Improved guideline compliance and textbook oncologic outcomes among patients undergoing multimodal treatment and minimally invasive surgery for locally advanced gastric cancer.

BACKGROUND: Although receipt of neoadjuvant chemotherapy has been identified to improve unfavorable survival outcomes among patients with locally advanced gastric cancer (LAGC), several randomized controlled trials have not demonstrated a difference in oncological outcomes/overall survival (OS) among patients undergoing minimally invasive surgery (MIS) versus open gastrectomy. This study aimed to investigate National Comprehensive Cancer Network (NCCN) guideline adherence and textbook oncological outcome (TOO) among patients undergoing MIS versus open surgery for LAGC. METHODS: In this cross-sectional study, patients with stage II/III LAGC (cT2-T4N0-3M0) who underwent curative-intent treatment between 2013 and 2019 were evaluated using the National Cancer Database. Multivariable analysis was performed to assess the association between surgical approach, NCCN guideline adherence, TOO, and OS. The study was registered on the International Standard Randomised Controlled Trial Number registry (registration number: ISRCTN53410429) and conducted according to the Strengthening The Reporting Of Cohort Studies in Surgery and Strengthening the Reporting of Observational Studies in Epidemiology guidelines. RESULTS: Among 13,885 patients, median age at diagnosis was 68 years (IQR, 59-76); most patients were male (n = 9887, 71.2%) and identified as White (n = 10,295, 74.1%). Patients who underwent MIS (n = 4692, 33.8%) had improved NCCN guideline adherence and TOO compared with patients who underwent open surgery (51.3% vs 43.5% and 36.7% vs 27.3%, respectively; both P < .001). Adherence to NCCN guidelines and likelihood to achieve TOO increased from 2013 to 2019 (35.6% vs 50.9% and 31.4% vs 46.4%, respectively; both P < .001). Moreover, improved median OS was observed among patients with NCCN guideline adherence and TOO undergoing MIS versus open surgery (57.3 vs 49.8 months [P = .041] and 68.4 vs 60.6 months [P = .025], respectively). CONCLUSIONS: An overall increase in guideline-adherent treatment and achievement of TOO among patients with LAGC undergoing multimodal and curative-intent treatment in the United States was observed. Adoption of minimally invasive gastrectomy may result in improved short- and long-term outcomes.

Non-cirrhotic hyperammonaemic encephalopathy secondary to metastatic pancreatic neuroendocrine tumour treated with peptide receptor radio nucleotide therapy and transarterial chemoembolisation.

Neuroendocrine tumours (NETs) are rare cancers which often carry significant morbidity and mortality, frequently related to burden of liver metastases. Hyperammonaemia and subsequent hepatic encephalopathy carries a poor prognosis and has been described in these patients. We discuss a case of a woman in her 50s with hyperammonaemic encephalopathy and a new diagnosis of pancreatic NET with hepatic metastases. She presented with a reduced conscious state a few days post commencing chemotherapy. This was considered to have a multifactorial pathophysiology: the primary driver being large volume hepatic metastases and contributed by portosystemic microshunting, sepsis, severe weight loss and malnutrition. We describe how each of these exacerbating factors was addressed and highlight the effective multimodal treatment approach consisting of sequential transarterial chemoembolisation followed by peptide receptor radio nucleotide therapy, resulting in the resolution of hyperammonaemic encephalopathy and radiological partial metabolic response.

¿Está justificado hacer un screening a largo plazo para el cáncer de pulmón en los pacientes con un carcinoma de cabeza y cuello? / Is long-term screening for lung cancer justified in patients with head and neck carcinoma?

Objetivo Los pacientes con un carcinoma escamoso de cabeza y cuello (CECC) tienen un mayor riesgo de aparición de segundas neoplasias localizadas en el pulmón que la población general. El objetivo del presente estudio es evaluar la incidencia a largo plazo de segundas neoplasias pulmonares tras el diagnóstico de un CECC y considerar la conveniencia de la realización de un cribado de cáncer de pulmón en estos pacientes. Material y métodos Realizamos un estudio retrospectivo en 4.954 pacientes con un tumor índice localizado en la cavidad oral, orofaringe, hipofaringe o laringe durante el periodo 1985-2017. Resultados Durante el periodo de seguimiento 469 pacientes (9,5%) presentaron una segunda neoplasia pulmonar. La incidencia de segunda neoplasia pulmonar fue del 1,26% anual, y se mantuvo prácticamente constante a lo largo de los 25 años de seguimiento analizados. Según los resultados de un estudio multivariante, los pacientes varones, con edades comprendidas entre los 50 y los 80 años, con antecedentes de tabaquismo y con tumores localizados en la orofaringe o en la supraglotis fueron los que presentaron un mayor riesgo de segunda neoplasia pulmonar. Conclusiones Los pacientes con un CECC como tumor índice tienen un alto riesgo de segundas neoplasias localizadas en el pulmón. Para conseguir un diagnóstico precoz de estas segundas neoplasias sería conveniente establecer protocolos de cribado basados en el uso de la TAC pulmonar de baja dosis, que deberían mantenerse indefinidamente durante el periodo de seguimiento. (AU)

