Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL, LT) is a subtype of cutaneous B-cell lymphoma with unfavorable prognosis usually requiring aggressive polychemotherapy for disease control. Only single cases of spontaneous regression of PCDLBCL, LT are reported in the literature, peaking 3 months post-biopsy following a clinical history of no longer than 1 year. Here, we report the first case of a spontaneously relapsing and remitting PCDLBCL, LT with complete regression after a clinical history of more than 9 years and thus an atypically indolent clinical course. The female patient presented with recurrent erythematous, non-ulcerated, non-raised plaques of the right lower leg for 6 years. Pathological workup and exclusion of a systemic disease confirmed the diagnosis of PCDLBCL, LT. Due to the history of repeated spontaneous remission, no therapy was initiated. Nine years after first occurrence the patient presented with complete clinical remission lasting for 64 months. We retrospectively identified four additional PCDLBCL, LT patients with spontaneous remission lasting up to 53 months. Our data provide evidence for a distinct PCDLBCL, LT patient subgroup that clinicians should be aware of and warrants a watch-and-wait treatment regime.

This study analyzes the development, US Food and Drug Administration (FDA) approval, benefits, innovation, trials, epidemiology, and price of cancer drugs with multiple special designations: orphan, fast track, accelerated approval, priority review, and breakthrough therapy.

In total, 355 FDA-approved cancer drug indications with 841 special designations were identified (2012-2022). Trial, epidemiology, and price data were collected from FDA labels, the Global Burden of Disease study, and Medicare and Medicaid. The association between efficacy outcomes and indications' number of special designations were compared in meta-analyses.

Median development times were 7.3, 7.8, and 5.4 months (P = .027) for drugs with 0 to 1, 2 to 3, and 4 to 5 special designations, respectively. Multiple special designations were associated with higher biotechnological and clinical innovation. Median patient enrollment in trials were 615, 471, 398, 168, 104, and 120 (P < .001) for indications with 0 to 5 special designations. Drugs for rare diseases supported by open-label phase 1/2 trials of single-arm design were granted more special designations. Hazard ratios for overall survival (0.80 vs 0.73 vs 0.73 vs 0.69 vs 0.56 vs 0.52; P = .003) and progression-free survival (0.70 vs 0.61 vs 0.59 vs 0.44 vs 0.37 vs 0.67; P < .001) substantially declined while tumor response increased with more special designations. Mean monthly prices increased for drugs with 0 to 4 but not 5 special designations ($21 596 vs $14 753 vs $32 410 vs $41 240 vs $38 703 vs $19 184).

Multiple special designations are associated with faster clinical development and greater benefits for patients with unmet needs but also with nonrobust trial evidence and a tendency toward higher drug prices.

Randomized clinical trials (RCTs) testing innovative drugs must strive to use optimal control groups to reflect the best available treatments. A comprehensive evaluation of the quality of control groups in pivotal RCTs supporting systemic rheumatic disease (SRD) drug approvals by the Food and Drug Administration (FDA) is lacking.

To examine the proportion of pivotal RCTs that used optimal control groups among RCTs supporting newly approved SRD drugs in the US over the past decade.

In this study, individual RCTs supporting SRD new drug approvals by the FDA between January 2012 and October 2022 were analyzed for design, study duration, control group, and primary end point. The quality of control groups was determined by comparison with published guidelines before and during the trial.

The primary measure was the proportion of RCTs using optimal control groups. Differences in response rate between investigating and control groups and the response rate of placebo control groups were also examined.

Between January 2012 and October 2022, the FDA approved 44 SRD drugs, involving 65 pivotal RCTs. Overall, 16 RCTs used optimal control groups. In 55 trials, no active groups were used, and more than 80% of these trials were suboptimal (47 trials [85.5%]). Among 56 trials for systemic arthritis, 49 trials used suboptimal control groups, mainly placebo or dose-response controls (47 trials), with a few active controls (2 trials). Studies of other SRDs frequently used placebo or dose-response controls but were considered optimal controls (8 trials). There was significant improvement in response rates of investigating compared with placebo groups, with relative risk mostly exceeding 1.50 (range, 0.90; 95% CI, 0.69-1.17 for anifrolumab to 11.00; 95% CI, 2.69-44.96 for mepolizumab). In all placebo-controlled trials, the median (IQR) response rate in placebo groups was 26.0% (19.2%-32.3%).

