Search Results

Background: We sought to identify the absolute risk of specific HPV genotype for cervical intraepithelial neoplasia grade 2/3 or worse (CIN2+/3+) and to develop a risk-based management strategy in an HPV-positive population. Methods: HPV genotyping was performed based on a 3-year cervical cancer screening cohort. The study endpoints were histologic CIN2+/3+. The prevalence of specific HPV genotype was calculated by minimum, any type, and hierarchical attribution estimate. The absolute CIN2+/3+ risks of specific HPV genotype were estimated and risk-based management strategy was established according to the American Society for Colposcopy and Cervical Pathology guideline. The efficacy of conventional and risk-based management strategies for non-16/18 HPVs were further evaluated. Results: Eligible data were available for 8,370 women with a median age of 48 years (interquartile range, 42–53 years). At baseline, there were 1,062 women with HPV-positive disease, including 424 with multiple and 639 with single infections. CIN2+/3+ cases represented 113/74, 23/8, 20/7, and 52/31 patients at baseline and first-, second-, and third-year visits, respectively. Women with multiple HPV infections at baseline were more prone to persistent infection than those with single infection (P<.0001). HPV16 and HPV52 were the top 2 ranking among baseline and 3-year cumulative CIN2+/3+ cases. Based on the absolute risk of specific HPV genotype combined with cytology for CIN2+/3+, all non-16/18 HPVs were divided into 4 risk-stratified groups. Compared with conventional strategy, the risk-based strategy had higher specificity (P=.0000) and positive predictive value (P=.0322) to detect CIN3+ and needed fewer colposcopies for each CIN3+ case. Conclusions: Based on our study findings, we propose a new extended HPV genotyping protocol, which would provide a better strategy for achieving precise risk-based management of HPV-positive populations.

Hematopoietic neoplasms with FGFR1 rearrangements are rare. Clinically, patients often present with a chronic myeloproliferative neoplasm with eosinophilia and an increased risk of transformation to acute leukemia. We report a patient who initially presented with B-cell acute lymphoblastic leukemia (B-ALL) with t(8;22)(p11.2;q11.2) and an additional derivative chromosome 22 [der(22)t(8;22)]. After induction chemotherapy, B-ALL blasts were eradicated; however, a chronic myeloproliferative process emerged showing persistent t(8;22) (p11.2;q11.2) but not der(22)t(8;22). Combined morphologic and fluorescence in situ hybridization revealed that both lymphoblasts and myeloid cells harbored t(8;22)(p11.2;q11.2); but only lymphoblasts carried the additional der(22)t(8;22). This case provides direct evidence to illustrate the clonal relationship of chronic phase and blast phase in myeloid neoplasms with FGFR1 rearrangement, and demonstrates that clonal cytogenetic evolution plays an important role in disease progression.

Background: Immune-mediated diarrhea and colitis (IMDC) is a common immune-related adverse effect related to immune checkpoint inhibitors. We aimed to identify risk factors for chronic IMDC and its prognostic value in cancer outcomes. Methods: We retrospectively collected data on patients with a diagnosis of IMDC between January 2018 and October 2019 and grouped them based on disease duration into acute (≤3 months) and chronic (>3 months) categories. A logistic regression model and the Kaplan-Meier method with log-rank tests were used for biostatistical analysis. Results: In our sample of 88 patients, 43 were in the chronic group and 45 were in the acute group. Genitourinary cancer and melanoma accounted for 70% of malignancies. PD-1/L1 monotherapy (52%) was the more frequently used regimen. We showed that chronic IMDC was associated with proton pump inhibitor use (odds ratio [OR], 3.96; P=.026), long duration of IMDC symptoms (OR, 1.05; P<.001) and hospitalization (OR, 1.07; P=.043), a histologic feature of chronic active colitis (OR, 4.8; P=.025) or microscopic colitis (OR, 5.0; P=.045), and delayed introduction of selective immunosuppressive therapy (infliximab/vedolizumab; OR, 1.06; P=.047). Chronic IMDC also reflected a better cancer response to immune checkpoint inhibitors (30% vs 51%; P=.002) and was accompanied by improved overall survival (P=.035). Similarly, higher doses of selective immunosuppressive therapy were associated with better overall survival (P=.018). Conclusions: Chronic IMDC can develop among patients with a more aggressive disease course and chronic features on colon histology. It likely reflects a prolonged immune checkpoint inhibitor effect and is associated with better cancer outcome and overall survival.

