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Background: As more patients with early-stage breast cancer receive neoadjuvant endocrine therapy (NET), there is a need for reliable biomarkers that can identify patients with HR+ HER2- tumors who are likely to benefit from NET. NBRST (NCT01479101) compared the prognostic value of the 70-gene risk classification and 80-gene molecular subtyping signatures with conventional pathological classification methods in response to neoadjuvant therapy. We evaluated the association of these signatures with clinical response and 5-year outcome of patients treated with NET., Methods: 1091 patients with early-stage breast cancer scheduled to receive neoadjuvant therapy were prospectively enrolled into NBRST, and a sub-analysis of 67 patients treated with NET was performed. Patients received standard of care genomic testing using the 70-gene and 80-gene signatures and were treated with NET, per physician's discretion. The primary endpoint was pathologic partial response (pPR) and secondary endpoints were distant metastasis-free survival (DMFS) and overall survival (OS). Clinical benefit was defined as having a pPR or stable disease (SD) with NET., Results: Overall, 94.4% of patients with genomically (g) Luminal A-Type (50.0% pPR and 44.4% SD) and 95.0% with Luminal B-Type tumors (55.0% pPR and 40.0% SD) exhibited clinical benefit. At 5 years, patients with gLuminal B tumors had significantly worse DMFS (75.6%, 95% CI 50.8-89.1) than patients with gLuminal A (91.1%; 95% CI 74.8-97.1; p = 0.047), with a similar trend for OS, albeit not significant (81.0%, 95% CI 56.9-92.4 and 91.1%, 95% CI 74.8-97.1, respectively; p = 0.13)., Conclusions: Genomic assays offer a broader understanding of the underlying tumor biology, which adds precision to pathology as a preoperative risk classifier. Patients with 70-gene signature Low Risk, gLuminal A tumors treated with endocrine therapy alone have excellent 5-year outcomes. Most patients with genomically-defined Luminal A- and B-Type tumors respond well to NET, suggesting these patients may be safely treated with NET, while those with gLuminal B tumors will also require post-operative chemotherapy or CDK4/6 inhibitors to improve long-term outcomes. Overall, these findings demonstrate that genomic classification, defined by the combined 70- and 80-gene signatures, is associated with tumor response and prognostic of long-term outcomes., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The prospective Neoadjuvant Breast Registry Symphony Trial compared the 80-gene molecular subtyping signature with clinical assessment by immunohistochemistry and/or fluorescence in situ hybridization in predicting pathologic complete response (pCR) and 5-year outcomes in patients with early-stage breast cancer., Methods: Standard-of-care neoadjuvant chemotherapy combined with trastuzumab or trastuzumab plus pertuzumab was given to patients with human epidermal growth factor receptor 2 (HER2)-positive tumors (n = 295). pCR was the primary end point, with secondary end points of distant metastasis-free survival and overall survival at 5 years., Results: Among clinically defined HER2-positive (cHER2) tumors, the 80-gene assay identified 29.5% (87 of 295) as Luminal-Type (cHER2/gLuminal), 14.9% (44 of 295) as Basal-Type (cHER2/gBasal), and 55.6% (164 of 295) as HER2-Type (cHER2/genomically classified as HER2 [gHER2]). Patients with cHER2/gHER2 tumors had a higher pCR rate (61.6%) compared with non-gHER2 tumors (26.7%; P < .001). Dual targeting for cHER2/gHER2 tumors yielded a higher pCR rate (75%) compared with those treated with single HER2-targeted therapy (54%; P = .006). For cHER2/gBasal tumors, the 42.9% pCR rate observed with dual targeting was not different from that with trastuzumab alone (46.4%; P = .830). Among those with cHER2/gBasal tumors, 5-year distant metastasis-free survival (68.6%; 95% CI, 49.1 to 81.9) was significantly worse than in patients with cHER2/gLuminal tumors (88.9%; 95% CI, 78.0 to 94.6) and cHER2/gHER2 tumors (87.4%; 95% CI, 80.2 to 92.2; P = .010), with similar corresponding overall survival differences., Conclusion: The 80-gene assay identified meaningful genomic diversity in patients with cHER2 disease. Patients with cHER2/gHER2 tumors, who benefitted most from dual HER2-targeted therapy, accounted for approximately half of the cHER2 cohort. Genomically Luminal tumors had low pCR rates but good 5-year outcomes. cHER2/gBasal tumors derived no benefit from dual therapy and had significantly worse 5-year prognosis; these patients merit special consideration in future trials., Competing Interests: Pat W. WhitworthEmployment: Integra LifeSciences (I)Leadership: Integra LifeSciences (I)Stock and Other Ownership Interests: Targeted Medical Education Inc, Integra LifeSciences (I)Honoraria: Puma BiotechnologyConsulting or Advisory Role: ImpediMed, Prelude Therapeutics, Becton DickinsonResearch Funding: Prelude Therapeutics, Agendia, MedneonTravel, Accommodations, Expenses: Targeted Medical Education Inc Peter D. BeitschEmployment: InvitaeLeadership: Targeted Medical Education IncStock and Other Ownership Interests: Targeted Medical Education Inc, InvitaeResearch Funding: InvitaeExpert Testimony: Dune Medical Devices, ImpediMedUncompensated Relationships: Medneon Paul D. RichardsStock and Other Ownership Interests: NanoViricidesResearch Funding: Carrick Therapeutics (Inst) James V. PellicaneStock and Other Ownership Interests: PreludeDxHonoraria: Agendia, PreludeDxSpeakers' Bureau: Agendia, PreludeDx Beth B. DupreeLeadership: Caliber MedicalStock and Other Ownership Interests: Videra SurgicalHonoraria: Medtronic, Perimeter Medical William DooleyLeadership: Shaga Medical LLCStock and Other Ownership Interests: Shaga MedicalResearch Funding: Agendia, XoftPatents, Royalties, Other Intellectual Property: patent pending—microendoscopy system Shiyu WangEmployment: Agendia Patricia DauerEmployment: AgendiaStock and Other Ownership Interests: AgendiaTravel, Accommodations, Expenses: Agendia Andrea R. MenicucciEmployment: Agendia Erin B. YoderEmployment: AgendiaStock and Other Ownership Interests: AgendiaTravel, Accommodations, Expenses: Agendia Lisa E. BlumencranzEmployment: Agendia William AudehEmployment: AgendiaLeadership: AgendiaStock and Other Ownership Interests: AgendiaConsulting or Advisory Role: Celanese, Private HealthResearch Funding: AgendiaTravel, Accommodations, Expenses: AgendiaNo other potential conflicts of interest were reported.

Background: The Neoadjuvant Breast Symphony Trial (NBRST) demonstrated the 70-gene risk of distant recurrence signature, MammaPrint, and the 80-gene molecular subtyping signature, BluePrint, precisely determined preoperative pathological complete response (pCR) in breast cancer patients. We report 5-year follow-up results in addition to an exploratory analysis by age and menopausal status., Methods: The observational, prospective NBRST (NCT01479101) included 954 early-stage breast cancer patients aged 18-90 years who received neoadjuvant chemotherapy and had clinical and genomic data available. Chemosensitivity and 5-year distant metastasis-free survival (DMFS) and overall survival (OS) were assessed. In a post hoc subanalysis, results were stratified by age (≤ 50 vs. > 50 years) and menopausal status in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) tumors., Results: MammaPrint and BluePrint further classified 23% of tumors to a different subtype compared with immunohistochemistry, with more precise correspondence to pCR rates. Five-year DMFS and OS were highest in MammaPrint Low Risk, Luminal A-type and HER2-type tumors, and lowest in MammaPrint High Risk, Luminal B-type and Basal-type tumors. There was no significant difference in chemosensitivity between younger and older patients with Low-Risk (2.2% vs. 3.8%; p = 0.64) or High-Risk tumors (14.5% vs. 11.5%; p = 0.42), or within each BluePrint subtype; this was similar when stratifying by menopausal status. The 5-year outcomes were comparable by age or menopausal status for each molecular subtype., Conclusion: Intrinsic preoperative chemosensitivity and long-term outcomes were precisely determined by BluePrint and MammaPrint regardless of patient age, supporting the utility of these assays to inform treatment and surgical decisions in early-stage breast cancer., (© 2022. The Author(s).)