These findings suggest that the quality of control groups in RCTs leading to SRD drug approval needs improvement and that despite challenges in translating scientific theories to clinical scenarios, it is crucial to consistently prioritize efforts to promote appropriate control group selection to ensure the accurate assessment of innovative drug efficacy.

Spontaneous regression (SR) of cancer is an exceedingly rare phenomenon. While SR is well-documented for some cancers, very few reports exist in oropharyngeal squamous cell carcinomas (OPSCCs) and none in human papillomavirus (HPV)-positive OPSCCs.

A 67-year old man presented with a left-sided neck mass. Neck CT, PET, and biopsies showed a SCC in a left-sided lymph node without a primary lesion. Immunohistochemistry confirmed HPV16. Six weeks after biopsy, the patient underwent left selective tonsillectomy and neck dissection.

Surgery revealed a left tonsillar SCC and no lymph nodes with tumor. Histology revealed homogenous fibrosis and intermixed immune cells indicative of tumor regression analogous to reports of immune-related pathologic responses. AE1/AE3 immunostain was also negative for tumor. All lymph nodes remained negative at 1 year follow-up.

We described a spontaneously regressed lymph node in a tonsillar HPV-positive SCC. The unique immune environment of HPV-positive OPSCCs, and unknown environmental or host factors, may have played a role in our patient's SR which requires future studies to elucidate.

Spontaneous regression of advanced solid tumors is infrequent but may occur. Quantifying response rates from placebo in cancer drug trials may provide important information for physicians, patients, and regulators. We aimed to provide a pooled placebo response rate from drug trials in advanced solid tumors.

We pooled the overall response rate (ORR), complete response rate (CR) and partial response rates (PR) in the placebo arm of placebo-controlled randomized controlled trials (RCTs) of cancer drugs for advanced solid tumors published during 2015-2021 using random-effects model.

45 phase 3 RCTs including 5684 patients on placebo met our inclusion criteria and formed the study cohort. The pooled overall ORR, CR and PR rates in the placebo arm were 1% (95% CI, 0%-2%), 0% (95% CI, 0%-0%), and 1% (95% CI, 0%-2%) respectively. Higher placebo responses were observed in prostate cancer and sarcoma trials.

Overall, 1% patients with advanced solid tumors can expect to achieve some response even in absence of treatment. However, complete regression without treatment is extremely rare, almost zero percent. This information will be helpful to patients in their decisions, as well as regulators in evaluating cancer drugs' efficacy based on response rates alone.

None.

Clinical trial evidence is routinely evaluated for initial drug approvals, yet the benefit of indication extensions remains uncertain. This study evaluates the clinical benefit supporting new cancer drugs' initial and supplemental US Food and Drug Administration (FDA) indication approval.

Clinical trial evidence supporting each indication's FDA approval was collected from the Drugs@FDA database between 2003 and 2021. Drug, indication, and clinical trial characteristics are described. Hazard ratios (HRs) for overall survival (OS), progression-free survival (PFS), and relative risk for tumor response were meta-analyzed.

Out of 124 FDA-approved drugs, 78 were approved across multiple indications. Out of 374 indications, 141 were approved as combination therapies, 255 for solid cancers, 121 with biomarkers, and 182 as first-line therapy. Approval was mostly supported by open-label (267 [71%]) phase III (238 [64%]) concurrent randomized controlled trials (248 [66%]) with a median of 331 enrolled patients (interquartile range [IQR], 123-665 patients). Across 234 randomized controlled trials with available data, drugs' HRs were 0.73 (95% CI, 0.72 to 0.75; I² = 29.6%) for OS and 0.57 (95% CI, 0.54 to 0.60; I² = 90.6%) for PFS, whereas tumor response was 1.38 (95% CI, 1.33 to 1.42; I² = 80.7%). Novel pharmaceuticals increased patient survival by a median of 2.80 months (IQR, 1.97-4.60 months) for OS and 3.30 months (IQR, 1.50-5.58 months) for PFS. Initial indications more frequently received accelerated approval, supported by single-arm trials for advanced-line monotherapies, than indication extensions. Initial approvals provided a higher PFS (HR, 0.48 v 0.58; P = .002) and tumor response (relative risk, 1.76 v 1.36; P < .001).