Objective Patients with head and neck squamous cell carcinoma (HNSCC) have a higher risk of second lung neoplasms than the general population. The aim of the present study is to evaluate the long-term incidence of second lung malignancies after the diagnosis of a HNSCC and to consider the convenience of the screening for lung cancer in these patients. Material and methods We conducted a retrospective study performed on 4,954 patients with an index tumor located in the oral cavity, oropharynx, hypopharynx, or larynx during the period 1985-2017. Results During the follow-up period 469 patients (9.5%) presented a second pulmonary neoplasm. The incidence of second lung neoplasm was 1.26% per year and remained practically constant throughout the 25-year follow-up period analyzed. According to the results of a multivariate study, male patients, aged between 50 and 80 years, with a history of tobacco use, and with tumors located in the oropharynx or the supraglottis were those with the highest risk of second lung neoplasms. Conclusion Patients with a HNSCC index tumor have a high risk of second neoplasms located in the lung. In order to achieve an early diagnosis of these second neoplasms, it would be advisable to establish screening protocols based on the use of low-dose lung CT, which should be maintained indefinitely during the follow-up period. (AU)

Head and neck cancer with synchronous nodules of the lung as a diagnostic and therapeutic challenge - A systematic review.

Head and neck squamous cell carcinoma (HNSCC) often presents with synchronous nodules of the lung (sNL), which may be benign nodules, second primary malignancies or metastases of HNSCC. We sought to gain an insight into the incidence of sNL and synchronous second primary of the lung (sSPML) in HNSCC patients and current opinions on useful diagnostic and therapeutic approaches. We conducted a systematic search of the PubMed database for articles that reported the simultaneous detection of HNSCC and sNL/sPML, within the timeframe of diagnosis and staging. Only studies involving humans were included, without restrictions for sex, age, ethnicity, or smoking history. All articles were categorised according to the Oxford Centre of Evidence-Based Medicine levels and their data collected. Data from 24 studies were analysed. Amongst HNSCC, the mean overall incidence rate of sNL and sSPML was 11.4% (range: 1.3-27%) and 2.95% (range: 0.4-7.4%), respectively. The possibility of a sNL to be a sSPML cannot be ignored (mean: 35.2%). Studies investigating smoking habits showed that the majority (98-100%) of HNSCC patients with sSPML were previous or active smokers. Detection of human papillomavirus through DNA analysis, p16 immunohistochemistry, and identification of clonal evolution were useful in differentiating metastasis from sSPML. 18FDG-PET scan was the most reliable method to diagnose sSPML (sensitivity: 95%; specificity: 96%; positive predictive value: 80%). With early sSPML detection and curative treatment, the 5-year overall survival rate is 34-47%. However, the proposed advantage of early detection warrants further evidence-based justification.

Does the Clinical Presentation of Secondary Osteosarcoma in Patients Who Survive Retinoblastoma Differ From That of Conventional Osteosarcoma and How Do We Detect Them?

BACKGROUND: Osteosarcoma is the most common secondary malignancy among survivors of retinoblastoma. Most previous reports on secondary malignancy of retinoblastoma included all types of secondary malignancies without a focus on osteosarcoma, owing to its rarity. In addition, there are few studies suggesting tools for regular surveillance for early detection. QUESTIONS/PURPOSES: (1) What are the radiologic and clinical characteristics of secondary osteosarcoma after retinoblastoma? (2) What is the clinical survivorship? (3) Is a radionuclide bone scan a reasonable imaging modality for early detection in patients with retinoblastoma? METHODS: Between February 2000 and December 2019, we treated 540 patients for retinoblastoma. Twelve patients (six male, six female) subsequently developed an osteosarcoma in the extremities; two of these patients had two sites of osteosarcoma (10 femurs, four tibiae) . A Technetium-99m bone scan image was examined annually in all patients for regular surveillance after the treatment of retinoblastoma as per our hospital's policy. All patients were treated with the same strategy as that used for primary conventional osteosarcoma, namely neoadjuvant chemotherapy, wide excision, and adjuvant chemotherapy. The median follow-up period was 12 years (range 8 to 21 years). The median age at the time of diagnosis of osteosarcoma was 9 years (range 5 to 15 years), and the median interval from retinoblastoma diagnosis to osteosarcoma diagnosis was 8 years (range 5 to 15 years). Radiologic characteristics were assessed with plain radiographs and MRI, while clinical characteristics were assessed through a retrospective review of medical records. For clinical survivorship, we evaluated overall survival, local recurrence-free survival, and metastasis-free survival. We reviewed the results of bone scans and clinical symptoms at the time of diagnosis for osteosarcoma after retinoblastoma. RESULTS: In nine of 14 patients, the tumor had a diaphyseal center, and five of the tumors were located at the metaphysis. The femur was the most common site (n = 10), followed by the tibia (n = 4). The median tumor size was 9 cm (range 5 to 13 cm). There was no local recurrence after surgical resection of the osteosarcoma, and the 5-year overall survival rate after the diagnosis of osteosarcoma was 86% (95% CI 68% to 100%). In all 14 tumors, the Technetium bone scan showed increased uptake in the lesions. Ten of 14 tumors were examined in clinic because of patient complaints of pain in the affected limb. Four patients showed no clinical symptoms detected by abnormal uptake on bone scan. CONCLUSION: For unclear reasons, secondary osteosarcomas in patients who were alive after the treatment of retinoblastoma had a slight predilection for the diaphysis of the long bone compared with patients with spontaneous osteosarcoma in other reports. The clinical survivorship of osteosarcoma as a secondary malignancy after retinoblastoma may not be inferior to that of conventional osteosarcoma. Close follow-up with at least yearly clinical assessment and bone scans or other imaging modalities appears to be helpful in detecting secondary osteosarcoma after the treatment of patients with retinoblastoma. Larger multi-institutional studies will be needed to substantiate these observations.Level of Evidenc e Level IV, therapeutic study.