Purpose: The 80-gene molecular subtyping signature (80-GS) reclassifies a proportion of immunohistochemistry (IHC)-defined luminal breast cancers (estrogen receptor-positive [ER+], human epidermal growth factor receptor 2-negative [HER2-]) as Basal-Type. We report the association of 80-GS reclassification with neoadjuvant treatment response and 5-year outcome in patients with breast cancer., Methods: Neoadjuvant Breast Registry Symphony Trial (NBRST; NCT01479101) is an observational, prospective study that included 1,069 patients with early-stage breast cancer age 18-90 years who received neoadjuvant therapy. Pathologic complete response (pCR) and 5-year distant metastasis-free survival (DMFS) and overall survival (OS) were assessed in 477 patients with IHC-defined ER+, HER2- tumors and in a reference group of 229 patients with IHC-defined triple-negative breast cancer (TNBC)., Results: 80-GS reclassified 15% of ER+, HER2- tumors (n = 73) as Basal-Type (ER+/Basal), which had similar pCR compared with TNBC/Basal tumors (34% v 38%; P = .52), and significantly higher pCR than ER+/Luminal A (2%; P < .001) and ER+/Luminal B (6%; P < .001) tumors. The 5-year DMFS (%, [95% CI]) was significantly lower for patients with ER+/Basal tumors (66% [52.6 to 77.3]), compared with those with ER+/Luminal A tumors (92.3% [85.2 to 96.1]) and ER+/Luminal B tumors (73.5% [44.5 to 79.3]). Importantly, patients with ER+/Basal or TNBC/Basal tumors that had a pCR exhibited significantly improved DMFS and OS compared with those with residual disease. By contrast, patients with ER+/Luminal B tumors had comparable 5-year DMFS and OS whether or not they achieved pCR., Conclusion: Significant differences in chemosensitivity and 5-year outcome suggest patients with ER+/Basal molecular subtype may benefit from neoadjuvant regimens optimized for patients with TNBC/Basal tumors compared with patients with ER+/Luminal subtype. These data highlight the importance of identifying this subset of patients to improve treatment planning and long-term survival., Competing Interests: Pat W. WhitworthEmployment: Integra LifeSciencesLeadership: Integra LifeSciencesStock and Other Ownership Interests: Targeted Medical Education, Inc, Cerebrotech Medical Systems, Medneon, Integra LifeSciencesHonoraria: Puma BiotechnologyConsulting or Advisory Role: ImpediMed, Prelude Therapeutics, Becton DickinsonResearch Funding: Prelude Therapeutics, Agendia, MedneonTravel, Accommodations, Expenses: Targeted Medical Education, Inc Peter D. BeitschEmployment: InVitaeLeadership: Targeted Medical Education, IncStock and Other Ownership Interests: Targeted Medical Education, Inc, InVitaeResearch Funding: InVitaeExpert Testimony: Dune Medical Devices, ImpediMedUncompensated Relationships: Medneon James V. PellicaneStock and Other Ownership Interests: PreludeDxHonoraria: Agendia, PreludeDxSpeakers' Bureau: Agendia, PreludeDx Paul L. BaronHonoraria: Myriad GeneticsConsulting or Advisory Role: Myriad GeneticsSpeakers' Bureau: Myriad GeneticsTravel, Accommodations, Expenses: Myriad Genetics William C. DooleyLeadership: Shaga Medical, LLCStock and Other Ownership Interests: Shaga MedicalResearch Funding: Agendia, XoftPatents, Royalties, Other Intellectual Property: Patent pending: microendoscopy system Kenneth H. CowanStock and Other Ownership Interests: United Health GroupConsulting or Advisory Role: MerckResearch Funding: Merck Beth-Ann LesnikoskiEmployment: HCA HealthcareStock and Other Ownership Interests: HCA HealthcareResearch Funding: Agendia (Inst), Seattle Genetics (Inst)Open Payments Link: https://openpaymentsdata.cms.gov/physician/246359 Beth B. DupreeHonoraria: Medtronic Shiyu WangEmployment: AgendiaStock and Other Ownership Interests: Agendia Andrea R. MenicucciEmployment: Agendia Erin B. YoderEmployment: AgendiaStock and Other Ownership Interests: AgendiaTravel, Accommodations, Expenses: Agendia Kate CorcoranEmployment: Agendia Lisa E. BlumencranzEmployment: Agendia William AudehEmployment: AgendiaLeadership: AgendiaStock and Other Ownership Interests: AgendiaConsulting or Advisory Role: Celanese, Private HealthResearch Funding: AgendiaTravel, Accommodations, Expenses: AgendiaNo other potential conflicts of interest were reported.

Background: Pertuzumab became a standard part of neoadjuvant therapy for human epidermal growth factor receptor 2-positive (HER2+) breast cancers approximately halfway through Neoadjuvant Breast Registry Symphony Trial (NBRST) enrollment, providing a unique opportunity to determine biologically which clinical HER2+ patients benefit most from dual targeting. As a neoadjuvant phase 4 study, NBRST classifies patients by both conventional and molecular subtyping., Methods: Of 308 clinical HER2+ patients enrolled in NBRST between 2011 and 2014 from 62 U.S. institutions, 297 received neoadjuvant chemotherapy (NCT) with HER2-targeted therapy and underwent surgery. This study compared the pathologic complete response (pCR) rate of BluePrint versus clinical subtypes with treatment, specifically differences between trastuzumab (T) treatment and trastuzumab and pertuzumab (T/P) treatment., Results: In this study, 60% of the patients received NCT-T, and 40% received NCT-T/P. The overall pCR rate (ypT0/isN0) was 47%. BluePrint classified 161 tumors (54%) as HER2 type, with a pCR rate of 65%. This was significantly higher than the pCR rate for the 91 HER2+ tumors (31%) classified as luminal (18%) (p = 0.00001) and the 45 tumors (15%) classified as basal (44%) (p = 0.0166). The patients treated with T/P had higher pCR rates than those treated with trastuzumab alone. The difference was most pronounced in the BluePrint luminal patients (8 vs. 31%). The highest pCR was reached by the BluePrint HER2-type patients treated with T/P (76%)., Conclusions: The addition of pertuzumab leads to increased pCR rates for all HER2+ patient groups except for the BluePrint basal-type patients. This better response was most pronounced for the BluePrint luminal-type patients.

Purpose: Hormone receptor-positive (HR+) tumors have heterogeneous biology and present a challenge for determining optimal treatment. In the Neoadjuvant Breast Registry Symphony Trial (NBRST) patients were classified according to MammaPrint/BluePrint subtyping to provide insight into the response to neoadjuvant endocrine therapy (NET) or neoadjuvant chemotherapy (NCT)., Objective: The purpose of this predefined substudy was to compare MammaPrint/BluePrint with conventional 'clinical' immunohistochemistry/fluorescence in situ hybridization (IHC/FISH) subtyping in 'clinical luminal' [HR+/human epidermal growth factor receptor 2-negative (HER2-)] breast cancer patients to predict treatment sensitivity., Methods: NBRST IHC/FISH HR+/HER2- breast cancer patients (n = 474) were classified into four molecular subgroups by MammaPrint/BluePrint subtyping: Luminal A, Luminal B, HER2, and Basal type. Pathological complete response (pCR) rates were compared with conventional IHC/FISH subtype., Results: The overall pCR rate for 'clinical luminal' patients to NCT was 11 %; however, 87 of these 474 patients were reclassified as Basal type by BluePrint, with a high pCR rate of 32 %. The MammaPrint index was highly associated with the likelihood of pCR (p < 0.001). Fifty-three patients with BluePrint Luminal tumors received NET with an aromatase inhibitor and 36 (68 %) had a clinical response., Conclusions: With BluePrint subtyping, 18 % of clinical 'luminal' patients are classified in a different subgroup, compared with conventional assessment, and these patients have a significantly higher response rate to NCT compared with BluePrint Luminal patients. MammaPrint/BluePrint subtyping can help allocate effective treatment to appropriate patients. In addition, accurate identification of subtype biology is important in the interpretation of neoadjuvant treatment response since lack of pCR in luminal patients does not portend the worse prognosis associated with residual disease in Basal and HER2 subtypes.

