Presence Of Distant Disease Research Articles

Mortality risk prediction for primary appendiceal cancer

BackgroundAccurately predicting survival in patients with cancer is crucial for both clinical decision-making and patient counseling. The primary aim of this study was to generate the first machine-learning algorithm to predict the risk of mortality following the diagnosis of an appendiceal neoplasm. MethodsPatients with primary appendiceal cancer in the Surveillance, Epidemiology, and End Results database from 2000 to 2019 were included. Patient demographics, tumor characteristics, and survival data were extracted from the Surveillance, Epidemiology, and End Results database. Extreme gradient boost, random forest, neural network, and logistic regression machine learning models were employed to predict 1-, 5-, and 10-year mortality. After algorithm validation, the best-performance model was used to develop a patient-specific web-based risk prediction model. ResultsA total of 16,579 patients were included in the study, with 13,262 in the training group (80%) and 3,317 in the validation group (20%). Extreme gradient boost exhibited the highest prediction accuracy for 1-, 5-, and 10-year mortality, with the 10-year model exhibiting the maximum area under the curve (0.909 [±0.006]) after 10-fold cross-validation. Variables that significantly influenced the predictive ability of the model were disease grade, malignant carcinoid histology, incidence of positive regional lymph nodes, number of nodes harvested, and presence of distant disease. ConclusionHere, we report the development and validation of a novel prognostic prediction model for patients with appendiceal neoplasms of numerous histologic subtypes that incorporate a vast array of patient, surgical, and pathologic variables. By using machine learning, we achieved an excellent predictive accuracy that was superior to that of previous nomograms.

Outcomes and after Hyperfractionated, Accelerated Reirradiation for Recurrent Anal Squamous Cell Carcinoma

Abdominoperineal resection (APR) is the standard salvage treatment for recurrent or persistent squamous cell carcinoma of the anus (SCCA). However, reirradiation (reRT) can be used preoperatively or for those who are not candidates for surgery. Using a single institutional database, patients were identified who underwent reRT for SCCA from 2003 to 2022. Response to reRT and outcomes after reRT were recorded. Variables analyzed included age at reRT, sex, reason for reRT (recurrent SCCA vs new SCCA after pelvic radiation for a different malignancy), interval between initial radiation and reRT, reRT dose, concurrent chemotherapy, receipt of APR and the presence of distant metastases at the time of reRT. Cox Proportional Hazard Model was used; multivariable analysis for all factors with a univariate P-value <0.1 on univariable analysis. A total of 42 patients received reRT, which consisted of 1.5 Gray (Gy) twice daily fractions with ≥6-hour interval to a total dose ranging 30Gy to 54Gy (median [IQR] 39Gy [39-42Gy]. Thirty-eight patients (90.5%) received concurrent chemotherapy; most often with weekly cisplatin and 5-fluorouracil (N = 23, 54.8%). Median [IQR] follow-up after reRT was 11.4 months [4.9-40.8 months]. Median [IQR] initial radiation dose was 54Gy [54-58Gy], and median [IQR] interval between initial radiation and reRT was 3.6 years [2.1-6.0 years]. For 8 patients (19.1%), the initial radiation was given for a different pelvic malignancy prior to being diagnosed with SCCA. Four of these patients received brachytherapy alone or in conjunction with external beam. For the remaining 34 patients, the initial radiation was for SCCA and the reRT was for recurrent SCCA either in the anal canal (N = 23, 67.6%) or regional nodes (N = 11, 32.3%). Four patients (9.5%) had distant disease at the time of reRT. Eleven patients (26.2%) had planned APR after preoperative reRT; 1 patient had a pathologic complete response (pCR), 2 patients had a near pCR (<5% viable cancer). Twenty-nine patients (69.0%) were treated with reRT alone; 15 (51.7%) attained a clinical CR. Two patients (4.8%) were treated with palliative intent and response was not assessed. Median local recurrence free survival (LRFS) was 9.9 months; 2- and 3-year LRFS were both 41%. Median distant metastasis free survival (DMFS) was 11.8 months; 2- and 3-year DMFS were 38% and 34%, respectively. Median overall survival (OS) was 40.5 months; 2- and 3-year OS were 54% and 51%, respectively. On multivariable analysis, only the presence of distant disease at the time of reRT was significantly associated with worse LRFS (HR (95% CI) 4.14 (1.34-12.81); P = .014), worse DMFS (4.06 (1.37-12.06); P = .012) and worse OS (5.73 (1.57-20.9); P = .008). ReRT is an option for patients presenting with either recurrent SCCA or new SCCA after prior pelvic radiation for a different malignancy. ReRT can be given prior to planned salvage APR or alone for patients who are not surgical candidates with an approximate 50% cCR rate.

Can 68 Ga-PSMA positron emission tomography and multiparametric MRI guide treatment for biochemical recurrence after radical prostatectomy?