A case report: Secondary cancers due to oncological treatment modalities.

Background: Breast cancer (BC) is one of the most common cancers worldwide. In recent years, numerous non-chemotherapy agents have been developed for BC treatment, including targeted agents, new hormonal therapies, and immunotherapies. However, despite the widespread use of these agents, chemotherapies are still an important cornerstone in BC treatment. Similarly, serious de-escalation studies in radiotherapy use have been conducted in recent years. These two treatment modalities, which we frequently use in the treatment of BC due to their effectiveness, may also have serious side effects. Case Presentation: In this article, I will present a case of multiple myeloma (MM) and myxofibrosarcoma (MFS) that occurred many years later in a patient who completed adjuvant chemotherapy and radiotherapy for BC. MM has developed due to previous chemotherapy and MFS has developed due to previous radiotherapy. Conclusion: We usually treat our cancer patients with chemotherapy or radiotherapy to prolong their lives. In addition to the benefits we provide, may negatively affect the lifetime and quality of life by causing the development of metachronous secondary cancers in some patients. In this case report, I will present the "ironic" side of oncology science and treatment.

A nationwide study on cancer recurrences, second primary tumours, distant metastases and survival after treatment for primary head and neck cancer in the Netherlands.

INTRODUCTION: There is no consensus on the optimal duration of post-treatment follow-up after head and neck cancer (HNC). To generate site-specific input for follow-up guidelines, this study describes the incidence and timing of manifestations of disease during five years of follow-up. METHODS: All patients diagnosed with HNC in the Netherlands in 2015 were selected from the Netherlands Cancer Registry. The follow-up events local recurrence (LR), regional recurrence (RR), second primary tumour (SPT), distant metastasis (DM) and death were studied per follow-up-year. The cumulative incidence of these events was calculated using competing risk analyses, with LR, RR and SPT of the head and neck (SPHNC) as events and SPT outside the head-neck (SPOHN), DM and death as competing events. Analyses were performed for oral cavity-, oropharynx-, larynx- and hypopharynx squamous cell carcinoma (SCC), and all HNC patients. RESULTS: The 1-, 1.5-, and 2-year cumulative incidence of an event (LR, RR, SPHNC) were 10% (95%CI 8-13), 12% (95%CI 10-15), and 13% (95%CI 10-16) for oral cavity SCC; 6% (95%CI 4-9), 10% (95%CI 7-14), and 11% (95%CI 8-15) for oropharynx SCC; 7% (95%CI 5-10), 11% (95%CI 9-15), and 13% (95%CI 10-16) for larynx SCC and 11% (95%CI 6-19), 19% (95%CI 12-27), and 19% (95%CI 12-27) for hypopharynx SCC. CONCLUSIONS: One year of follow-up for oral cavity SCC, and 1.5 years for oropharynx-, larynx-, and hypopharynx SCC suffices for the goal of detecting disease manifestations after treatment. More research into other aspects of follow-up care should be performed to determine the optimal follow-up regimen.

Variation in second breast cancer risk after primary invasive cancer by time since primary cancer diagnosis and estrogen receptor status.

BACKGROUND: In women with previously treated breast cancer, occurrence and timing of second breast cancers have implications for surveillance. The authors examined the timing of second breast cancers by primary cancer estrogen receptor (ER) status in the Breast Cancer Surveillance Consortium. METHODS: Women who were diagnosed with American Joint Commission on Cancer stage I-III breast cancer were identified within six Breast Cancer Surveillance Consortium registries from 2000 to 2017. Characteristics collected at primary breast cancer diagnosis included demographics, ER status, and treatment. Second breast cancer events included subsequent ipsilateral or contralateral breast cancers diagnosed >6 months after primary diagnosis. The authors examined cumulative incidence and second breast cancer rates by primary cancer ER status during 1-5 versus 6-10 years after diagnosis. RESULTS: At 10 years, the cumulative second breast cancer incidence was 11.8% (95% confidence interval [CI], 10.7%-13.1%) for women with ER-negative disease and 7.5% (95% CI, 7.0%-8.0%) for those with ER-positive disease. Women with ER-negative cancer had higher second breast cancer rates than those with ER-positive cancer during the first 5 years of follow-up (16.0 per 1000 person-years [PY]; 95% CI, 14.2-17.9 per 1000 PY; vs. 7.8 per 1000 PY; 95% CI, 7.3-8.4 per 1000 PY, respectively). After 5 years, second breast cancer rates were similar for women with ER-negative versus ER-positive breast cancer (12.1 per 1000 PY; 95% CI, 9.9-14.7; vs. 9.3 per 1000 PY; 95% CI, 8.4-10.3 per 1000 PY, respectively). CONCLUSIONS: ER-negative primary breast cancers are associated with a higher risk of second breast cancers than ER-positive cancers during the first 5 years after diagnosis. Further study is needed to examine the potential benefit of more intensive surveillance targeting these women in the early postdiagnosis period.