New cancer drugs substantially reduce the risk of death and tumor progression, yet only marginally extend patient survival. The FDA, physicians, patients, and insurers must evaluate and decide on a drug's safety and efficacy approval, pricing, coverage, and reimbursement on an indication-specific level.

Methotrexate-associated lymphoproliferative disorder (MTX-LPD) is a major complication of methotrexate (MTX) therapy that can develop in patients with rheumatoid arthritis (RA), although primary hepatic MTX-LPD is extremely rare. Discontinuation of MTX results in remission in half of the patients with MTX-LPDs and is one treatment approach.

A 64-year-old Japanese woman suffering from rheumatoid arthritis treated with MTX presented with upper abdominal pain.

Pathological evaluation showed that the tumor contained geographic necrosis and proliferation of large atypical lymphocytes strongly positive for cluster of differentiation 20 (CD20) antigen with immunohistochemical staining and Epstein-Barr Virus-encoded RNA transcript by in situ hybridization. The tumor was finally diagnosed as a primary hepatic MTX-associated Epstein-Barr Virus positive B-cell LPD.

Left hepatic lobectomy was performed for diagnosis and therapy.

No sighs of recurrence were observed for 2 years.

This patient demonstrated that MTX-LPD could arise in the liver, although it is rare. If liver tumors arise in patients taking MTX, examination of sIL-2R, Epstein-Barr virus-VCA IgG and EBNA might support the diagnosis of MTX-LPD. In this case, the primary hepatic MTX-LPD became necrotic without discontinuation of MTX. It is generally believed that withdrawal of MTX restores antitumor immunity resulting in tumor necrosis. This case indicates that spontaneous regression might occur without any treatment in some patients treated for RA with MTX-LPD. The relationship between MTX-LPD and spontaneous necrosis is unclear and further data is required to characterize the types of patients that will develop spontaneous regression without intervention.

Limited information exists about the design of placebo-controlled cancer trials. Through a systematic review of trials published in 2013, we describe placebo use in randomized trials testing anticancer agents and analyze strategies that increase exposure to the experimental regimen.

Trials were classified as add-on (placebo in combination with standard treatment) or placebo-only. Strategies to allow more than half of the participants to receive the experimental regimen were reviewed. The risk-benefit ratio of receiving the experimental agent was considered favorable if the difference in primary outcome was significant (p ≤ 0.05), neutral if there was no significant difference in the primary outcome and the experimental agent did not add substantial toxicity, and unfavorable otherwise.

Eighty trials were included (32,694 participants). Most trials were add-on (69%). The risk-benefit outcome was favorable, neutral, and unfavorable to the experimental agent in 52%, 32%, and 16% of placebo-only trials and 25%, 53%, and 22%, respectively, of add-on trials. Four strategies increased exposure to the experimental regimen: one-way crossover (23%), uneven randomization (21%), three-arms (13%), and randomized discontinuation design (4%); these strategies were used more often in placebo-only trials.

A minority of participants received placebo alone and strategies to increase experimental exposure were used commonly. Fewer than half of the studies had favorable outcomes, thus defending the use of placebo controls, when there is no established treatment. Strategies that increase patient exposure to experimental agents rather than placebo may expose them to non-beneficial, sometimes toxic, experimental agents.