As nipple-sparing mastectomy gains increasing popularity, minimizing the risk of nipple necrosis continues to be of critical importance to patients and surgeons. Patients with large or ptotic breasts, scars from previous cosmetic and/or oncologic breast surgery, or previous irradiation have often been denied nipple-sparing mastectomy (NSM) because of increased risk of nipple necrosis. A variety of interventions have been suggested to minimize the ischemic insult to the nipple-areolar complex (NAC). This article presents our experience in 26 high-risk patients with surgical delay of the NAC.

Background: The prospective Neoadjuvant Breast Symphony Trial (NBRST) study found that MammaPrint/BluePrint functional molecular subtype is superior to conventional immunohistochemistry/fluorescence in situ hybridization subtyping for predicting pathologic complete response (pCR) to neoadjuvant chemotherapy. The purpose of this substudy was to determine if the rate of pCR is affected by tumor size., Methods: The NBRST study includes breast cancer patients who received neoadjuvant chemotherapy. MammaPrint/BluePrint subtyping classified patients into four molecular subgroups: Luminal A, Luminal B, HER2 (human epidermal growth factor receptor 2), and Basal type. Probability of pCR (ypT0/isN0) as a function of tumor size and molecular subgroup was evaluated., Results: A total of 608 patients were evaluable with overall pCR rates of 28.5 %. Luminal A and B patients had significantly lower rates of pCR (6.1 and 8.7 %, respectively) than either basal (37.1 %) or HER2 (55.0 %) patients (p < 0.001). The probability of pCR significantly decreased with tumor size >5 cm [p = 0.022, odds ratio (OR) 0.58, 95 % confidence interval (CI) 0.36, 0.93]. This relationship was statistically significant in the Basal (p = 0.026, OR 0.46, 95 % CI 0.23, 0.91) and HER2 (p = 0.039, OR 0.36, 95 % CI 0.14, 0.95) subgroups. In multivariate logistic regression analyses, the dichotomized tumor size variable was not significant in any of the molecular subgroups., Discussion: Even though tumor size would intuitively be a clinical determinant of pCR, the current analysis showed that the adjusted OR for tumor size was not statistically significant in any of the molecular subgroups. Factors significantly associated with pCR were PR status, grade, lymph node status, and BluePrint molecular subtyping, which had the strongest correlation.

Background: Intraoperative radiation therapy (IORT) and whole breast irradiation (WBI) are both effective adjuvant radiotherapy methods for ductal carcinoma in situ (DCIS) or early-stage breast cancer (BC) patients undergoing breastconserving surgery (BCS). We aim to evaluate the long-term oncological efficacy and refine patient selection criteria based on our findings. Methods: Female patients who underwent either IORT or WBI from January 2016 to December 2019, with a minimum follow-up of 12 months were collected. IORT was administered as a single fraction of 20 Gray (Gy) to the lumpectomy cavity using the Axxent electronic brachytherapy system, while WBI consisted of a standard fractionation of 50 Gy in 25 fractions, along with a reduced boost of 10 Gy. The clinicopathologic characteristics and oncological outcomes were retrospectively analyzed. Results: A total of 247 patients were enrolled, comprising 164 with BC and 83 with DCIS. Among them, 112 underwent IORT, and 135 received WBI after BCS. The median age was 62.2 years, with median tumor sizes of 1.5 cm for BC and 1.2 cm for DCIS. At a median follow-up of 64.6 months, IORT demonstrated 11 locoregional recurrences (LRR), 1 metastasis, and 1 death, compared to 4 LRR, 5 metastases, and 2 deaths in the WBI group. WBI yielded significantly higher locoregional control (97.0% vs. 90.2%, p = 0.033), although metastasis-free (96.3% vs. 99.1%, p = 0.166) and overall survival rates (98.4% vs. 99%, p = 0.688) did not differ. The LRR rate was significantly higher in the IORT group among the DCIS or BC patients (p = 0.043). The hazard ratio for locoregional recurrence significantly increased in estrogen-receptor-negative (ER-) patients in both univariate analysis (HR = 4.98, 95% CI = 1.76-14.09, p = 0.002) and multivariate analysis (HR = 40.88, 95% CI = 1.29-1297.84, p = 0.035). Additionally, IORT was associated with increased LRR in the multivariate analysis (HR = 4.71, 95% CI = 1.16-19.06, p = 0.030). Conclusion: At a long-term follow-up, the LRR rate was higher in the BCS followed by IORT, without significant differences in metastasis-free or overall survival rates. Our data confirmed the importance of exclusion ER-patients for IORT. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of the NBRST study is to compare a multigene classifier to conventional immunohistochemistry (IHC)/fluorescence in situ hybridization (FISH) subtyping to predict chemosensitivity as defined by pathological complete response (pCR) or endocrine sensitivity as defined by partial response., Methods: The study includes women with histologically proven breast cancer, who will receive neoadjuvant chemotherapy (NCT) or neoadjuvant endocrine therapy. BluePrint in combination with MammaPrint classifies patients into four molecular subgroups: Luminal A, Luminal B, HER2, and Basal., Results: A total of 426 patients had definitive surgery. Thirty-seven of 211 (18 %) IHC/FISH hormone receptor (HR)+/HER2- patients were reclassified by Blueprint as Basal (n = 35) or HER2 (n = 2). Fifty-three of 123 (43 %) IHC/FISH HER2+ patients were reclassified as Luminal (n = 36) or Basal (n = 17). Four of 92 (4 %) IHC/FISH triple-negative (TN) patients were reclassified as Luminal (n = 2) or HER2 (n = 2). NCT pCR rates were 2 % in Luminal A and 7 % Luminal B patients versus 10 % pCR in IHC/FISH HR+/HER2- patients. The NCT pCR rate was 53 % in BluePrint HER2 patients. This is significantly superior (p = 0.047) to the pCR rate in IHC/FISH HER2+ patients (38 %). The pCR rate of 36 of 75 IHC/FISH HER2+/HR+ patients reclassified as BPLuminal is 3 %. NCT pCR for BluePrint Basal patients was 49 of 140 (35 %), comparable to the 34 of 92 pCR rate (37 %) in IHC/FISH TN patients., Conclusions: BluePrint molecular subtyping reclassifies 22 % (94/426) of tumors, reassigning more responsive patients to the HER2 and Basal categories while reassigning less responsive patients to the Luminal category. These findings suggest that compared with IHC/FISH, BluePrint more accurately identifies patients likely to respond (or not respond) to NCT.

Background: Accelerated partial breast irradiation (APBI) is emerging as a valid alternative to whole-breast radiation therapy (WBRT) in breast-conserving therapy (BCT) for early-stage breast cancer. Axxent electronic brachytherapy (EBX) is a form of portable, balloon-based APBI that utilizes an electronic source of kilovoltage irradiation delivery with minimal shielding requirements. As such, EBX becomes a logical and convenient modality for delivery of intraoperative radiation therapy (IORT). We report 1-year results and clinical outcomes of a trial that utilizes EBX to deliver IORT for patients with early-stage breast cancer., Methods: Eleven patients were enrolled on an institutional review board (IRB)-approved protocol. Inclusion criteria were patient age >45 years, unifocal tumors with infiltrating ductal or ductal carcinoma in situ (DCIS) histology, tumors ≤3 cm, and uninvolved lymph nodes. Preloaded radiation plans were used to deliver radiation prescription dose of 20 Gy to the balloon surface., Results: The mean time for radiation delivery was 22 min; the total mean procedure time was 1 h 39 min. All margins of excision were negative on final pathology. At mean follow-up of 12 months, overall cosmesis was excellent in 10 of 11 patients. No infection, fat necrosis, desquamation, rib fracture or cancer recurrence has been observed. There was no evidence of fibrosis at last follow-up., Conclusion: IORT utilizing EBX is emerging as a feasible, well-tolerated alternative to postsurgical APBI. Further research and longer follow-up data on EBX and other IORT methods are needed to establish the clinical efficacy and safety of this treatment.