Background: Biomarkers for chemotherapy efficacy in non–small cell lung cancer (NSCLC) are lacking. This retrospective study assesses the association between blood-based tumor mutational burden (bTMB) and clinical benefit of chemotherapy. Methods: Clinical and targeted next-generation sequencing data from the OAK trial (training set; n=318) and POPLAR trial (validation set; n=106) in the docetaxel arm were analyzed. The cutoff value of bTMB for outcome prediction was determined based on a time-dependent receiver operating characteristic curve in the training set, and propensity score matching (PSM) was conducted. The primary outcome was overall survival (OS). Durable clinical benefit (DCB) was defined as OS lasting >12 months. Interaction between treatment and bTMB was assessed in the combined set. Results: A lower bTMB was observed in patients with DCB compared with no durable benefit, and in those with a partial response and stable disease compared with progressive disease. The optimized cutoff value of bTMB for predicting OS was 7 single-nucleotide variants per megabase. In the training set, a low bTMB was significantly associated with longer OS and progression-free survival (PFS). The prognostic value of bTMB was confirmed in the validation set and PSM set. The interaction between bTMB and treatment was significant for PFS (interaction P=.043) in the combined set. Mutations in KEAP1 were associated with high bTMB and a lack of benefit from chemotherapy. Conclusions: Low bTMB is associated with a survival advantage in patients with NSCLC treated with docetaxel, suggesting the prognostic and predictive potential of bTMB for determining chemotherapy efficacy.

Background: The optimal surveillance strategy after resection of colorectal liver metastases (CLM) is unknown. We evaluated changes in recurrence risk after CLM resection and developed a surveillance algorithm. Methods: Patients undergoing CLM resection during 1998 to 2015 were identified from a prospectively compiled database and analyzed if they had the potential for follow-up longer than the longest observed time to recurrence in this cohort. Changes in recurrence risk and risk factors for recurrence were evaluated. All statistical tests were 2-sided. Results: Among 2,105 patients who were initially identified and underwent CLM resection, the latest recurrence was observed at 87 months; 1,221 consecutive patients from 1998 through 2011 with the potential for at least 87 months of follow-up were included. The risk of recurrence was highest at 0 to 2 years after CLM resection, lower at 2 to 4 years after CLM resection, and steadily lower after 4 years after CLM resection. Factors associated with increased recurrence risk at the time of surgery were primary lymph node metastasis (hazard ratio [HR], 1.54; 95% CI, 1.21–1.97; P<.001), multiple CLM (HR, 1.31; 95% CI, 1.06–1.63; P=.015), largest liver metastasis diameter >5 cm (HR, 1.64; 95% CI, 1.23–2.19; P<.001), and RAS mutation (HR, 1.29; 95% CI, 1.04–1.59; P=.020). In patients without recurrence at 2 years, the only factor still associated with increased recurrence risk was RAS mutation. In those patients, the recurrence rate at 4 years was 59.3% in patients with RAS mutation versus 27.8% in patients with RAS wild-type (P=.019). Conclusions: For patients who have undergone CLM resection, we propose surveillance every 3 to 4 months during years 0 to 2, every 3 to 4 months (if mutant RAS) versus every 4 to 6 months (if RAS wild-type) during years 2 to 4, and every 6 to 12 months if recurrence-free at 4 years.

Background: Although immune checkpoint inhibitors (ICIs) have provided practice-changing outcomes in treating many cancers, ICI-related gastrointestinal toxicity can limit their use. Upper gastrointestinal toxicity is not common nor as well described as lower gastrointestinal toxicity. We aimed to characterize the clinical presentation, endoscopic and histologic features, treatment response, and outcomes of ICI-related esophagitis. Methods: We retrospectively studied patients at The University of Texas MD Anderson Cancer Center in whom esophagitis developed after receiving ICIs from June 2011 through January 2020. We included patients with endoscopic evidence of esophagitis and excluded those with other obvious causes of esophagitis. A chi-square test was used to assess associations between categorical variables. The Mann-Whitney U test was used to compare differences between continuous variables. Results: Of 657 consecutive patients who underwent esophagogastroduodenoscopy (EGD) during or within 6 months of completing ICI-based therapy, 21 (3%) had esophagitis deemed to be from ICIs. Of these patients, 1 (5%) received an inhibitor of CTLA-4 alone, 15 (71%) received anti–PD-1 or PD-L1 monotherapy, and 5 (24%) received a combination of these. Median time from ICI initiation to onset of esophagitis was 4 months. Upon evaluation with EGD, only 3 patients (14%) had isolated esophageal involvement; 18 (86%) had concurrent involvement of the stomach, duodenum, or both. Most patients (67%) were treated with proton pump inhibitors, and 4 (19%) received steroids (prednisone or budesonide). The mortality rate was 38% (median follow-up, 15 months). Conclusions: Esophagitis associated with ICI use is rare. The diagnosis is one of exclusion because its clinical presentation appears similar to that of inflammation resulting from other causes. It often occurs in conjunction with other upper gastrointestinal toxicity. Symptoms are mild and respond well to nonimmunosuppressive treatment, with few severe complications.

