliomas continue to have dismal prognosis despite advances made in understanding the molecular genetics, signaling pathways, cytoskeletal dynamics, and the role of stem cells in gliomagenesis. Conventional treatment approaches, including surgery, radiotherapy, and cytotoxic chemotherapy, have been used with limited success. Therapeutic advances using molecular targeted therapy, immunotherapy, and others such as dietary treatments have not been able to halt tumor progression and disease-related death. High-grade gliomas (World Health Organization grades III/IV) are histologically characterized by cellular and nuclear atypia, neoangiogenesis, and necrosis. The expression of vascular endothelial growth factor, a molecular mediator, plays a key role in vascular proliferation and tumor survival. Targeting vascular endothelial growth factor has demonstrated promising results, with improved quality of life and progression-free survival. Bevacizumab, a humanized monoclonal antibody to vascular endothelial growth factor, is approved by the Food and Drug Administration as a single agent in recurrent glioblastoma and is associated with manageable toxicity. This review discusses the efficacy, practical aspects, and response assessment challenges with the use of bevacizumab in the treatment of high-grade gliomas.

Idiopathic pulmonary fibrosis in a referral center in Iran: are patients developing the disease at a younger age?

UNLABELLED:   BACKGROUND: The incidence of idiopathic pulmonary fibrosis (IPF) appears to be increasing.  In the western literature, the average age of presentation is in the seventh decade of life while it has been reported to be earlier in the Middle East and India.  Given that a paucity of epidemiological data exists in Iran, we sought to describe the clinical pattern and course of the disease at a large Iranian referral center. METHODS: A retrospective review was conducted of 132 patients diagnosed with IPF at the National Research Institute of Tuberculosis and Lung Diseases (NRITLD) in Tehran, Iran from 1988 through 2008. Data were collected from the medical records which consisted of demographics, clinical history, laboratory tests, pulmonary function tests (PFT), radiographic and pathology findings, treatment, and outcomes of the disease.   RESULTS: The mean age at diagnosis was 56.6 years (95% CI: 53.8 - 59.4) with no significant sex predilection. Common presenting symptoms included dyspnea and cough, which occurred for a mean period of 21 months prior to diagnosis. Common signs included end-inspiratory crackles and digital clubbing, which were found in 85.6% and 55.3% of the patients, respectively. Radiographically, reticular and reticulonodular opacities were seen in 47.3% and 20.9% of the patients, respectively on high resolution computed tomography (HRCT). In patients who underwent lung biopsy, diffuse interstitial fibrosis was seen in 91.1%. The mean follow-up time for all patients was 32.8 months (95% CI: 23.2 - 42.4, range: 1 - 257 months).  There were 16 patients who died during the study period. The mean age of death was 56.8 years (95% CI: 46.2 - 67.4), which is significantly lower than the life expectancy in Iran (P-value: 0.017). The mean survival time for patients who died was 1.1 years (95% CI: 0.5 - 1.7) after diagnosis.  The one- and three- year overall survival rates for all patients were 88% and 79%, respectively.  CONCLUSION: The clinical characteristics of IPF in Iran are similar to those in the western literature.  However, Iranian patients appear to be developing the disease a decade earlier than western patients.