Different situations of identifying second primary malignant tumors in lymphoma patients with synchronous solid tumors.

BACKGROUND: To our knowledge, the different situations of identifying second primary malignant tumors (SPMTs) in lymphoma patients with synchronous solid tumors remain to be comprehensively investigated. METHODS: We retrospectively collected information pertaining to lymphoma patients with synchronous solid tumors (diagnosed within 6 months) at Peking University Cancer Hospital & Institute between 2009 and 2019. The non-parametric Aalen-Johansen estimator was applied to calculate cumulative incidence function in the competing risk model. Furthermore, propensity score-matched analysis was performed to compare survival differences in lymphoma patients with or without synchronous solid tumors. RESULTS: Thirty-eight patients were enrolled. There were three situations of identifying SPMTs. First, in 15 patients (39.5%), SPMTs were identified before the initiation of any treatment. Among them, priority was given to anti-lymphoma treatment in case of only three patients. Second, in 17 patients (44.7%), SPMTs were unexpectedly detected on surgical specimen assessment; of them, 13 received anti-lymphoma treatment after surgery. Third, in six patients (15.8%), SPMTs were identified after the outset of treatment for the primary tumor; in this population, three of four patients with lymphoma switched toward the treatment plan for SPMTs. The 5-year overall survival was 58.7%. The cumulative incidence function within 5 years was 26.6% for lymphoma and 14.7% for other solid tumors. The early identification of SPMTs was associated with better outcomes (p = 0.048). After balancing the baseline characteristics, no differences in survival were observed between lymphoma patients with and without synchronous solid tumors (p = 0.664). CONCLUSIONS: This is the first study to present the different situations of identifying SPMTs in lymphoma patients with synchronous solid tumors. In only <50% patients, SPMTs were identifiable at baseline. SPMT identification at different situations may make it difficult to choose the optimal therapeutic option, which may consequently impact patient survival.

Multiple malignant primary tumors (non-head and neck): Contemplation needed.

BACKGROUND: The incidence of multiple malignant primary tumors (MMPT) is increasing which needs attention. Hence, we undertook this study to analyze clinico-demographic details and treatment outcomes in patients with non-head and neck MMPT. MATERIALS AND METHODS: Hospital case records of patients with histopathology proven MMPT registered in the radiation oncology department from January 1, 2008 to December 31, 2020 were retrospectively studied. Modified Warren-Gates criteria were used to define MMPT. Patients with MMPT of the head and neck (both an index and second primary as head-neck) were excluded from the study. Demographic and clinical details were recorded and analyzed. RESULTS: Forty-two eligible cases of non-head and neck MMPT were studied. The median age at diagnosis of an index case was 55 years (minimum 21, maximum 85) with a male to a female sex ratio of 5:37. Twelve patients had synchronous (28.57%) and 30 had metachronous (71.42%) MMPT. The average period between metachronous tumors was 77.77 months (minimum 12, maximum 312). The most common site of an index and second primary tumor was the breast (26; 61.90% and 23; 54.76%, respectively). Seventeen (65.38%) out of 26 index breast cancer were bilateral breast cancer and nine were others. In six cases of MMPT, there was an association between the breast and cervix. CONCLUSION: Breast cancer was the most common site for both an index and second primary malignancy followed by genital cancers. With cautious monitoring and patient education, second primary tumor could be detected earlier and managed better giving a good quality of life to patients.

Clinical significance of clonal hematopoiesis in the setting of autologous stem cell transplantation for lymphoma.

Autologous stem cell transplantation (ASCT) remains a key therapeutic strategy for treating patients with relapsed or refractory non-Hodgkin and Hodgkin lymphoma. Clonal hematopoiesis (CH) has been proposed as a major contributor not only to the development of therapy-related myeloid neoplasms but also to inferior overall survival (OS) in patients who had undergone ASCT. Herein, we aimed to investigate the prognostic implications of CH after ASCT in a cohort of 420 lymphoma patients using ultra-deep, highly sensitive error-correction sequencing. CH was identified in the stem cell product samples of 181 patients (43.1%) and was most common in those with T-cell lymphoma (72.2%). The presence of CH was associated with a longer time to neutrophil and platelet recovery. Moreover, patients with evidence of CH had inferior 5-year OS from the time of first relapse (39.4% vs. 45.8%, p = .043) and from the time of ASCT (51.8% vs. 59.3%, p = .018). The adverse prognostic impact of CH was not due to therapy-related myeloid neoplasms, the incidence of which was low in our cohort (10-year cumulative incidence of 3.3% vs. 3.0% in those with and without CH, p = .445). In terms of specific-gene mutations, adverse OS was mostly associated with PPM1D mutations (hazard ratio (HR) 1.74, 95% confidence interval (CI) 1.13-2.67, p = .011). In summary, we found that CH is associated with an increased risk of non-lymphoma-related death after ASCT, which suggests that lymphoma survivors with CH may need intensified surveillance strategies to prevent and treat late complications.