Background: The rate of involved margins after the excision of breast lesions using standard surgical techniques has historically ranged from approximately 20% to 45%. The localization and excision of breast lesions using intraoperative ultrasound has provided significant improvement. The authors report their collective experience with a novel technique utilizing the Phantom flexible loop electrosurgical device under ultrasound guidance for the intraoperative excision of breast lesions., Methods: Seventy-nine breast lesions were excised using the Phantom device with intraoperative ultrasound. Rate of reexcision, excised specimen size, and size of the lumpectomy incision were reviewed., Results: Fifty-nine of 79 lesions were malignant. Fifty-one (86.4%) had noninvolved final margins; 8 (13.6%) involved margins. The average specimen size was 21.3 cm3, compared with a range of 60 to 100 cm3 in the literature., Conclusions: These results demonstrate improved efficiency, a decrease in the volume of excision, smaller incision size, and very low need for reoperation secondary to involved margins using the Phantom device for real-time, ultrasound-guided lumpectomy.

Meckel's diverticulum (MD) is the most common congenital anomaly of the small intestine, occurring in up to 4 percent of the population. The majority of MD cases are discovered incidentally; however, they can occasionally cause serious bleeding or obstructive or inflammatory complications. We reviewed the charts of 58 patients with MD from 1984 to 1994 collecting data on age, sex, presentation, therapy, pathology, and surgical complications to try to identify factors suggestive of the need for surgical therapy and the associated morbidity and mortality of resection. There was a 1.3:1 male:female ratio, and although patients with MD were found at all ages, the majority were found in patients in the 4th and 5th decade of life. Forty-five of 58 were incidental, and 13 of 58 were symptomatic. The most common symptom was bowel obstruction (10 of 13). Forty-five of 58 MD cases were managed surgically, 71 percent by diverticulectomy and the remainder by segmental resection, with no associated morbidity or mortality. Symptomatic patients were more often male (77 vs 23%; P 0.06, Fisher's exact test), more often had ectopic mucosa (31 vs 16%; P, not significant), and were evenly distributed over all ages. These data suggest that, with the possible exception of male sex, there is no factor predictive of the development of symptoms in incidentally found MD. In light of this finding, the low operative morbidity and mortality, and the even age distribution in patients with complications of their MD, we recommend that MD be resected when found incidentally in the absence of an absolute contraindication.

Nonocclusive intestinal infarction (NOII) is described as bowel necrosis at celiotomy or autopsy without evidence of thromboembolism, vasculitis, or mechanical obstruction. The mortality for this entity is as high as 90 per cent in some series. From January 1990 to January 1995, we identified 15 patients who met the criteria for NOII identified at celiotomy or autopsy. We collected data on demographics, comorbidities, presenting signs and symptoms, laboratory workup, time to definitive therapy, and outcome. Our goal was to improve our ability to identify and treat this devastating surgical problem. There was a 4.5:1 female to male ratio, and patients had an average age of 73 +/- 10 years. Significant comorbidities included coronary artery disease (87%) and atrial fibrillation (73%). Eleven patients were diagnosed at celiotomy and four at autopsy. Overall mortality was 67 per cent. The most common presenting symptoms were abdominal pain (93%) and distention (80%) and mental status changes (60%). Peritonitis was less common, present in only 40 per cent of the patients. Leukocytosis, bandemia, increased creatinine, metabolic acidosis, and hypoxemia were common among all patients. There was a significant difference in time to definitive therapy in survivors versus nonsurvivors (1.2 +/- 0.89 vs 4.8 +/- 2.0 days; P < 0.02, t test). These data suggest that NOII is a lethal surgical problem. A history of coronary artery disease and atrial fibrillation was common among all patients. Various nonspecific presenting signs, symptoms, and laboratory values are suggestive of this diagnosis. A high index of suspicion in select patients and early intervention may lead to improved outcome.

Unlabelled: The role of cytokines in normal wound healing remains poorly defined. In vitro, tumor necrosis factor alpha (TNF-alpha) decreases collagen accumulation, perhaps by increasing collagenase activity. The current study was undertaken to test the hypothesis that cytokines impair wound healing and collagen production. Wounds in C3H/HeJ (J) mice, which are characterized by a genetic defect in macrophage production of TNF and other cytokines in response to endotoxin, were compared with wounds in normal endotoxin-sensitive C3H/HeN (N) mice., Methods: TNF (by murine ELISA) and collagenolytic activity (CA by in vivo labelled collagen fibril degradation assay) were measured in wound fluid from silicone reservoirs on post-wounding days 1, 3, and 5 (n = 5 per group). Hydroxyproline (HOP, nmol/mg sponge) incorporation (by HPLC) in polyvinylacohol sponges and breaking strength (BS, as determined by tensiometry) in linear wounds were assessed on days 5, 7, 10, and 14 (n = 5 per group). The data demonstrate significantly increased BS at 5 and 7 days in endotoxin-resistant J mice compared with that in endotoxin-sensitive N mice. An early, significant reduction in TNF production in J mice corresponded with a significant increase in CA on day 1, increased collagen production at day 7, and increased procollagen gene transcription at early time points. Conclusion. The reduced production of inflammatory cytokines including TNF in the wound fluid of J mice corresponded with an early improvement in wound tensile strength. An accelerated accumulation of collagen in the wounds of J mice, perhaps resulting from a significant decrease in collagenolytic activity or increased collagen production, are potential mechanisms. The data suggest that cytokines produced in normal healing of clean wounds may contribute to a delay in increased tensile strength.

Although C3H/HeJ mice, characterized by a genetic deficiency in macrophage cytokine release in response to endotoxin, have been studied extensively to gain insight into the possible role of various cytokines in sepsis, few past studies have examined the physiologic response to hemorrhagic shock in this "endotoxin-resistant" strain. We utilized a fixed-volume model of hemorrhagic shock and two different levels of hemorrhage severity (50 and 67% blood volume) to compare C3H/HeJ mice to normal C3H/HeN mice. An additional group of endotoxin-sensitive C3H/HeN mice were treated with 2.5 mg/kg of anti-tumor necrosis factor (TNF) antibody to define the possible role of TNF in shock physiology. Hematocrit, circulating neutrophils, and plasma glucose and lactate concentrations were measured following hemorrhage. TNF increased significantly following hemorrhage in normal mice but did not increase in C3H/HeJ mice or in C3H/HeN mice treated with anti-TNF antibody. No difference between groups was identified in hematocrit, circulating neutrophils, or glucose. Whereas plasma lactate increased significantly by 30 min in all groups, lactate returned to baseline levels in C3H/HeJ mice at 60 min, but remained persistently elevated in C3H/HeN mice and in C3H/HeN mice treated with anti-TNF antibody. The data demonstrate attenuated lactate accumulation in C3H/HeJ mice following hemorrhage. Inhibition of circulating TNF activity with anti-TNF antibody failed to reproduce this late decrease in plasma lactate in normal mice. The data suggest that macrophage products other than TNF known to be deficient in C3H/HeJ mice contribute to anaerobic metabolism in hemorrhagic shock.

