Detection of Residual Peritoneal Metastases Following Cytoreductive Surgery Using Pegsitacianine, a pH-Sensitive Imaging Agent: Final Results from a Phase II Study.

BACKGROUND: For patients with peritoneal carcinomatosis, extent of disease and completeness of cytoreductive surgery (CRS) are major prognostic factors for long-term survival. Assessment of these factors could be improved using imaging agents. Pegsitacianine is a pH-sensitive polymeric micelle conjugated to the fluorophore indocyanine green. The micelle disassembles in acidic microenvironments, such as tumors, resulting in localized fluorescence unmasking. We assessed the utility of pegsitacianine in detecting residual disease following CRS. PATIENTS AND METHODS: NCT04950166 was a phase II, non-randomized, open-label, multicenter US study. Patients eligible for CRS were administered an intravenous dose of pegsitacianine at 1 mg/kg 24-72 h before surgery. Following CRS, the peritoneal cavity was reexamined under near-infrared (NIR) illumination to evaluate for fluorescent tissue. Fluorescent tissue identified was excised and evaluated by histopathology. The primary outcome was the rate of clinically significant events (CSE), defined as detection of histologically confirmed residual disease excised with pegsitacianine or a revision in the assessment of completeness of CRS. Secondary outcomes included acceptable safety and pegsitacianine performance. RESULTS: A total of 53 patients were screened, 50 enrolled, and 40 were evaluable for CSE across six primary tumor types. Residual disease was detected with pegsitacianine in 20 of 40 (50%) patients. Pegsitacianine showed high sensitivity and was well tolerated with no serious adverse events (SAEs). Transient treatment-related, non-anaphylactic infusion reactions occurred in 28% of patients. CONCLUSIONS: Pegsitacianine was well tolerated and facilitated the recognition of occult residual disease following CRS. The high rate of residual disease detected suggests that the use of pegsitacianine augmented surgeon assessment and performance during CRS.

Ernst Bertner: A Surgeon with Prescient Vision for the Largest Medical Center in the World.

More than 75 years ago, surgeon Ernst Bertner envisioned the Texas Medical Center (TMC) as "breathtaking in the scope and breadth of its conception," that would be "one of the largest in the world"; a gigantic medical enterprise that would "attract the greatest scientists of the world" and would combine patient care, research, and education, on a scale that was "second to none." During the next 3 years, Bertner accomplished important pieces of the Herculean task to bring onto the campus 11 major buildings, including the University of Texas MD Anderson Hospital for Cancer Research, for which he was the interim director. This was an extraordinary accomplishment because at the outset he had only a strategic plan, the deed to 134 acres of forest, and financial support from the MD Anderson Foundation! Bertner further forecasted world-class clinical and educational programs in the TMC, stating: "We envision the time when the Medical Center will become a great magnet, drawing leaders in education, medicine, and dental professions. It will provide the physical facilities and the environment in which research will flourish and bring forth for all of us new discoveries in the field of medicine." So how did his bold vision and passionate leadership culminate in the TMC today? By any criteria of scale and program excellence, the TMC today can be regarded as the largest medical center in the world. Occupying a contiguous campus of 1345 acres (2.1 square miles), it comprises 162 buildings, 60+ member institutions, 21 hospitals (> 9200 beds), 21 academic institutions, 4 medical schools, 7 nursing schools, 3 public health schools, 2 pharmacy schools, and a dental school. More than 106,000 patients and visitors come daily to the TMC, which has more than 120,000 employees, including 5000 physicians, 5700 researchers, and 11,000 registered nurses. Ernst Bertner is credited for transforming the original vision of the TMC into a workable program, and whose dynamic devotion to the idea captured the devotion of others to accomplish this extraordinary feat. Thus, during this short interval from 1946 to 1950, Bertner transitioned the leadership of the MD Anderson Cancer Hospital to Dr. R. Lee Clark, conducted a busy general surgery and gynecologic practice, facilitated the monumental transfer of the Baylor Medical School from Dallas to Houston, helped to recruit Dr. Michael DeBakey from New Orleans, and fought a heroic battle against rhabdomyosarcoma, a very rare and aggressive cancer.

Prediction of nonsentinel lymph node metastasis in acral melanoma with positive sentinel lymph nodes.