Role of Germline Predisposition to Therapy-Related Myeloid Neoplasms.

PURPOSE OF REVIEW: Therapy-related myeloid neoplasms (t-MNs) are aggressive leukemias that develop following exposure to DNA-damaging agents. A subset of patients developing t-MN may have an inherited susceptibility to develop myeloid neoplasia. Herein, we review studies reporting t-MN and their association with a germline or inherited predisposition. RECENT FINDINGS: Emerging evidence suggests that development of t-MN is the result of complex interactions including generation of somatic variants in hematopoietic stem cells and/or clonal selection pressure exerted by the DNA-damaging agents, and immune evasion on top of any inherited genetic susceptibility. Conventionally, alkylating agents, topoisomerase inhibitors, and radiation have been associated with t-MN. Recently, newer modalities including poly (ADP-ribose) polymerase inhibitors (PARPi) and peptide receptor radionucleotide therapy (PRRT) are associated with t-MN. At the same time, the role of pathogenic germline variants (PGVs) in genes such as BRCA1/2, BARD1, or TP53 on the risk of t-MN is being explored. Moreover, studies have shown that while cytotoxic therapy increases the risk of developing myeloid neoplasia, it may be exposing the vulnerability of an underlying germline predisposition. t-MN remains a disease with poor prognosis. Studies are needed to better define an individual's inherited neoplastic susceptibility which will help predict the risk of myeloid neoplasia in the future. Understanding the genes driving the inherited neoplastic susceptibility will lead to better patient- and cancer-specific management including choice of therapeutic regimen to prevent, or at least delay, development of myeloid neoplasia after treatment of a prior malignancy.

Risk factors for rebleeding and long-term outcomes in patients with head and neck cancer bleeding: a multicenter study.

BACKGROUND: Acute, catastrophic bleeding in patients with head and neck cancer (HNC) is challenging and also a burden for their families and frontline physicians. This study analyzed the risk factors for rebleeding and long-term outcomes in these patients with HNC. METHODS: Patients who presented to the emergency department (ED) with HNC bleeding were enrolled in this study (N = 231). Variables of patients with or without rebleeding were compared, and associated factors were investigated using Cox's proportional hazard model. RESULTS: Of the 231 patients enrolled, 112 (48.5%) experienced a recurrent bleeding event. The cumulative rebleeding incidence rate was 23% at 30 days, 49% at 180 days, and 56% at 1 year. Multivariate Cox regression analyses demonstrated that overweight-to-obesity (HR = 0.52, 95% CI 0.28-0.98, p = 0.043), laryngeal cancer (hazard ratio [HR] = 2.13, 95% confidence interval [CI] 1.07-4.23, p = 0.031), chemoradiation (HR = 1.49, 95% CI 1.001-2.94, p = 0.049), and second primary cancer (HR = 1.75, 95% CI 1.13-2.70, p = 0.012) are significant independent predictors of rebleeding, and the prognostic factors for overall survival included underweight (HR = 1.89, 95% CI 1.22-2.93, p = 0.004), heart rate > 110 beats/min (HR = 1.58, 95% CI 1.04-2.39, p = 0.032), chemoradiation (HR = 2.31, 95% CI 1.18-4.52, p = 0.015), and local recurrence (HR = 1.74, 95% CI 1.14-2.67, p = 0.011). CONCLUSIONS: Overweight-to-obesity is a protective factor, while laryngeal cancer, chemoradiation and a second primary cancer are risk factors for rebleeding in patients with HNC. Our results may assist physicians in risk stratification of patients with HNC bleeding.

PD-1 Inhibitor Combined With Radiotherapy and GM-CSF (PRaG) in Patients With Metastatic Solid Tumors: An Open-Label Phase II Study.