Although tumor necrosis factor (TNF) has been implicated in sepsis-induced mortality, its role in the pathophysiology of hemorrhagic shock (HS) remains ill defined. We studied three groups of acutely anesthetized mice undergoing HS to determine the role of TNF in HS mortality. Shock was initiated in each group after heparinization by arterial bleeding of 4 mL/100 g body weight followed by 12 mL/100 g body weight resuscitation with normal saline at 1 hour. The C3H/HeJ mice (n = 14), characterized by a genetic defect in macrophage production of TNF and other cytokines in response to endotoxin, were compared with the closely related C3H/HeN strain (n = 18), which do produce TNF. A second group of C3H/HeN mice were passively immunized to TNF by pretreatment with 2.5 mg/kg anti-murine TNF antibody (Ab) before HS. In contrast to the high TNF levels measured following HS in C3H/HeN controls, post-HS TNF was undetectable in C3H/HeJ mice. Five-day survival rate and survival time were significantly greater in C3H/HeJ mice when compared with C3H/HeN controls. Anti-TNF Ab pretreatment of C3H/HeN mice abolished the increase in TNF but did not improve survival. The data demonstrate a striking improvement in survival of TNF-deficient C3H/HeJ mice following severe HS. However, the improved survival does not appear to result from deficient TNF production, since Ab pretreatment did not decrease HS mortality. The improved survival in C3H/HeJ mice suggests that cytokines other than TNF may play a role in the pathophysiology of HS.

Background: This study was designed to determine the role of interleukin-1 (IL-1) in hemorrhagic shock death., Methods: Pentobarbital anesthetized C3H/HeN mice (n = 59) were prepared with a femoral arterial catheter and were randomized to treatment with an IL-1 receptor antagonist (IL-1ra, 10 mg/kg, n = 29) or an equal volume of phosphate-buffered saline solution (vehicle, n = 30) by subcutaneous bolus injection at 15 minutes before hemorrhage and again at 120 minutes. Continuous posthemorrhage delivery of IL-1ra or vehicle was performed in each group (1.5 mg IL-1ra in 30 microliters/day) through a subcutaneous osmotic pump. Rapid hemorrhage of 4 ml/100 gm weight was followed by normal saline resuscitation of 12 ml/100 gm 60 minutes later., Results: Survival analysis by Wilcoxon rank sum analysis revealed a significantly improved 5-day survival in IL-1ra-treated mice (n = 15, 20%) as compared with vehicle-treated mice (n = 14, 6%, p < 0.001). To determine a possible mechanism of this survival advantage, the remaining mice in each treatment group were killed at 30 minutes to obtain blood and tissue samples from the heart, liver, and kidney for measurement of adenosine-5'-triphosphate (ATP). No difference in hematocrit, circulating neutrophils, or levels of glucose, lactate, or tumor necrosis factor was identified between groups to explain the improved outcome. IL-1ra prevented hemorrhage-induced ATP depletion observed in vital organs of vehicle-treated mice., Conclusions: The data implicate IL-1 in shock-induced ATP depletion and suggest IL-1ra may improve hemorrhagic shock survival by preventing ATP depletion in vital organs.

We reviewed 374 consecutive trauma patients over age 65 years to determine (1) if the emergency room Trauma Score (TS) could predict mortality, thereby improving ICU triage, and (2) the frequency of preventable complications in patients who died (n = 31). Fifty-two percent of deaths (n = 16) occurred in patients with TS = 15 or 16. Multiple organ failure/sepsis (MOF/S) was the most common cause of death overall (42%) and was also the most frequent cause of death in patients with a TS = 15-16 (63%). Nonsurvivors in the TS = 15-16 subgroup were older (80.9 +/- 2.0 vs. 74.9 +/- 0.5 years, p less than 0.02) and had greater ISSs (15.8 +/- 3.7 vs. 8.0 +/- 0.4, p = 0.001) than survivors. Patients with a TS less than 15 suffered high overall mortality (45%). Preventable complications contributed to mortality in 32% of all deaths and in 62% of MOF/S deaths. Aggressive care to prevent avoidable complications may improve survival in elderly trauma victims.

In this narrative review, we aim to explore the ability of radiation therapy to eradicate breast cancer regional node metastasis. It is a journey through data of older trials without systemic therapy showing the magnitude of axillary therapy (surgery versus radiation) on cancer control. Considering that both systemic and loco-regional therapies were shown to reduce any recurrence with a complex interaction, our review includes surgical, radiation, and radiobiology consideration for breast cancer, and provide our view of future practise. The aim is to provide information optimise radiation therapy in the era of primary systemic therapy. [ABSTRACT FROM AUTHOR]

Purpose: The role of neoadjuvant chemotherapy (NAC) in node-positive (N+) ER+/HER2- breast cancer (BC) is debated, given low total pathologic complete response (pCR) rates. However, the rate and impact of nodal pCR is unknown. We sought to evaluate nodal pCR rates and the impact on overall survival (OS). Further, we sought to validate the association between nodal pCR with age and Ki67. Methods: We queried the National Cancer Database for cN + ER+/HER2- BC patients treated with NAC and surgery. Data from 2010 to 2018 were used to evaluate nodal pCR and OS, with multivariable Cox proportional hazards modeling for OS, as well as Ki67 for the years 2018–2019. Results: From 2010 to 2018, we identified 19,611 cN + ER+/HER2- BC patients treated with NAC. While total pCR occurred in only 7.4%, nodal pCR rates were nearly double (14.3%). Nodal pCR (+/- breast pCR) was seen in 21.7% and associated with 5-year OS rate of 86.1% (95% CI: 84.9–87.4%) versus 77.1% (95% CI: 76.3–77.9%) in patients without nodal pCR (p < 0.001). On multivariable analysis, nodal pCR had better OS (adjusted HR 0.57, 95% CI 0.52–0.63, p < 0.001) across all age groups. Of 2,444 patients with available Ki67, those with age < 50 and Ki67 ≥ 20% had the highest nodal pCR at 31.6%. Conclusion: In cN + ER+/HER2- BC treated with NAC, nodal pCR is common, associated with age and Ki67, and prognostic for OS. These data strongly suggest that for cN + patients, eradication of nodal disease is critical for OS, and total pCR may not be the optimal measure of NAC benefit. [ABSTRACT FROM AUTHOR]

Determining pathological complete response (pCR) could be an important step in planning individual treatment, hence improving the prognosis in terms of survival. Achieving breast pCR not only improves survival but is also linked to a disease-free axilla, therefore increasing the likelihood of avoiding axillary surgery safely. The current trend in de-escalating axillary management surgically or in applying radiotherapy to the axilla is dependent primarily on breast cancer (BC) patients achieving pCR. Studies have demonstrated that certain characteristics can predict pCR, even though it is still difficult to identify these elements. A review of the literature was carried out to determine these factors and their clinical applications. A search was carried out in the MEDLINE database using PubMed, Google Scholar, and EMBASE. This yielded 1368 studies, of which 60 satisfied the criteria. The studies were categorized according to the subject they dealt with. These parameters included age, race, subtypes, clinicopathological, immunological, imaging, obesity, Ki-67 status, vitamin D, and genetics. These factors, in combination, can be used for specific subtypes to individualize treatment and monitor response to therapy. The predictors of pCR are diverse and should be utilized to personalize patient treatment, ultimately inducing the best outcomes. These determinants can also be employed for monitoring responses to neoadjuvant therapy, thereby adjusting treatment. The development of standardized markers for the diversity of BC subtypes still needs additional future research. These factors must be applied in concert in order to provide optimal results. [ABSTRACT FROM AUTHOR]