BACKGROUND: Metastasis in a nonsentinel lymph node (non-SLN) is an unfavorable independent prognostic factor in cutaneous melanoma (CM). Recent data did suggest potential value of completion lymph node dissection (CLND) in CM patients with non-SLN metastasis. Prediction of non-SLN metastasis assists clinicians in deciding on adjuvant therapy without CLND. We analyzed risk factors and developed a prediction model for non-SLN status in acral melanoma (AM). METHODS: This retrospective study enrolled 656 cases of melanoma who underwent sentinel lymph node biopsy at Fudan University Shanghai Cancer Center from 2009 to 2017. We identified 81 SLN + AM patients who underwent CLND. Clinicopathologic data, including SLN tumor burden and non-SLN status were examined with Cox and Logistics regression models. RESULTS: Ulceration, Clark level, number of deposits in the SLN (NumDep) and maximum size of deposits (MaxSize) are independent risk factors associated with non-SLN metastases. We developed a scoring system that combines ulceration, the cutoff values of Clark level V, MaxSize of 2 mm, and NumDep of 5 to predict non-SLN metastasis with an efficiency of 85.2% and 100% positive predictive value in the high-rank group (scores of 17-24). CONCLUSIONS: A scoring system that included ulceration, Clark level, MaxSize, and NumDep is reliable and effective for predicting non-SLN metastasis in SLN-positive AM.

Single-cell profile of tumor and immune cells in primary breast cancer, sentinel lymph node, and metastatic lymph node.

PURPOSE: Little is known about the host-tumor interaction in the lymph-node basin at a single cell level. This study examines single cell sequences in breast cancer nodal metastases of a patient with triple-negative breast cancer. METHODS: The primary breast tumor, sentinel lymph node, an adjacent lymph node with metastatic involvement and a clinically normal-appearing lymph node were collected during surgery. Single-cell sequencing was performed on all four specimens. RESULTS: 14,016 cells were clustered into 6 cell subpopulations. Cancer cells demonstrated the molecular characteristics of TNBC basal B subtype and highly expressed genes in the MAPK signaling cascade. Tumor-associated macrophages regulated antigen processing and presentation and other immune-related pathways to promote tumor invasion. CD8 + and CD4 + T lymphocytes concentrated more in sentinel lymph node and mainly stratified into two transcriptional states. The immune-cell amount variation among primary tumor, sentinel and normal lymph nodes showed a similar tendency between the sc-RNA-seq profile of TNBC samples and a previous reported bulk RNA-seq profile of a breast cancer cohort, including all four breast cancer subtype samples. DISCUSSION: Single-cell sequencing analysis suggested that the sentinel lymph node was the initial meeting site of tumor infiltration and immune response, where partial T lymphocytes perform anti-tumor activity, while other T cells exhibit an exhausted state. We proposed a molecular explanation to the well-established clinical principle that the 5-year and 10-year survival outcomes were noninferior between SLND and ALND.

Prognostic impact of Breslow thickness in acral melanoma: A retrospective analysis.

BACKGROUND: Evidence for the prognostic importance of tumor thickness in acral melanoma (AM) patients is limited. OBJECTIVE: The objective of the study was to determine the prognostic impact of Breslow thickness in AM. METHODS: This multicenter study enrolled patients diagnosed with localized AM between January 1, 2000 and December 31, 2017. Melanoma-specific survival (MSS) in different tumor thickness strata (T1-T4: ≤1, >1-2, >2-4, >4 mm, respectively) was estimated by the Kaplan-Meier method. Comparisons were performed by the log-rank test and multivariable Cox regression. RESULTS: A total of 853 patients with clinical N0 (cN0) AM were included in the analysis. The median follow-up time was 60.1 months. The median MSS in patients with T1-T4 disease was not reached, 111.0, 92.8, and 67.1 months, respectively. MSS differed significantly among cN0 patients with T1-T3 AM (log-rank P = .004, .012, <0.001 for T1 vs T2, T2 vs T3, and T1 vs T3, respectively); however, there was no significant difference between T3 and T4 AM (hazard ratio = 0.82, 95% CI, 0.62-1.09). Six-subgroup analyses confirmed that survival outcomes were similar between different subgroups with tumor thickness >2 mm. LIMITATIONS: The limitations were retrospective design and some missing variables. CONCLUSIONS: There was no association between tumor thickness and survival in AM patients with a Breslow thickness >2 mm.