To evaluate the role of multiparametric magnetic resonance imaging (mpMRI) and Gallium-68 (68 Ga)-prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/computed tomography (CT) in guiding salvage therapy for patients with biochemical recurrence (BCR) post-radical prostatectomy. Patients were evaluated with paired mpMRI and 68 Ga-PSMA PET/CT scans for BCR (prostate-specific antigen [PSA] >0.2 ng/mL). Patient, tumour, PSA and imaging characteristics were analysed with descriptive statistics. A total of 117 patients underwent paired scans to investigate BCR, of whom 53.0% (62/117) had detectable lesions on initial scans and 47.0% (55/117) did not. Of those without detectable lesions, 8/55 patients proceeded to immediate salvage radiotherapy (sRT) and 47/55 were observed. Of patients with negative imaging who were initially observed, 46.8% (22/47) did not reach threshold for repeat imaging, while 53.2% were rescanned due to rising PSA levels. Of these rescanned patients, 31.9% (15/47) were spared sRT due to proven distant disease, or due to absence of disease on repeat imaging. Of the original 117 patients, 53 (45.3%) were spared early sRT due to absence of disease on imaging or presence of distant disease, while those undergoing delayed sRT still maintained good PSA responses. Of note, patients with high-risk features who underwent sRT despite negative imaging demonstrated satisfactory PSA responses to sRT. Study limitations include the observational design and absence of cause-specific or overall survival data. Our findings support the use of mpMRI and 68 Ga-PSMA PET/CT in guiding timing and necessity of salvage therapy tailored to detected lesions, with potential to reduce unnecessary sRT-related morbidity. Larger or randomized trials are warranted to validate this.

Potential of miR-21 to Predict Incomplete Response to Chemoradiotherapy in Rectal Adenocarcinoma.

Background: Patients with locally advanced rectal adenocarcinoma (LARC) are treated with neoadjuvant chemoradiotherapy (CRT). However, biomarkers for patient selection are lacking, and the association between miRNA expression and treatment response and oncological outcomes is unclear.Objectives: To investigate miRNAs as predictors of response to neoadjuvant CRT and its association with oncological outcomes.Methods: This retrospective study analyzed miRNA expression (miR-16, miR-21, miR-135b, miR-145, and miR-335) in pre- and post-chemoradiation rectal adenocarcinoma tissue and non-neoplastic mucosa in 91 patients treated with neoadjuvant CRT (50.4 Gy) and proctectomy. Two groups were defined: a pathological complete responders group (tumor regression grade—TRG 0) and a pathological incomplete responders group (TRG 1, 2, and 3).Results: miR-21 and miR-135b were upregulated in tumor tissue of incomplete responders comparing with non-neoplastic tissue (p = 0.008 and p < 0.0001, respectively). Multivariate analysis showed significant association between miR-21 in pre-CRT tumor tissue and response, with a 3.67 odds ratio (OR) of incomplete response in patients with higher miR-21 levels (p = 0.04). Although with no significance, patients treated with 5-fluorouracil (5-FU) presented reduced odds of incomplete response compared with those treated with capecitabine (OR = 0.19; 95% confidence interval (CI) 0.03–1.12, p = 0.05). Moreover, significant differences were seen in overall survival (OS) in relation to clinical TNM stage (p = 0.0004), cT (p = 0.0001), presence of distant disease (p = 0.002), mesorectal tumor deposits (p = 0.003), and tumor regression grade (p = 0.04).Conclusion: miR-21 may predict response to CRT in rectal cancer (RC).

Abstract P5-04-04: The spatial interactions between FOXP3+ Tregs, CD8+ cytotoxic T cells and tumor cells predict response to therapy and prognosis in inflammatory breast cancer