Patients with metastatic cancer refractory to standard systemic therapies have a poor prognosis and few therapeutic options. Radiotherapy can shape the tumor microenvironment (TME) by inducing immunogenic cell death and promoting tumor recognition by natural killer cells and T lymphocytes. Granulocyte macrophage-colony stimulating factor (GM-CSF) was known to promote dendric cell maturation and function, and might also induce the macrophage polarization with anti-tumor capabilities. A phase II trial (ChiCTR1900026175) was conducted to assess the clinical efficacy and safety of radiotherapy, PD-1 inhibitor and GM-CSF (PRaG regimen). This trial was registered at http://www.chictr.org.cn/index.aspx. A PRaG cycle consisted of 3 fractions of 5 or 8 Gy delivered for one metastatic lesion from day 1, followed by 200 µg subcutaneous injection of GM-CSF once daily for 2 weeks, and intravenous infusion of PD-1 inhibitor once within one week after completion of radiotherapy. The PRaG regimen was repeated every 21 days for at least two cycles. Once the PRaG therapy was completed, the patient continued PD-1 inhibitor monotherapy until confirmed disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). A total of 54 patients were enrolled with a median follow-up time of 16.4 months. The ORR was 16.7%, and the disease control rate was 46.3% in intent-to-treat patients. Median progression-free survival was 4.0 months (95% confidence interval [CI], 3.3 to 4.8), and median overall survival was 10.5 months (95% CI, 8.7 to 12.2). Grade 3 treatment-related adverse events occurred in five patients (10.0%) and grade 4 in one patient (2.0%). Therefore, the PRaG regimen was well tolerated with acceptable toxicity and may represent a promising salvage treatment for patients with chemotherapy-refractory solid tumors. It is likely that PRaG acts via heating upthe TME with radiotherapy and GM-CSF, which was further boosted by PD-1 inhibitors.

Effect of Electronic Symptom Monitoring on Patient-Reported Outcomes Among Patients With Metastatic Cancer: A Randomized Clinical Trial.

Importance: Electronic systems that facilitate patient-reported outcome (PRO) surveys for patients with cancer may detect symptoms early and prompt clinicians to intervene. Objective: To evaluate whether electronic symptom monitoring during cancer treatment confers benefits on quality-of-life outcomes. Design, Setting, and Participants: Report of secondary outcomes from the PRO-TECT (Alliance AFT-39) cluster randomized trial in 52 US community oncology practices randomized to electronic symptom monitoring with PRO surveys or usual care. Between October 2017 and March 2020, 1191 adults being treated for metastatic cancer were enrolled, with last follow-up on May 17, 2021. Interventions: In the PRO group, participants (n = 593) were asked to complete weekly surveys via an internet-based or automated telephone system for up to 1 year. Severe or worsening symptoms triggered care team alerts. The control group (n = 598) received usual care. Main Outcomes and Measures: The 3 prespecified secondary outcomes were physical function, symptom control, and health-related quality of life (HRQOL) at 3 months, measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30; range, 0-100 points; minimum clinically important difference [MCID], 2-7 for physical function; no MCID defined for symptom control or HRQOL). Results on the primary outcome, overall survival, are not yet available. Results: Among 52 practices, 1191 patients were included (mean age, 62.2 years; 694 [58.3%] women); 1066 (89.5%) completed 3-month follow-up. Compared with usual care, mean changes on the QLQ-C30 from baseline to 3 months were significantly improved in the PRO group for physical function (PRO, from 74.27 to 75.81 points; control, from 73.54 to 72.61 points; mean difference, 2.47 [95% CI, 0.41-4.53]; P = .02), symptom control (PRO, from 77.67 to 80.03 points; control, from 76.75 to 76.55 points; mean difference, 2.56 [95% CI, 0.95-4.17]; P = .002), and HRQOL (PRO, from 78.11 to 80.03 points; control, from 77.00 to 76.50 points; mean difference, 2.43 [95% CI, 0.90-3.96]; P = .002). Patients in the PRO group had significantly greater odds of experiencing clinically meaningful benefits vs usual care for physical function (7.7% more with improvements of ≥5 points and 6.1% fewer with worsening of ≥5 points; odds ratio [OR], 1.35 [95% CI, 1.08-1.70]; P = .009), symptom control (8.6% and 7.5%, respectively; OR, 1.50 [95% CI, 1.15-1.95]; P = .003), and HRQOL (8.5% and 4.9%, respectively; OR, 1.41 [95% CI, 1.10-1.81]; P = .006). Conclusions and Relevance: In this report of secondary outcomes from a randomized clinical trial of adults receiving cancer treatment, use of weekly electronic PRO surveys to monitor symptoms, compared with usual care, resulted in statistically significant improvements in physical function, symptom control, and HRQOL at 3 months, with mean improvements of approximately 2.5 points on a 0- to 100-point scale. These findings should be interpreted provisionally pending results of the primary outcome of overall survival. Trial Registration: ClinicalTrials.gov Identifier: NCT03249090.

Guideline discordant care in patients with metastatic germ cell tumors.