The Pivotal Leadership of Doctors R. Lee Clark and Murray M. Copeland in Transforming the Commission on Cancer (1955-1965).

In September 1959, Dr. Clark was appointed as Chair and Dr. Murray M Copeland as Vice Chair of the Committee on Cancer. With their typical leadership style to improve the functions and value of organizations, they reorganized and revitalized the Committee on Cancer during the next 6 years. Thus, Drs. Clark and Copeland and the Committee members developed more uniform standards of cancer registries, implemented the American Joint Committee on Cancer Staging and End Results Reporting (with Dr. Copeland as Chair), published a revised Manual for Cancer Programs (which defined minimum standards requisite for approval of a cancer service), established a new regionalization program (with liaison surgeons from each state), and planned all the cancer educational programs for the College's annual Clinical Congress and Sectional Meetings. Importantly, Clark and Copeland led a 10-year strategic plan (called the "Program of the Sixties") to expand and revitalize the scale and scope of the Committee's activities and to reorganize the Committee structure by including liaison members from other physician, oncologic, and hospital organizations. As Dr. Clark completed his 5-year tenure as Committee Chair in October 1964, he formally recommended a reorganization of the Committee on Cancer to assume an even greater role in the cancer community as the Commission on Cancer. As the new Committee Chair, Dr. Copeland shepherded this recommendation to the ACS Board of Regents, which was approved and implemented in July 1965. The Regents emphasized that the functions and activities of the Committee on Cancer had become so complex and far reaching (under Clark's and Copeland's leadership) that its many subcommittees had already assumed duties of committee stature. Dr. Copeland thus became the first Chair of the Commission on Cancer until October 1965, when Dr. John Cline became Chair. For his contributions to the cancer field and to the College of Surgeons, Dr. Clark received their Distinguished Service Award in October 1969 "for his life-long devotion to the treatment of patients and to research in cancer, for notable service to this College, particularly as Chairman of the Cancer Commission from 1960 to 1964."

An Evidence-Based Staging System for Mucosal Melanoma: A Proposal.

BACKGROUND: There is no widely employed staging system for mucosal melanoma (MuM) that incorporates all anatomic sites. We hypothesized that MuM patients arising from different anatomical sites could be staged using a common approach. METHODS: A prospective database contained 1814 MuM patients with a median follow-up of 5.14 years was employed. Overall survival (OS) was calculated from the time of pathological diagnosis to the date of death from any cause. Multivariate analyses of prognostic variables and OS were performed using the Cox proportional hazard model. RESULTS: For localized MuM, the most significant median OS differences were primary tumors invading submucosa (i.e., T1) versus deeper (i.e., T2/T3/T4): 4.3 versus 3.4, 3.1, and 2.9 years, respectively (p < 0.001). For patients only with regional node metastasis at presentation, the most significant were: 1 versus ≥ 2 regional nodes (N1 vs. N2, 2.5 vs. 2.1 years, p < 0.001). For patients with distant metastasis at presentation, the median OS was 1.5, 1.2, 0.8, and 0.6 years respectively for skin/subcutaneous tissue/distant lymph nodes (M1a), lung metastasis (M1b), all other visceral sites except brain (M1c), and brain (M1d) (p < 0.001). Based on these results, the staging system for MuM is proposed: (1) Stage I: T1N0M0 (median OS, 4.3 years); (2) Stage II: T2-4N0M0 (3.1 years); (3) Stage IIIA: T1-4N1M0 (2.5 years), Stage IIIB: T1-4N2M0 (2.1 years); (4) Stage IV: TanyNanyM1 (0.9 years) (p < 0.001). CONCLUSIONS: A single, unified, staging system for mucosal melanoma inclusive of all anatomical primary tumor sites can harmonize staging of MuM and the design of clinical trials.

Distinct clinical and somatic mutational features of breast tumors with high-, low-, or non-expressing human epidermal growth factor receptor 2 status.