Background: Neoadjuvant chemotherapy (NCT) increases the feasibility of surgical resection by downstaging large primary breast tumors and nodal involvement, which may result in surgical de-escalation and improved outcomes. This subanalysis from the Multi-Institutional Neo-adjuvant Therapy MammaPrint Project I (MINT) trial evaluated the association between MammaPrint and BluePrint with nodal downstaging. Patients and Methods: The prospective MINT trial (NCT01501487) enrolled 387 patients between 2011 and 2016 aged ≥ 18 years with invasive breast cancer (T2–T4). This subanalysis includes 146 patients with stage II–III, lymph node positive, who received NCT. MammaPrint stratifies tumors as having a Low Risk or High Risk of distant metastasis. Together with MammaPrint, BluePrint genomically (g) categorizes tumors as gLuminal A, gLuminal B, gHER2, or gBasal. Results: Overall, 45.2% (n = 66/146) of patients had complete nodal downstaging, of whom 60.6% (n = 40/66) achieved a pathologic complete response. MammaPrint and combined MammaPrint and BluePrint were significantly associated with nodal downstaging (p = 0.007 and p < 0.001, respectively). A greater proportion of patients with MammaPrint High Risk tumors had nodal downstaging compared with Low Risk (p = 0.007). When classified with MammaPrint and BluePrint, more patients with gLuminal B, gHER2, and gBasal tumors had nodal downstaging compared with HR+HER2−, gLuminal A tumors (p = 0.538, p < 0.001, and p = 0.013, respectively). Conclusions: Patients with genomically High Risk tumors, defined by MammaPrint with or without BluePrint, respond better to NCT and have a higher likelihood of nodal downstaging compared with patients with gLuminal A tumors. These genomic signatures can be used to select node-positive patients who are more likely to have nodal downstaging and avoid invasive surgical procedures. [ABSTRACT FROM AUTHOR]

Background: The 70-gene signature (70-GS, MammaPrint) test has been recommended by the main guidelines to evaluate prognosis and chemotherapy benefit of hormonal receptor positive human epidermal receptor 2 negative (HR + /Her2−) early breast cancer (BC). However, this expensive assay is not always accessible and affordable worldwide. Based on our previous study, we established nomogram models to predict the binary and quartile categorized risk of 70-GS. Methods: We retrospectively analyzed a consecutive cohort of 150 female patients with HR + /Her2− BC and eligible 70-GS test. Comparison of 40 parameters including the patients' medical history risk factors, imaging features and clinicopathological characteristics was performed between patients with high risk (N = 62) and low risk (N = 88) of 70-GS test, whereas risk calculations from established models including Clinical Treatment Score Post-5 years (CTS5), Immunohistochemistry 3 (IHC3) and Nottingham Prognostic Index (NPI) were also compared between high vs low binary risk of 70-GS and among ultra-high (N = 12), high (N = 50), low (N = 65) and ultra-low (N = 23) quartile categorized risk of 70-GS. The data of 150 patients were randomly split by 4:1 ratio with training set of 120 patients and testing set 30 patients. Univariate analyses and multivariate logistic regression were performed to establish the two nomogram models to predict the the binary and quartile categorized risk of 70-GS. Results: Compared to 70-GS low-risk patients, the high-risk patients had significantly less cardiovascular co-morbidity (p = 0.034), more grade 3 BC (p = 0.006), lower progesterone receptor (PR) positive percentage (p = 0.007), more Ki67 high BC (≥ 20%, p < 0.001) and no significant differences in all the imaging parameters of ultrasound and mammogram. The IHC3 risk and the NPI calculated score significantly correlated with both the binary and quartile categorized 70-GS risk classifications (both p < 0.001). The area under curve (AUC) of receiver-operating curve (ROC) of nomogram for binary risk prediction were 0.826 (C-index 0.903, 0.799–1.000) for training and 0.737 (C-index 0.785, 0.700–0.870) for validation dataset respectively. The AUC of ROC of nomogram for quartile risk prediction was 0.870 (C-index 0.854, 0.746–0.962) for training and 0.592 (C-index 0.769, 0.703–0.835) for testing set. The prediction accuracy of the nomogram for quartile categorized risk groups were 55.0% (likelihood ratio tests, p < 0.001) and 53.3% (p = 0.04) for training and validation, which more than double the baseline probability of 25%. Conclusions: To our knowledge, we are the first to establish easy-to-use nomograms to predict the individualized binary (high vs low) and the quartile categorized (ultra-high, high, low and ultra-low) risk classification of 70-GS test with fair performance, which might provide information for treatment choice for those who have no access to the 70-GS testing. [ABSTRACT FROM AUTHOR]

Aim: The aim of the study was to assess the role of Magee Equation 3 (MagEq3), IHC4 score, and HER2-low status in predicting "satisfactory response (SR)" to neoadjuvant chemotherapy (NAC) in HR+/HER2− breast cancer (BC) patients. Methods: In a retrospective study, female patients of any age with T1–4, N0–2, M0 HR+/HER2− BC who received NAC and underwent adequate locoregional surgical treatment were included. Patients were grouped according to 2 outcomes: (a) overall response to NAC in breast and axilla by using residual cancer burden (RCB) criteria and (b) axillary downstaging after NAC by using N staging. 2 cohorts for overall response were overall SR (RCB 0–1) and no SR (RCB 2–3). On the other hand, for axillary downstaging, 2 cohorts constituted from axillary SR (ypN0 and ypN0i+) and no SR (ypNmic-N3). MagEq3 and IHC4 scores were calculated from their pathological tumor slides in each patient. HER2 status was categorized as either "no" or "low." In addition, patient age, family history, tumor histology, stage at admission, and Ki-67 status were compared between cohorts according to predefined outcomes. Results: In a total of 230 BC patients, 228 patients were included to compare according to their RCB levels. The mean age of patients with overall SR was significantly lower than those without. Patients with high Ki-67 expression, high (>30) MagEq3 score, high ICH4 quartile, and HER2-low status had significantly more overall SR. On the other hand, only patients with high Ki-67 expression had significantly more axillary SR. MagEq3 score levels, ICH4 quartiles, and HER2 status were similar between patients with axillary SR and not. Conclusion: MagEq3 and IHC4 tools seemed to be useful to predict those HR+/HER2− BC patients who are most likely to get benefit from NAC. But, only high Ki-67 expression level significantly predicted satisfactory axillary downstaging in HR+/HER2− BC patients. [ABSTRACT FROM AUTHOR]

Objectives: The study aimed to analyze the poor prognosis of microcalcification in breast cancer (BC), including the pathological complete response (pCR) to neoadjuvant chemotherapy (NACT) and the risk of bone metastases. Materials and methods: 313 breast cancer patients received NACT to evaluate pCR and 1182 patients from a multicenter database to assess bone metastases were retrospectively included. Two groups were divided according to the presence or absence of mammography microcalcification. Clinical data, image characteristics, neoadjuvant treatment response, bone involvement, and follow-up information were recorded. The pCR and bone metastases were compared between subgroups using the Mann–Whitney and χ2 tests and logistic regression, respectively. Results: Mammographic microcalcification was associated with a lower pCR than uncalcified BC in the NACT cohort (20.6% vs 31.6%, P = 0.029). Univariate and multivariate analysis suggested that calcification was a risk factor for poor NACT response [OR = 1.780, 95%CI (1.065–2.974), P = 0.028], [OR = 2.352, 95%CI (1.186–4.667), P = 0.014]. Microcalcification was more likely to be necrosis on MRI than those without microcalcification (53.0% vs 31.7%, P < 0.001), multivariate analysis indicated that tumor necrosis was also a risk factor for poor NACT response [OR = 2.325, 95%CI (1.100–4.911), P = 0.027]. Age, menopausal status, breast density, mass, molecular, and pathology type were not significantly associated with non-pCR risk assessment. In a multicenter cohort of 1182 patients with pathologically confirmed BC, those with microcalcifications had a higher proportion of bone metastases compared to non-calcified BC (11.6% vs 4.9%, P < 0.001). Univariate and multivariate analysis showed that microcalcification was an independent risk factor for bone metastasis [OR = 2.550, 95%CI (1.620–4.012), P < 0.001], [OR = 2.268(1.263–4.071), P = 0.006)]. Osteolytic bone metastases predominated but there was no statistical difference between the two groups (78.9% vs 60.7%, P = 0.099). Calcified BC was mainly involved in axial bone, but was more likely to involve the whole-body bone than non-calcified BC (33.8% vs 10.7%, P = 0.021). Conclusion: This study provides important insights into the poor prognosis of microcalcification, not only in terms of poor response to NACT but also the risk factor of bone metastases. [ABSTRACT FROM AUTHOR]