INTRODUCTION: Despite high curability, patients with metastatic germ cell tumors (GCT) in the United States general population persistently face inferior outcomes compared with those treated in specialty referral centers. We characterized guideline discordant management in patients with metastatic GCT who experienced relapse after first-line chemotherapy and compared those who were initially treated in community practices vs. academic referral centers. PATIENTS/METHODS: Retrospective analysis of 53 patients with relapsed GCT between 2005 and 2018. First-line GCT management was assessed against the National Comprehensive Cancer Network guidelines. Guideline discordant management, predictors of discordance, and associations with outcomes were assessed. RESULTS: Of 53 patients with relapsed GCT, 34% received guideline discordant care in the first-line setting. Guideline discordant care was more prevalent in patients initially treated in community practices (12/30, 40%) vs. those initially treated in academic centers (3/22, 14%), though in multivariate logistic regression, this difference was not statistically significant (odds ratio: 4.07, P = 0.08). Most patients in community settings who received guideline discordant care were undertreated (10/12, 83%). There were 3 major reasons for guideline discordant care: (1) failure to resect residual masses after chemotherapy (27%, 4/15), (2) mismanagement of chemotherapy-related adverse events (27%, 4/15), and (3) under staging at diagnosis, resulting either insufficient chemotherapy regimen intensity (13%, 2/15) and/or inappropriately receiving primary surgical resection for metastatic disease (20%, 3/15). CONCLUSION: Under treatment was identified in nearly half of patients initially treated in a community setting who later developed relapsed GCT. Referral to specialized centers for a second opinion should be considered for all metastatic GCT patients in the first-line setting and all patients with post-chemotherapy residual disease. More effective methods should be developed to facilitate second opinions from expert centers in the United States.

Impact of FDG PET/CT on detection of synchronous and metachronous malignancies and clinical management in patients with multiple primary cancers.

Multiple primary cancers are usually defined as primary malignant tumors of different histological origins in one person. Recently, there has been an increase in the number of patients diagnosed with multiple primary cancers. The study aims to evaluate the role of PET/CT in detecting second primary and subsequent tumors as well as to demonstrate the influence on the treatment management in patients with histologically proven synchronous or metachronous tumors. Fifty patients with clinically proven at least one malignancy have been evaluated and followed up for a year. Another inclusion criterion was a biopsy-proven additional primary synchronous (within 2-6 months after the first one) or metachronous (more than 6 months after the diagnosis of the first one) malignant tumor in a different organ. All patients were scanned on GE Discovery PET/CT 16 slices scanner from the top of the head to mid-thigh. The study was performed one hour after injection, using the weight-adjusted activity, hydration of patients with diuretic stimulation, and oral/i.v. contrast intake. Thirty out of 50 patients were females. The youngest patient was 25 years old, while the highest age was 84 years. Ten of the patients had third primary tumors and one patient had four different malignancies. Metachronous tumors were 2.4-fold higher than synchronous ones. The minimum time to detect a second tumor was 1 month, while the maximum was 15 years. As second malignancies we detected fourteen gastrointestinal cancers (28%), ten urogenital ones (20%), ten pulmonary tumors (20%), five breast cancers (10%), four lymphoma patients (8%), four head and neck squamous cell carcinomas (8%), two NET (4%), and one sarcoma (2%). As a result of the 18F-FDG PET/CT scan, the therapy plans of all 50 patients required modification at the minimum for the second tumor. 64% of the patients had multimodality therapy for their first cancer, which suggests that this approach could play an important role in the development of MPM. 81% of the additional malignancies in the female group, detected by PET/CT were in stages I or II, which provides a higher probability of cure. On the other hand, we detected advanced stage second primary disease in 70% of the patients in the male group. PET/CT can identify a significant number of additional primary neoplasms in patients with known primary cancer, acquiring combined metabolic and morphologic information, as well as its whole-body protocol. Integrated PET/CT can significantly modify the assessment of the tumor's dissemination and often change patient management substantially. Subsequent primary lesions identified after PET/CT scan are mainly in the early stage and thus have an excellent likelihood of being cured if treated promptly and aggressively.

Rationale and design of a prospective, multicenter, phase II clinical trial of safety and efficacy evaluation of long course neoadjuvant chemoradiotherapy plus tislelizumab followed by total mesorectal excision for locally advanced rectal cancer (NCRT-PD1-LARC trial).

BACKGROUND: Long course radiotherapy plus neoadjuvant chemotherapy followed by resection (total mesorectal excision, TME) has accepted widespread recognized in the treatment of locally advanced rectal cancer (LARC). Tislelizumab, an anti-PD1 humanized IgG4 monoclonal antibody, has been demonstrated with clinical activity and is approved for treating recurrent/refractory classical Hodgkin lymphoma and locally advanced/metastatic urothelial carcinoma in China. However, the safety and efficacy of long course (neoadjuvant chemoradiotherapy, NCRT) plus tislelizumab followed by TME for LARC is still uncertain. METHODS: This NCRT-PD1-LARC trial will be a prospective, multicenter and phase II clinical trial designed to evaluate the safety and efficacy of LARC patients treated with long course NCRT plus tislelizumab followed by TME. This trial will consecutively enroll 50 stage II/III LARC patients (cT3N0M0 and cT1-3N1-2M0) with the tumor distal location ≤ 7 cm from anal verge at 7 centers in China. The enrolled patients will receive long course radiotherapy (50 Gy/25 f, 2 Gy/f, 5 days/week) and three 21-day cycles capecitabine (1000 mg/m2, bid, po, day1-14) plus three 21-day cycles tislelizumab (200 mg, iv.gtt, day8), followed by TME 6-8 weeks after the end of radiotherapy. The primary efficacy endpoint will be the pathological complete response (pCR) rate, which is defined as absence of viable tumor cells in the primary tumor and lymph nodes. DISCUSSION: To our knowledge, this trial is the first multicenter clinical trial in China to assess the safety and efficacy of NCRT plus anti-PD1 therapy followed by TME to treat patients with LARC. NCRT followed by TME was recognized as the most recommended treatment against LARC while could not be completely satisfied in clinic. This study expects to provide a solid basis and encouraging outcomes for this promising combination of radiotherapy, chemotherapy and immunotherapy in LARC. TRIAL REGISTRATION: Name of the registry: ClinicalTrials.gov. TRIAL REGISTRATION NUMBER: NCT04911517. Date of registration: 23 May 2021. URL of trial registry record: https://www. CLINICALTRIALS: gov/ct2/show/NCT04911517?id=BFH-NCRTPD&draw=2&rank=1 .