BACKGROUND: HER2-low breast cancers were reported to have distinct clinicopathological characteristics from HER2-zero; however, the difference in their genetic features remains unclear. This study investigated the clinical and molecular features of breast tumors according to HER2 status. METHODS: We analyzed the clinicopathological and genomic data of 523 Chinese women with breast cancer. Genomic data was generated by targeted next-generation sequencing (NGS) of breast tumor samples using a commercial 520 gene panel. The cohort was stratified according to HER2 status as HER2-zero (n = 90), HER2-low (n = 231), and HER2-positive (n = 202) according to their immunohistochemistry and fluorescence in situ hybridization results. RESULTS: HER2-low breast tumors were enriched with hormone receptor-positive tumors, and who had lower Ki67 expression levels. Genes were differentially mutated across HER2 subgroups. HER2-low tumors had significantly more mutations involved in PI3K-Akt signaling than HER2-positive (p < 0.001) and HER2-zero breast tumors (p < 0.01). HER2-zero tumors had more mutations in checkpoint factors (p < 0.01), Fanconi anemia (p < 0.05), and p53 signaling and cell cycle pathway (p < 0.05) compared to HER2-low breast tumors. Compared with HER2-zero tumors, HER2-low tumors had significantly lower pathological complete response rates after neoadjuvant therapy (15.9% vs. 37.5%, p = 0.042) and proportion of relapsed/progressed patients across follow-up time points (p = 0.031), but had comparable disease-free survival (p = 0.271). CONCLUSION: Our results demonstrate the distinct clinical and molecular features and clinical outcomes of HER2-low breast tumors.

Trends in leadership at breast surgical oncology fellowships.

Introduction: Breast surgical oncology is a defined sub-specialty of general surgery that focuses on the surgical management of breast disease and malignancy within a multidisciplinary context. The fellowship directors (FD) that lead these programs have been selected for their abilities. As programs do research to ensure proper training for the next generation of breast surgical oncologists, we wanted to look into the FDs responsible for their training. Methods: The Breast Surgical Oncology care program list was compiled via the Society of Surgical Oncology and American Society of Breast Surgeons Accredited programs (n = 60). The demographic information that was of interest included, but was not limited to, gender, age, ethnicity/background, past residency training, past fellowship training, year graduated from residency and fellowship, year since graduation to FD appointment, time at institution till FD appointment, and Hirsch index (h-index). Results: Data were collected on all 60 FDs. The average age of FDs was 52 years old, 27% of FDs are men and 73% of FDs are women. The average H-index, number of publications, and number of citations were 19, 67, and 2648, respectively. The mean graduation year from residency was 2003, and from fellowship was 2006; with a mean of 9 years post fellowship graduation until becoming an FD. The most frequently attended residency was Rush (n = 4), and the most common fellowships were Memorial Sloan Kettering (n = 8), MD Anderson Cancer Center (n = 7), and John Wayne Cancer Institute (n = 4). Nine of the FDs stayed at the same institution after doing both residency and fellowship there (15%). Conclusion: This is the first study to examine the demographics of those in FD positions in Surgical Breast Oncology, which is a relatively young fellowship. We found that FDs in Breast Surgical Oncology are defined by their high output of research. This qualification may be why the average age, and the number of years to FD are higher compared to other specialties where this research has been undertaken. Initial evaluation of FDs suggest more diversity in this field is needed. Further insight into the leaders training our next generation of surgeons is warranted.

The Politics of Recruiting Dr. R Lee Clark Jr. as the First Permanent Director of The University of Texas MD Anderson Hospital for Cancer Research : Part II: The Process and Politics of Recruiting Lt. Colonel R. Lee Clark Jr. to The University of Texas MD Anderson Hospital.