Purpose of Review: Clinical decisions for (neo)adjuvant treatment in early breast cancer (eBC) have been based mostly on clinical factors over the last decades. We have reviewed development and validation of such assays in the HR + /HER2 eBC and discuss possible future directions in this field. Recent Findings: Increasing knowledge about the biology of hormone-sensitive eBC, based on the precise and reproducible multigene expression analysis, has led to a significant change in the treatment pathways and reduction of overtreatment in particular by chemotherapy in HR + /HER2 eBC with up to 3 positive lymph nodes based on results from several retrospective-prospective trials used several genomic assays and in particular prospective trials (TAILORx, RxPonder, MINDACT, and ADAPT used OncotypeDX® and Mammaprint®). Summary: Precise evaluation of tumor biology together with endocrine responsiveness assessment appears as promising tools for individualized treatment decisions together with clinical factors and menopausal status in early hormone-sensitive/HER2-negative breast cancer. [ABSTRACT FROM AUTHOR]

Background: We sought to better define estrogen receptor-low-positive (ER-low+) breast cancer biology and determine the utility of the Oncotype DX Breast Recurrence Score ® (RS) assay in this population., Methods: Patients with information regarding percentage ER positivity and PAM50 subtype were identified in The Cancer Genome Atlas (TCGA) and subtype distribution was determined. Next, patients with ER-low+ (ER 1-10%), HER2- breast cancer undergoing upfront surgery with known RS result were identified in the National Cancer Database (NCDB) and our institutional Dana-Farber Brigham Cancer Center (DF/BCC) database; RS distribution was examined. Finally, patients with ER-low+, HER2- breast cancer treated at DF/BCC from 2011 to 2020 without prior RS results and in whom tissue was available to perform the assay were identified. RS results, treatment, recurrence and breast cancer-specific survival (BCSS) were determined., Results: Of 1033 patients in TCGA, ER percentage and PAM50 subtype were available for 342 (33.1%) patients. Forty-six (13.5%) had ER-low+/HER2- tumors, among whom 82.6% were basal and 4.3% were luminal A. Among 3423 patients with ER-low+/HER2- disease in the NCDB, RS results were available for 689 (20.1%) patients; 67% had an RS ≥26. In our institutional database, only two patients with ER-low+/HER2- disease and an RS were identified, both with RS ≥26. Among 37 patients in our institutional cohort without prior RS, 35 (97.4%) had an RS ≥26, determined with testing. After a median follow-up of 40 months (range 3-106), three patients, all treated with chemotherapy, recurred. Three-year BCSS was 97.0% (95% confidence interval 96.9-97.1%)., Conclusions: Most ER-low+/HER2- breast cancers are basal-like, with RS ≥26 suggesting these tumors are similar to triple-negative disease., (© 2023. Society of Surgical Oncology.)

DNA mismatch repair system (MMR) is considered a leading genetic mechanism in stabilizing DNA structure and maintaining its function. DNA MMR is a highly conserved system in bacteria, prokaryotic, and eukaryotic cells, and provides the highest protection to DNA by repairing micro-structural alterations. DNA MMR proteins are involved in the detection and repair of intra-nucleotide base-to-base errors inside the complementary DNA strand recognizing the recently synthesized strand from the parental template. During DNA replication, a spectrum of errors including base insertion, deletion, and miss-incorporation negatively affect the molecule’s structure and its functional stability. A broad spectrum of genomic alterations such as promoter hyper methylation, mutation, and loss of heterozygosity (LOH) in MMR genes including predominantly hMLH1, hMSH2, hMSH3, hMSH6, hPMS1, and hPMS2 lead to their loss of base-to-base error repairing procedure. Microsatellite instability (MSI) refers to the DNA MMR gene alterations that are observed in a variety of malignancies of different histological origins. In the current review, we present the role of DNA MMR deficiency in breast adenocarcinoma, a leading cancer-based cause of death in females worldwide. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is the most common malignancy worldwide and neoadjuvant therapy (NAT) plays an important role in the treatment of patients with early BC. However, only a subset of BC patients can achieve pathological complete response (pCR) and benefit from NAT. It is therefore necessary to predict the responses to NAT. Although many models to predict the response to NAT based on gene expression determined by the microarray platform have been proposed, their applications in clinical practice are limited due to the data normalization methods during model building and the disadvantages of the microarray platform compared with the RNA-seq platform. In this study, we first reconfirmed the correlation between immune profiles and pCR in an RNA-seq dataset. Then, we employed multiple machine learning algorithms and a model stacking strategy to build an immunological gene based model (Ipredictor model) and an immunological gene and receptor status based model (ICpredictor model) in the RNA-seq dataset. The areas under the receiver operator characteristic curves for the Ipredictor model and ICpredictor models were 0.745 and 0.769 in an independent external test set based on the RNA-seq platform, and were 0.716 and 0.752 in another independent external test set based on the microarray platform. Furthermore, we found that the predictive score of the Ipredictor model was correlated with immune microenvironment and genomic aberration markers. These results demonstrated that the models can accurately predict the response to NAT for BC patients and will contribute to individualized therapy. [ABSTRACT FROM AUTHOR]

Purpose: The neoadjuvant treatment of breast cancer (NABC) is a rapidly changing area that benefits from guidelines integrating evidence with expert consensus to help direct practice. This can optimize patient outcomes by ensuring the appropriate use of evolving neoadjuvant principles. Methods: An expert panel formulated evidence-based practice recommendations spanning the entire neoadjuvant breast cancer treatment journey. These were sent for practice-based consensus across Canada using the modified Delphi methodology, through a secure online survey. Final recommendations were graded using the GRADE criteria for guidelines. The evidence was reviewed over the course of guideline development to ensure recommendations remained aligned with current relevant data. Results: Response rate to the online survey was almost 30%; representation was achieved from various medical specialties from both community and academic centres in various Canadian provinces. Two rounds of consensus were required to achieve 80% or higher consensus on 59 final statements. Five additional statements were added to reflect updated evidence but not sent for consensus. Conclusions: Key highlights of this comprehensive Canadian guideline on NABC include the use of neoadjuvant therapy for early stage triple negative and HER2 positive breast cancer, with subsequent adjuvant treatments for patients with residual disease. The use of molecular signatures, other targeted adjuvant therapies, and optimal response-based local regional management remain actively evolving areas. Many statements had evolving or limited data but still achieved high consensus, demonstrating the utility of such a guideline in helping to unify practice while further evidence evolves in this important area of breast cancer management. [ABSTRACT FROM AUTHOR]