Abstract Background: Inflammatory breast cancer (IBC) is a rare and aggressive type of locally advanced breast cancer. A 79-gene signature, reported by our lab, is shaped by specific immune response programs and discriminates between IBC and non-IBC (nIBC). However, it remains an enigma how infiltrating immune cells are able to determine the IBC phenotype. Furthermore, the presence of immune cells like FOXP3+ Tregs and CD8+ cytotoxic T cells is associated with outcome in proliferative subtypes of breast cancer and the interaction between these cells plays a role in the functional immune response. Therefore, we aimed to assess the spatial associations between immune cells in IBC. Additionally, we used deep-learning to examine interactions between cancer and immune cells. Methodology: Immunostainings (Hematoxylin-DAB, H-DAB) were done according to well-validated protocols for CD8 (cytotoxic T-cells), FOXP3 (Tregs) and CD163 (tumor-associated macrophages, TAMs) in a large population of 134 IBC patients. All slides were digitalized and evaluated using VISIOPHARM® software, allowing virtual multiplexing. We quantified the number of DAB+ immune cells and each positive immune cell was located using XY coordinates. Spatial co-localization was examined using statistics developed for ecological studies based on point pattern and quadrant analysis. TILs were scored according to the TIL working group guidelines on H&amp;E slides. Tumor cell coordinates were collected using a deep-learning algorithm applied to the CD8 stained slide. To perform deep-learning, we aligned two consecutive slides: one PanCK stained slide and one slide stained for CD8 (H-DAB). Using virtual multiplexing and the PanCK staining, we determined the tumor regions on the H-DAB stained slide. Subsequently, 18 images were incorporated to train the algorithm with more than 150.000 iterations (Deeplabv3+), after which the algorithm was evaluated in a test set of 12 images, approved and applied to all images to locate the tumor cells. Results: Most of the patients presented with a hormone receptor (HR) positive carcinoma (60.6%, n= 82/132). The presence of distant disease, HR status and TIL score were associated with overall survival (OS), but the density of the different immune cells or the CD8/FOXP3 ratio was not. However, using an effector index we demonstrated that patients with more FOXP3+ cells in a radius of 30 μm surrounding a CD8+ cell had a significant worse outcome (Median OS: 2.7 vs. 6.3 years, P= .01) and this remained significant in a multivariate model (HR: 2.85, P&amp;lt; .001). Complete pathological response (pCR) after neo-adjuvant chemotherapy was achieved by 28.7% (n= 27/94) of the patients with initially localized disease. Infiltration with CD8+ T cells (P= .005), TAMs (P= .008) and TILs (P= .002) predicted pCR, but a likelihood ratio test showed no difference between a model using CD8+ cells, TAMs or TILs. Interestingly, pCR was less often achieved in patients that had colocalization of FOXP3+ cells near the tumor cells (P= .003). This colocalization was determined using a Morista-Horn index and independent of the number of Tregs, CD8+ cells or TILs. The deep-learning algorithm had a mean dice coefficient in the test set of 0.83, indicating a good overlap between the tumor area determined by the AI on the CD8 slides and the area on the PanCK stained slides. Conclusions: We have created a deep learning algorithm that adequately detects IBC tumor cells on H-DAB stained images and show, in a large cohort of 132 patients, that the negative impact of Tregs appears to depend on the spatial arrangement. While solely the number of Tregs is not associated with pCR or OS, patients with FOXP3+ Tregs that cluster together near CD8+ cytotoxic T cells had a worse outcome and pCR was achieved more often in patients with less Tregs near the tumor cells. Citation Format: Christophe Van Berckelaer, Charlotte Rypens, Steven Van Laere, Koen Marien, Pieter-Jan van Dam, Peter Vermeulen, Luc Dirix, Mark Kockx, Cecile Colpaert, Peter van Dam. The spatial interactions between FOXP3+ Tregs, CD8+ cytotoxic T cells and tumor cells predict response to therapy and prognosis in inflammatory breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-04-04.

Invasive cancer of the cervix

Invasive cervical cancer remains the second most common malignancy affecting women worldwide. Early-stage disease may be asymptomatic. Advances in imaging techniques have improved selection of the appropriate treatment modality. Treatment options vary for each stage. Cone biopsy is sufficient for treatment of micro-invasive disease (Ia1) provided the margins are clear. The management of stage Ia2 disease is more controversial. Surgery and radiation have similar survival rates for stages Ib–IIa disease, while the combination of both increases morbidity. Later stage tumours (IIb–IV) should be treated with chemo-radiation as it appears to improve survival but also toxicity in comparison to radiotherapy alone. More recent fertility-sparing surgical techniques such as radical trachelectomy may be appropriate in selected cases. Management of recurrent disease depends on the initial treatment modality used, the individual characteristics and the presence of distant disease. Management of cervical cancer during pregnancy remains a challenge and appropriate counselling on individual patient basis is necessary. As the disease usually affects young women, psychological morbidity is significant and emotional support is essential.

Is there a diminishing role for surgery for Merkel cell carcinoma of the skin? a review of current management.

Merkel cell carcinoma is a highly malignant skin tumour that must be managed in a multidisciplinary forum. Excisional biopsy of the primary is recommended and this should be followed by postoperative radiotherapy to the primary site, in-transit areas and the draining lymph nodes. The tumour is quite radiosensitive and radiation doses of the order of 50 Gy offer high levels of local control. Resection margins of 3 cm are not required provided postoperative radiotherapy is used. In the event of inoperable disease, patient refusal of surgery or a frail patient, radiotherapy should be used as the sole treatment modality, with high likelihood of achieving local control. Patients with involved nodes have a higher risk of distant disease. Traditionally, involved nodes have been managed with resection but, currently, there are protocols exploring the use of synchronous chemoradiotherapy as definitive treatment. Although adjuvant chemotherapy has been used in this setting to reduce the risk of distant seeding, the benefits at this stage have not been confirmed conclusively. The presence of distant disease carries a grave outlook and responses to chemotherapy occur frequently, but are usually shortlived.