Dr. R. Lee Clark Jr. was a man of bold and extraordinary vision. He was truly a surgical oncology leader of the twentieth century. His leadership had a significant impact on the cancer community nationally and internationally. Historically, it is intriguing that Dr. Clark almost did not become President of the UT MD Anderson Cancer Center, since five other candidates were first offered the position and turned it down, and then Clark himself almost withdrew during the search process because of the political stalemate among the UT Regents to select a candidate. The saga began in 1945, when the Acting Director of MD Anderson Hospital for Cancer Research, Dr. Ernst Bertner, pressed the UT Regents to recruit a permanent Director, since he had just been appointed as the first President of the Texas Medical Center. Bertner was a major figure in recruiting Dr. R. Lee Clark, who was then a Lt. Colonel in the Army Air Force. Dr. Clark's vision for this unique cancer facility was first drafted on Randolph Army Airfield stationary in February 1946. An interesting twist to the story is that Dr. Clark almost did not get the job because of an alternative candidate, and because of the political vicissitudes among the University of Texas Board of Regents. Many of these political barriers were eventually overcome, and Dr. Clark was unanimously approved as the first permanent Director on 13 July 1946, and his leadership over the next 32 years changed the course of history.

The Politics of Recruiting Dr. R. Lee Clark Jr as the First Permanent Director of the University of Texas MD Anderson Hospital for Cancer Research : Part I: Creating the Texas Cancer Hospital and Events that Might Have Changed the Course of History (1941-1945).

The MD Anderson Cancer Center is one of the world's largest programs in cancer patient care, research, and education; yet, there were many historical twists and turns that almost led the cancer hospital to be located in a different place, under a different authority, and under different leadership. Although it was finally located in Houston, Texas, historical events could possibly have resulted in the cancer hospital being located in Dallas, Galveston, or Austin, Texas. Although Dr. R. Lee Clark Jr eventually became the first permanent Director, five other physicians were offered the position before him. After the war ended, Dr. Bertner, as acting director, urged the university Regents to press their search for a permanent director, but the selection process was snafued and prolonged because Regent D. Frank Strickland filibustered for his own candidate for the permanent job. And it was not Dr. R. Lee Clark Jr, who was favored by the other eight Regents.

Genetic and immune characteristics of sentinel lymph node metastases and multiple lymph node metastases compared to their matched primary breast tumours.

BACKGROUND: Patients with breast cancer presenting with single lymph node metastasis (from a sentinel node) experience prolonged survival compared to patients with multiple lymph node metastases (≥3). However, little information is available on the genetic and immunological characteristics of breast cancer metastases within the regional lymph nodes as they progress from the sentinel lymph node (SLN) downstream to multiple regional lymph nodes (MLNs). METHODS: Genomic profiling was performed using a next-generation sequencing panel covering 520 cancer-related genes in the primary tumour and metastatic lymph nodes of 157 female patients with breast cancer. We included primary tumours, metastatic lymph nodes and adjacent clinically normal lymph nodes (20 patients from the SLN group and 28 patients from the MLNs group) in the whole transcriptome analysis. FINDINGS: The downstream metastatic lymph nodes (P = 0.029) and the primary breast tumours (P = 0.011) had a higher frequency of PIK3CA mutations compared to the SLN metastasis. We identified a distinct group of 14 mutations from single sentinel node metastasis and a different group of 15 mutations from multiple nodal metastases. Only 4 distinct mutations (PIK3CA, CDK4, NFKBIA and CDKN1B) were conserved in metastases from both lymph node settings. The tumour mutational burden (TMB) was significantly lower in single nodal metastasis compared to the paired primary breast cancer (P = 0.0021), while the decline in TMB did not reach statistical significance in the MLNs group (P = 0.083). In the gene set enrichment analysis, we identified 4 upregulated signatures in both primary tumour and nodal metastases from the MLNs group, including 3 Epithelial-mesenchymal transition(EMT) signatures and 1 angiogenesis signature. Both the CD8/Treg ratio and the CD8/EMT ratio were significantly higher in adjacent normal lymph nodes from patients with a single metastasis in the SLN compared with samples from the MLNs group (P = 0.045 and P = 0.023, respectively). This suggests that the immune defence from the MLNs patients might have a less favourable microenvironment, thus permitting multiple lymph nodes metastasis. INTERPRETATION: Single lymph node metastases and multiple lymph node metastases have significant differences in their molecular profiles and immune profiles. The findings are associated with more aggressive tumour characteristics and less favourable immune charactoristics in patients with multiple nodal metastases compared to those with a single metastasis in the sentinel node. FUNDING: This work was supported by funds from High-level Hospital Construction Project (DFJH201921), the National Natural Science Foundation of China (81902828 and 82002928), the Fundamental Research Funds for the Central Universities (y2syD2192230), and the Medical Scientific Research Foundation of Guangdong Province (B2019039).