Background: Randomized clinical trials (RCTs) of anticancer drugs without active comparators in patients who have exhausted standard of care treatment options are debated. We aimed to quantify the safety and the efficacy of anticancer drugs in advanced cancer patients who have exhausted standard of care treatments from RCTs without active comparators.Methods: This systematic review and meta-analysis was conducted according to preferred reporting Items for systematic review and Meta-Analyses (PRISMA) guidelines (CRD42021243968). A systematic literature search of English language publications from January 1, 2000, to January 7, 2021, was performed using MEDLINE (PubMed). Eligible trials included all RCTs evaluating anticancer drugs in adult patients with advanced solid tumors with a control arm without any anticancer drug consisting of best supportive care with or without a placebo. RCTs performed in the adjuvant, neoadjuvant or maintenance settings were excluded, as were clinical trials evaluating anticancer drugs in combination with radiotherapy. Two authors (C.M.B. and E.C.) independently reviewed the studies for inclusion. Data from published reports were extracted by investigators, and random-effects meta-analysis was performed to estimate the overall hazard ratios (HRs) of progression-free survival (PFS) and overall survival (OS). Correlations between severe toxicity and efficacy was assessed using R² measures.Findings: Of 3551 studies screened, 128 eligible trials were found involving 47,432 patients. The HRs for PFS and OS were 0·58 [95%CI: 0·53-0·63] and 0·82 [95%CI: 0·78-0·85]. The absolute benefits however were limited with PFS and OS gains of 2·1 and 0·5 months. The absolute excesses in all grade, severe grade III, IV and V (death) adverse events between the two arms were +13·9%, 10·2%, and +0·5%. A weak correlation was measured between the excess of severe toxicity and efficacy (all R² < 0·2).Interpretation: Anticancer drugs evaluated in RCTs against no active treatment benefited trial participants. Severe toxicity did not significantly correlate with efficacy.

None.

Diffuse large B cell lymphoma (DLBCL) is an aggressive disorder accounting for >30% of all lymphomas. Its prognosis is poor due to a high relapse rate. Spontaneous regression (SR) in DLBCL is rare, with only a few reported cases. Moreover, almost all of these were low-grade lymphomas with an average SR duration of 13 mo. As the cause of SR is unknown, there are many theories such as trauma, infection, medication, and an antitumor immune response. We present a patient with progressive DLBCL who demonstrated SR for >42 mo. Although treatment for lymphoma usually starts soon after diagnosis, insights into SR of lymphomas may lead to new treatment strategies.

Partial or complete spontaneous regression (SR) of cancer is unusual, particularly in patients with oesophageal cancer. This case report describes a patient with biopsy-proven squamous cell carcinoma of the oesophagus which spontaneously regressed without any treatment. Regression of the primary tumour was confirmed on histological examination of the resected specimen. The process of SR remains an enigma, but potential mechanisms are considered.

Gastric gastrinoma and spontaneous tumor regression are both very rarely encountered. We report the first case of spontaneous regression of gastric gastrinoma.

A 37-year-old man with a 9-year history of chronic abdominal pain was referred for evaluation of an 8 cm mass in the lesser omentum discovered incidentally on abdominal computed tomography. The tumor was diagnosed as grade 2 neuroendocrine neoplasm (NEN) on endoscopic ultrasound-guided fine-needle aspiration. Screening esophagogastroduodenoscopy revealed a 7 mm red polypoid lesion with central depression in the gastric antrum, also confirmed to be a grade 2 NEN. Laparoscopic removal of the abdominal mass confirmed it to be a metastatic gastrinoma lesion. The gastric lesion was subsequently diagnosed as primary gastric gastrinoma. Three months later, the gastric lesion had disappeared without treatment. The patient remains symptom-free with normal fasting serum gastrin and no recurrence of gastrinoma during 36 mo of follow-up.

Gastric gastrinoma may arise as a polypoid lesion in the gastric antrum. Spontaneous regression can rarely occur after biopsy.

Most guidelines still recommend active surveillance for patients with asymptomatic, unresectable neuroendocrine tumors (NETs). However, recent findings from several randomized placebo-controlled trials suggest that most patients would benefit from active treatment. We conducted a meta-analysis of pooled outcomes from clinical trials in which an active treatment arm was compared with placebo to determine whether active treatment provides a survival advantage.

This meta-analysis evaluated six trials that compared a medication with placebo in patients with an asymptomatic, metastatic NET. The trials were heterogenous with regard to the active medication (octreotide, lanreotide, sunitinib, everolimus, Lu-Dotatate) and tumor localizations (gastrointestinal, pancreas, lung). Overall survival (OS) and progression-free survival (PFS) for the placebo and active treatment arms were obtained from individual trial data and combined to obtain pooled outcomes.