Background: Angiosarcoma is a malignant neoplastic disease originating from or differentiating toward vascular endothelium, for which systemic pharmacologic treatment has limited durability. The molecular oncogenesis of angiosarcoma is often linked to inappropriate activations of vascular endothelial growth factor receptor (VEGFR) family members, which presents an opportunity for the use of therapy that selectively targets the machinery of vascular signaling. Methods: Hybridization capture of 3,320 exons of 182 cancer-related genes and the introns of 14 genes frequently rearranged in cancer was applied to more than 50 ng of DNA extracted from a formalin-fixed, paraffin-embedded biopsy of recurrent angiosarcoma and was sequenced to high, uniform coverage of 939x. Results: The angiosarcoma harbored amplifications of VEGFR2 (KDR) of 8 copies and VEGFR3 (FLT4) of 16 copies. The patient was initially treated with sorafenib, an inhibitor of VEGFR2, and developed progressive disease. The patient then received pazopanib, an inhibitor of VEGFR2 and VEGFR3 and experienced a potent antitumor response resulting in clinically stable disease for 6 months. Conclusions: This exceptional response to pazopanib treatment suggests that a subset of patients with angiosarcoma with genomic alterations in vascular signaling genes may respond well to pazopanib.

Understanding of the genetic basis and molecular pathogenesis of cancer has evolved substantially over the past century. The advent of high-throughput gene sequencing methods has unraveled hundreds of recurrent somatic genetic alterations in various malignancies, either causative or harboring major prognostic and/or predictive implications. Knowledge of these specific changes has dramatically altered diagnostic and therapeutic approaches to cancer, enabling personalized molecular therapies. This article shares approaches to adopting and fine-tuning the practice of molecular diagnostics as an essential component of diagnostic pathology in a tertiary care cancer hospital and proposes methods by which genetic testing in cancer can become standard of care in pathology departments across the nation.

Background: The therapeutic strategies for clinical stage T1–3N2 (cT1–3N2) lung cancer are controversial. For operable tumors, treatment can vary by center, region, and continent. This study aimed to identify the optimal therapeutic method and type of surgical strategy for cT1–3N2 lung cancer. Methods: This retrospective evaluation analyzed the records of 17,954 patients with cT1–3N2 lung cancer treated in 2010 through 2015 from the SEER database. The effects of different therapeutic methods and types of surgical strategies on overall survival (OS) were assessed. Univariate and multivariate analyses were performed using a Cox proportional hazards model. Results: The 5-year OS rates were 27.7% for patients with T1N2 disease, 21.8% for those with T2N2 disease, and 19.9% for T3N2 disease. Neoadjuvant therapy plus operation (OP) plus adjuvant therapy, and OP plus adjuvant therapy, provided better 5-year OS rates than OP alone or concurrent chemoradiotherapy (34.1%, 37.7%, 29.3%, and 16.1%, respectively). In the T1N2, T2N2, and T3N2 groups, lobectomy provided better 5-year OS than pneumonectomy, sublobectomy, and no surgery. Both univariate and multivariate analyses showed that young age, female sex, well-differentiated histologic grade, adenocarcinoma cell type, neoadjuvant and adjuvant therapy, lobectomy, and T1 stage were statistically associated with better 5-year OS rates. Conclusions: In cT1–3N2 lung cancer, multimodal treatments tended to provide better 5-year OS than OP alone or concurrent chemoradiotherapy. In addition, lobectomy was associated with better survival than other operative methods.