Breast-Gynaecological & Immuno-Oncology International Cancer Conference (BGICC) Consensus and Recommendations for the Management of Triple-Negative Breast Cancer.

Background: The management of patients with triple-negative breast cancer (TNBC) is challenging with several controversies and unmet needs. During the 12th Breast-Gynaecological & Immuno-oncology International Cancer Conference (BGICC) Egypt, 2020, a panel of 35 breast cancer experts from 13 countries voted on consensus guidelines for the clinical management of TNBC. The consensus was subsequently updated based on the most recent data evolved lately. Methods: A consensus conference approach adapted from the American Society of Clinical Oncology (ASCO) was utilized. The panellists voted anonymously on each question, and a consensus was achieved when ≥75% of voters selected an answer. The final consensus was later circulated to the panellists for critical revision of important intellectual content. Results and conclusion: These recommendations represent the available clinical evidence and expert opinion when evidence is scarce. The percentage of the consensus votes, levels of evidence and grades of recommendation are presented for each statement. The consensus covered all the aspects of TNBC management starting from defining TNBC to the management of metastatic disease and highlighted the rapidly evolving landscape in this field. Consensus was reached in 70% of the statements (35/50). In addition, areas of warranted research were identified to guide future prospective clinical trials.

The MD Anderson Cancer Hospital That R. Lee Clark Built.

The MD Anderson Hospital for Cancer Research (as it was named in 1946) incorporated pioneering changes that set new standards in hospital design, construction, and function. It is remarkable that surgeon R. Lee Clark, the new Director of the MD Anderson Hospital, and with no previous experience in hospital construction, personally led the design and supervision of a world class medical care and research facility. This is the untold story of his leadership and his diligence visiting hospitals and cancer facilities in America and Europe, his clever hiring, his supervision of the architectural firms (through 23 versions of architectural plans), his adaptability to the market when building costs were skyrocketing, and his extraordinary ability in raising enormous funds from private, state, and federal sources. He was such a creative genius in his inaugural building project that the new MD Anderson "cancer station" was described by national magazines as totally unique in its design that set new standards in cancer care delivery. With his typical determination, enthusiasm, and creative approach to problem-solving, Clark embarked on this building project in 1946 with a budget of $1,750,000, expecting to complete this project in 2 to 3 years. In fact, the entire project took 8 years and cost five times more than the original estimate, at almost $9,000,000! The process took 2 years for Dr. Clark to visit more than 30 cancer facilities and many academic hospitals in America and in Europe, 2 years of architectural planning, and 4 years of construction. When MD Anderson opened its doors in 1954, it was described by national magazines as "one of the most modern hospitals in the nation."

The first BGICC consensus and recommendations for breast cancer awareness, early detection and risk reduction in low- and middle-income countries and the MENA region.

In low-middle income countries (LMICs) and the Middle East and North Africa (MENA) region, there is an unmet need to establish and improve breast cancer (BC) awareness, early diagnosis and risk reduction programs. During the 12th Breast, Gynecological & Immuno-oncology International Cancer Conference - Egypt 2020, 26 experts from 7 countries worldwide voted to establish the first consensus for BC awareness, early detection and risk reduction in LMICs/MENA region. The panel advised that there is an extreme necessity for a well-developed BC data registries and prospective clinical studies that address alternative modalities/modified BC screening programs in areas of limited resources. The most important recommendations of the panel were: (a) BC awareness campaigns should be promoted to public and all adult age groups; (b) early detection programs should combine geographically distributed mammographic facilities with clinical breast examination (CBE); (c) breast awareness should be encouraged; and (d) intensive surveillance and chemoprevention strategies should be fostered for high-risk women. The panel defined some areas for future clinical research, which included the role of CBE and breast self-examination as an alternative to radiological screening in areas of limited resources, the interval and methodology of BC surveillance in women with increased risk of BC and the use of low dose tamoxifen in BC risk reduction. In LMICs/MENA region, BC awareness and early detection campaigns should take into consideration the specific disease criteria and the socioeconomic status of the target population. The statements with no consensus reached should serve as potential catalyst for future clinical research.