Impact of frontline treatment approach on outcomes in patients with secondary AML with prior hypomethylating agent exposure.

BACKGROUND: Treated secondary acute myeloid leukemia (ts-AML)-i.e., AML arising from a previously treated antecedent hematologic disorder-is associated with very poor outcomes. The optimal frontline treatment regimen for these patients is uncertain. METHODS: We retrospectively analyzed 562 patients who developed AML from preceding myelodysplastic syndrome or chronic myelomonocytic leukemia for which they had received a hypomethylating agent (HMA). Patients with ts-AML were stratified by frontline AML treatment with intensive chemotherapy (IC, n = 271), low-intensity therapy (LIT) without venetoclax (n = 237), or HMA plus venetoclax (n = 54). RESULTS: Compared with IC or LIT without venetoclax, HMA plus venetoclax resulted in higher CR/CRi rates (39% and 25%, respectively; P = 0.02) and superior OS (1-year OS 34% and 17%, respectively; P = 0.05). The benefit of HMA plus venetoclax was restricted to patients with non-adverse risk karyotype, where HMA plus venetoclax resulted in a median OS of 13.7 months and 1-year OS rate of 54%; in contrast, for patients with adverse risk karyotype, OS was similarly dismal regardless of treatment approach (median OS 3-5 months). A propensity score analysis accounting for relevant clinical variables confirmed the significant OS benefit of HMA plus venetoclax, as compared with other frontline treatment approaches. In a landmark analysis, patients with ts-AML who underwent subsequent hematopoietic stem cell transplantation (HSCT) had superior 3-year OS compared to non-transplanted patients (33% vs. 8%, respectively; P = 0.003). CONCLUSIONS: The outcomes of ts-AML are poor but may be improved with use of an HMA plus venetoclax-based regimen, followed by HSCT, particularly in those with a non-adverse risk karyotype.

Secondary myeloid neoplasms after CD19 CAR T therapy in patients with refractory/relapsed B-cell lymphoma: Case series and review of literature.

Background: Several chimeric antigen receptor T cells (CAR T) targeting CD19 have induced profound and prolonged remission for refractory/relapsed (R/R) B-cell lymphoma. The risk of secondary malignancies, especially myeloid neoplasms, is of particular concern in the CAR T community, which still remains unclear. Methods: Four patients with R/R B-cell lymphoma after CD19 CAR T therapy diagnosed with secondary myeloid neoplasms (SMN) from 2 hospitals in eastern China were presented, including 3 with myelodysplastic syndrome (MDS) and 1 with acute myeloid leukemia (AML). Using single-cell RNA sequencing (scRNA-seq), we compared the cellular components of bone marrow (BM) samples obtained from one of these MDS patients and a health donor. We also provided a review of recently published literature concerning SMN risk of CAR T therapy. Results: Relevant demographic, clinical, laboratory, therapeutic and outcome data were collected and presented by chart review. In our case series, the male-female ratio was 3.0 and the median age at MDS onset was 61.25 years old (range, 50-78). Median number of previous systemic therapies was 4.5 (range, 4-5), including autologous hematopoietic stem cell transplantation (auto-HSCT) in one patient. BM assessments prior to CAR T therapy confirmed normal hematopoiesis without myeloid neoplasms. Moreover, for 3 patients with SMN in our series, cytogenetic analysis predicted a relatively adverse outcome. In our experience and in the literature, treatment choices for the patients with SMN included allogeneic hematopoietic stem cell transplantation (allo-HSCT), hypomethylating agent (HMA), period filgrastim, transfusions and other supportive care. Finally, treatment responses of lymphoma, together with SMN, directly correlated with the overall survival of this community. Of note, it appeared that pathogenesis of MDS wasn't associated with the CAR T toxicities, since all 4 patients experienced a pretty mild CRS of grade 1-2. Additionally, scRNA-seq analysis described the transcriptional alteration of CD34+ cells, identified 13 T/NK clusters, and also indicated increased cytotoxic T cells in MDS BM. Conclusion: Our study illustrated the onset and progression of SMN after CD19 CAR T therapy in patients with R/R B-cell lymphoma, which provides useful information of this uncommon later event.