The individual trials all reported significantly better PFS outcomes for active treatment. The pooled data confirmed this advantage. At months 3, 6, 12, 18, and 24, pooled PFS rates for the placebo and treatment arms, respectively, were 92.9% versus 96.9%; 54.3% versus 83.7%; 35.5% versus 68.5%; 25.1% versus 54.7%; and 17.7% versus 61.0%. OS was also higher in the active treatment groups. At months 6, 12, 24, 36, 48, and 60, OS rates (placebo vs. active treatment), respectively, were 88.1% versus 93.4%; 84.1% versus 86.2%; 67.4% versus 76%; 56.6% versus 64.4%; 49.9% versus 61.0%; and 41.7% versus 45.9%.

This meta-analysis confirms findings from recent clinical trials indicating that active treatment yields better survival outcomes than placebo. Importantly, these findings were obtained across a wide range of patient profiles and diverse medical treatments for metastatic NETs. Given the lack of reliable prognostic factors to determine a priori which patients are unlikely to benefit from active treatment, these findings support early treatment in most patients.

Although most guidelines still recommend active surveillance for patients diagnosed with metastatic neuroendocrine tumors, the results of this meta-analysis, together with recent data from key clinical trials, suggest that most patients could benefit from upfront active treatment. However, more data are needed to confirm this.

Spontaneous tumor regression can be observed in many tumors, however, studies related to the altered expression of lncRNA in spontaneous glioma regression are limited, and the potential contributions of lncRNAs to spontaneous glioma regression remain unknown. To investigate the biological roles of lncRNA-135528 in spontaneous glioma regression. The cDNA fragment of lncRNA-135528 was obtained by rapid-amplification of cDNA ends (RACE) technology and cloned into the plvx-mcmv-zsgreen-puro vector. Additionally, we stably silenced or overexpressed lncRNA-135528 in G422 cells by transfecting with siRNA against lncRNA-135528 or lncRNA-135528 overexpression plasmid. Then, we examined lncRNA-135528 overexpressing and lncRNA-135528 silencing on glioma cells and its effects on CXCL10 and JAK/STAT pathways. The main findings indicated that lncRNA-135528 promoted glioma cell apoptosis, inhibited cell proliferation and arrested cell cycle progression; the up-regulation of lncRNA135528 led to significantly increased CXCL10 levels and the differential expression of mRNA associated with JAK/STAT pathway in glioma cells. lncRNA-135528 can inhibit tumor progression by up-regulating CXCL10 through the JAK/STAT pathway.

The past decade has seen tremendous advances in both our understanding of cancer immunosuppressive microenvironments and colonic bacteria facilitated by immune checkpoint inhibitor antibodies and next generation sequencing, respectively. Because an important role of the host immune system is to communicate with and regulate the gut microbial community, it should not come as a surprise that the behavior of one is coupled to the other. In this review, we will attempt to dissect some of the studies demonstrating cancer immunotherapy modulation by specific gut microbes and discuss possible molecular mechanisms for this effect.

Spontaneous regression of Hodgkin lymphoma (HL) is a rare event. We describe a 32-year-old woman with spontaneous regression of HL and review the literature. The patient presented with cervical lymphadenopathy and was diagnosed with stage IIA classical HL. The patient refused to receive any treatment for her disease. Positron emission tomography/computed tomography carried out 2 years later showed complete regression of the lymphadenopathy, without pathological uptake of fluorodeoxyglucose. At the last follow-up, 3.5 years after the initial presentation, the patient is with no evidence of disease. During workup for the HL, concomitant papillary thyroid carcinoma was diagnosed, for which the patient refused treatment as well. The thyroid malignancy has remained stable throughout the follow-up.

Immunotherapy with checkpoint inhibitors has arrived and begun to change the landscape of clinical oncology, including for patients with renal cell carcinoma. Specifically, drugs targeting the programmed death 1 and cytotoxic T-lymphocyte associated antigen pathways have demonstrated remarkable responses for patients in clinical trials. In this article, we review the most recent available data for immune checkpoint inhibitors for patients with renal cell carcinoma. We discuss potential strategies for rational combination therapies in these patients, some of which are currently being studied, and address important future considerations for use of these novel agents in the years to come.