Introduction: In locally advanced breast cancer, Neoadjuvant Chemotherapy (NACT) is the mainstay of treatment. NACT is also considered as a potentially helpful treatment option in earlystage HER2 positive and triple-negative breast cancer. Aim: To assess pathological Complete Response (pCR) in patients with breast cancer who received NACT and to evaluate the association with clinical and pathological factors. Materials and Methods: The present retrospective analysis was conducted at Breast Oncology Division of Regional Cancer Centre, Thiruvananthapuram, Kerala, India, from January 2013 to December 2015. The data of patients with invasive breast cancer who received NACT were retrieved from medical records and analysed in August 2021. In the surgical pathology specimens, pCR was defined as ypT0 ypN0: no residual invasive cancer and/or in-situ cancer in the breast or axillary lymph nodes. All factors identified with univariate analyses were entered into multivariate analysis, and statistical analysis was done using logistic regression. The p-value <0.05 was considered significant. Results: This study included 586 breast cancer patients who received NACT, with mean age of 50.7 years. The proportion of postmenopausal patients was higher than premenopausal patients (56.3% vs 43.7%). Overall, 21.3% patients (125/586) attained pCR (ypT0 ypN0). In univariate analysis, factors associated with pCR were higher histologic grade (grade III) of tumour {Odds Ratio (OR): 2.879, 95% Confidence Interval (CI): 1.615-5.129, p-value=0.001)}, lower composite clinical stage (OR: 2.236, 95% CI: 1.468-3.408, p-value=0.001), lack of Oestrogen Receptor (ER) expression (OR: 3.23,95% CI: 2.10-4.968, p-value=0.001) and lack of Progesterone Receptor (PR) expression (OR: 4.396, 95% CI: 2.714-7.121, p-value=0.001). Higher grade of tumour (OR: 2.211, 95% CI: 1.179-4.146, p-value=0.013), lower composite clinical stage (OR: 2.033, 95% CI: 1.262-3.276, p-value=0.004) and lack of PR expression (OR: 3.823, 95% CI: 2.301-6.350, p-value=0.001) remained predictive variables in multivariate analysis after correction for the other variables. Conclusion: The lower composite clinical stage, lack of Progesterone Receptor (PR) expression and higher histologic grade of tumour are associated with good response to NACT in breast cancer patients. [ABSTRACT FROM AUTHOR]

Background: The extent of cellular heterogeneity in breast cancer could have potential impact on diagnosis and long-term outcome. However, pathology evaluation is limited to biomarker immunohistochemical staining and morphology of the bulk cancer. Inter-cellular heterogeneity of biomarkers is not usually assessed. As an initial evaluation of the extent of breast cancer cellular heterogeneity, we conducted quantitative and spatial imaging of Estrogen Receptor (ER), Progesterone Receptor (PR), Epidermal Growth Factor Receptor-2 (HER2), Ki67, TP53, CDKN1A (P21/WAF1), CDKN2A (P16INK4A), CD8 and CD20 of a tissue microarray (TMA) representing subtypes defined by St. Gallen surrogate classification.Methods: Quantitative, single cell-based imaging was conducted using an Immunofluorescence protein multiplexing platform (MxIF) to study protein co-expression signatures and their spatial localization patterns. The range of MxIF intensity values of each protein marker was compared to the respective IHC score for the TMA core. Extent of heterogeneity in spatial neighborhoods was analyzed using co-occurrence matrix and Diversity Index measures.Results: On the 101 cores from 59 cases studied, diverse expression levels and distributions were observed in MxIF measures of ER and PR among the hormonal receptor-positive tumor cores. As expected, Luminal A-like cancers exhibit higher proportions of cell groups that co-express ER and PR, while Luminal B-like (HER2-negative) cancers were composed of ER+, PR- groups. Proliferating cells defined by Ki67 positivity were mainly found in groups with PR-negative cells. Triple-Negative Breast Cancer (TNBC) exhibited the highest proliferative fraction and incidence of abnormal P53 and P16 expression. Among the tumors exhibiting P53 overexpression by immunohistochemistry, a group of TNBC was found with much higher MxIF-measured P53 signal intensity compared to HER2+, Luminal B-like and other TNBC cases. Densities of CD8 and CD20 cells were highest in HER2+ cancers. Spatial analysis demonstrated variability in heterogeneity in cellular neighborhoods in the cancer and the tumor microenvironment.Conclusions: Protein marker multiplexing and quantitative image analysis demonstrated marked heterogeneity in protein co-expression signatures and cellular arrangement within each breast cancer subtype. These refined descriptors of biomarker expressions and spatial patterns could be valuable in the development of more informative tools to guide diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the association of various gene expression assays with pathologic complete response (pCR) in the setting of neoadjuvant chemotherapy among patients with breast cancer Methods: The National Cancer Database (NCDB) was queried for women diagnosed between 2010 and 2017 with stage I-III breast cancer who underwent neoadjuvant chemotherapy and either 21-gene recurrence score (RS) or 70-gene signature (GS). Logistic multivariable analysis (MVA) was performed to identify variables associated with pCR. Results: A total of 3009 patients met our inclusion criteria. The median follow up was 48.0 months (interquartile range 32.2–66.7 months). On logistic MVA for all patients, those with a high risk from GS (adjusted odds ratio [aOR] 3.23, 95% confidence interval [CI] 1.49–8.13, p = 0.006) or with RS ≥ 31 (aOR 1.99, 95% CI 1.41–2.82, p < 0.001) were more likely to have pCR. When compared to RS ≥ 31, a high risk from GS was not associated with pCR (aOR 1.01, 95% CI 0.75–1.37, p = 0.94). However, among those with favorable hormone receptor status, similar findings were noted, except that those with a high risk group from GS were less likely to have pCR compared to those with RS ≥ 31 (aOR 0.65, 95% CI 0.43–0.96, p = 0.03). When analyses were repeated using a high risk group from RS defined as RS ≥ 26 among those with favorable hormone receptor status, RS ≥ 26 was not associated with pCR when compared to the high risk from GS (aOR 0.74, 0.50–1.07, p = 0.12). Conclusions: To our knowledge, this is the largest study using a nationwide oncology database suggesting that high recurrence risk groups in both assays were associated with pCR. Among those with favorable hormone receptor status, RS ≥ 31 may be a more selective prognostic marker for pCR. [ABSTRACT FROM AUTHOR]

Background: Meckel's diverticulum is an embryologic remnant of the vitelline duct, occurring in approximately 2% of the adult population. A hernia containing a Meckel's diverticulum is called a Littré's hernia and is rarely reported in the medical literature. Clinically, a Littré's hernia is indistinguishable from a hernia containing small bowel and is often discovered incidentally during a repair. Case Presentation: Herein, we report a rare case of strangulated Littré's hernia in a patient's right groin. The sac contained a long segment of small bowel in addition to a large Meckel's diverticulum. The bowel was irreducible through the groin incision, and a lower midline laparotomy was made. Necrotic bowel including the Meckel's diverticulum was resected. Given the presence of necrotic bowel and potential for infection, the hernia was repaired with a Bassini herniorrhaphy, reinforced with absorbable mesh. The patient recovered uneventfully. Conclusion: Littré's hernia is a rare clinical entity. Treatment is similar to any bowel-containing hernia. Repair of the hernia defect with permanent mesh should be weighed against the risk of implant infection. [ABSTRACT FROM AUTHOR]

Purpose: To develop and validate an imaging-radiomics model for the diagnosis of male benign and malignant breast lesions. Methods: Ninety male patients who underwent preoperative mammography from January 2011 to December 2018 were enrolled in this study (63 in the training cohort and 27 in the validation cohort). The region of interest was segmented into a mediolateral oblique view, and 104 radiomics features were extracted. The minimum redundancy and maximum relevance (mRMR) and the least absolute shrinkage and selection operator (LASSO) methods were used to exclude radiomics features to establish the radiomics score (rad-score). Mammographic features were evaluated by two radiologists. Univariate logistic regression was used to select for imaging features, and multivariate logistic regression was used to construct an imaging model. An imaging-radiomics model was eventually established, and a nomogram was developed based on the imaging-radiomics model. Area under the curve (AUC) and decision curve analysis (DCA) were applied to assess the clinical value. Results: The AUC based on the imaging model in the validation cohort was 0.760, the sensitivity was 0.750, and the specificity was 0.727. The AUC, sensitivity and specificity based on the radiomics in the validation cohort were 0.820, 0.750, and 0.867, respectively. The imaging-radiomics model was better than the imaging and radiomics models; the AUC, sensitivity, and specificity of the imaging-radiomics model in the validation cohort were 0.870, 0.824, and 0.900, respectively. Conclusion: The imaging-radiomics model created by the imaging characteristics and radiomics features exhibited a favorable discriminatory ability for male breast cancer. [ABSTRACT FROM AUTHOR]