Research ArticleClinical Studies

Breast Textured Implants Determine Early T-helper Impairment: BIAL2.20 Study

GIANLUCA VANNI, MARCO MATERAZZO, MARCO PELLICCIARO, SADRI AMIR, FEDERICO TACCONI, VINCENZO AMBROGI and ORESTE CLAUDIO BUONOMO
Anticancer Research April 2021, 41 (4) 2123-2132; DOI: https://doi.org/10.21873/anticanres.14984

Abstract

Background/Aim: Surgical stress has been correlated with higher rate of postoperative complications. Breast implants’ surfaces (textured or smooth) represent an immunological stimulus. Our prospective study (BIAL2.20) evaluated post-operative leukocytes response at baseline and postoperative day (POD) 1 and 2 after implant-based breast reconstruction. Patients and Methods: Between January and July 2020, 41 patients underwent reconstruction with textured (n=23) or smooth (n=18) implants. A full blood count and lymphocyte subsets were collected before surgery, on POD1 and POD2. Data were evaluated as difference and relative difference from baseline by two-way analysis of variance test (2-way-ANOVA). Mann-Whitney U-test was performed at each POD, whenever between-group 2-way-ANOVA reached statistical significance. Results: Within-group-analysis showed statistically significant total leukocytosis in both groups. Within-group-analysis of lymphocytes subsets demonstrated statistically significant lymphopenia in the textured group for T-lymphocytes, and T-helper cells. Between-group-analysis showed statistically significant lymphopenia in T-helper subsets in the textured group at POD1 and POD2, when compared with the smooth group. Conclusion: Textured implants demonstrated a statistically significant impairment of T-helper trend during POD1 and POD2 when compared to smooth implants by between-group 2-way-ANOVA.

Key Words:

In surgical oncology, emerging evidence suggests that surgical stress may result in postoperative complications (1-5), as well as a higher risk of locoregional and distant disease relapse (2, 6-8).

Despite the popularization of conservative approaches (9-12), such as awake surgery and oncoplastic procedures (13-15), mastectomy followed by breast reconstruction is still necessary for a significant number of patients (16-18). This procedure results in higher surgical postoperative stress and surgical complications (16, 19-21) compared to breast conserving surgery (1, 2).

The features of breast implants may play a pivotal role in postoperative surgical stress (22-25). In particular, implant characteristics (shape and surface texture) may represent a stimulus for the immunological system of the patients (24-26). As demonstrated before, some textured implants (macrotextured) have been correlated with a higher risk of late onset breast implant-associated anaplastic large cell lymphoma (BIA-ALCL), and they were withdrawn from the market (24, 27). In fact, current theories about the onset of BIA-ALCL link chronic inflammatory periprosthetic microenvironment with monoclonal T-Helper expansion (28).

Despite available evidence in literature regarding the kinetics of the T-lymphocyte response to persistent antigens (27), data on breast implants’ surface, early periprosthetic environment and potential early immunological impairment are still missing. There have been descriptions of an oscillatory pattern in white blood cells after implant based breast reconstruction, in particular repeated prosthetic reconstruction has shown a decreased T-cell count (27, 29, 30), but the evidence of the impact of different prosthetic surface (textured vs. smooth) on postoperative immune system is still missing. Emerging evidence in literature suggests that early postoperative lymphopenia represents a risk factor for early postoperative complications (31, 32), and long term oncological disease control (33).

Our prospective study (BIAL2.20) aimed to evaluate early T-helper impairment on postoperative day (POD) 1 and 2 after textured versus smooth implant-based breast reconstruction.

Patients and Methods

Study design and patients’ selection. A single institution, prospective observational trial (textured implants group versus smooth implants group) (Figure 1) was undertaken. The local institutional review board approved the study with the code name of BIAL2.20 and registration number of CEI n° 15/20. BIAL2.20 was funded by the Ministry of Health (Fund N° CUP E84E19002740006). Sample size was calculated following preliminary data obtained from an observational study assuming a 10% difference between the groups in the absolute number of T-helper on POD2 as primary endpoint. After having set alpha error at 0.05 with power analysis of 80%, sample size was established to 32 patients, accounting 16 for each group. To avoid any detrimental effect on the quality of life due to the different implants, we decided not to randomize patients (10, 18). Group allocation was decided intraoperatively by the plastic surgeon, according to expected aesthetic results, leaving the breast surgeon and the other physicians involved in the study absolutely unaware before surgery of the kind of breast prosthesis to be implanted (single blinded).

Figure 1.
Figure 1.

Flow chart of BIAL2.20 study. POD: Postoperative day.

The primary inclusion criteria for the BIAL2.20 study were a previous diagnosis of non-metastatic breast cancer treated with mastectomy within one year and immediate two-stage breast reconstruction procedure with tissue expander (CPX™4 Tissue Expander, Medium Height, Style 8200 Mentor®, Johnson & Johnson, New Brunswick, NJ, USA). Other inclusion criteria were age between 18 and 70 years old, female gender, no usage of anti-inflammatory or β-agonists drugs during the 2 months prior to the operation. Patients with a history of connective tissue disease were excluded from the study. Moreover, patients who underwent a mastectomy following breast-conserving treatment for breast cancer and/or radiotherapy were excluded as well (11, 15, 34). Due to the nature of the study and T-helper subset POD 2 difference set as primary endpoint, the observational period was terminated at 30 days from the surgical procedure. According to these prerequisites and requirements, the BIAL2.20 study was activated in January 2020 and terminated in July 2020.

Preoperative assessment. Before recruitment, all patients were counselled regarding each type of surgical approach and signed specific written-informed consent for participation in the study. One-week prior to the surgery, all patients underwent a plastic surgery consultation. During the visit, the plastic surgeon chose both micro-textured and smooth implants tailored upon patients. As stated before, definitive decision about the kind of prosthesis were extemporaneously made during the procedure.

Venous blood sampling time points. At 7.30 a.m., prior to surgery, a venous blood sample was taken through the antecubital peripheral vein of the arm. On POD 1 and POD 2, samples were collected at the same hour. This specific time interval was selected as there are numerous studies in the literature that use this frame to evaluate lymphocyte response according to different surgical procedures (3, 10, 35-38).

Full blood count, total leukocyte, total lymphocytes, total T-lymphocytes, T-helper lymphocytes, T-cytotoxic lymphocytes, natural killer (NK) cell, and B-cell lymphocytes were collected in absolute numbers and percentages. Samples were processed using a cell counter (Coulter Beckmann, MedLab, Cupertino, CA, USA). BD FACS Calibur (BD Biosciences, Franklin Lakes, NJ, USA) was employed for three-color cytometry (39). Lymphocyte subsets were obtained by incubating blood samples for 30 minutes with monoclonal antibodies at 4°C. The percentage of subsets was calculated by differential gating after three-colors coloring.

Surgical techniques. All patients were placed in supine decubitus position and underwent CPX™4 Tissue Expander removal. Tissue expander volume was recorded. During the reconstruction, textured or smooth implant was placed in the sub-muscular plane, patients were divided into the study groups according to the prosthesis chosen by the surgeon, according to the expected aesthetic result (textured group vs. smooth group). All patients underwent inferior surgical capsulotomy of the implant pocket. At the end of the procedure, one or more suction drainages were placed according to the surgeon’s choice and removed when the serous fluid loss was less than 30 ml/24 h. Contralateral symmetrization techniques without breast implants [mastopexy or contralateral mirroring (15)] were admitted to the study, but no contralateral breast implants procedure were allowed in the study. To reduce the risk of potential bias due to the anesthetic regimen on the early immunological response, all procedures were carried out with endovascular administration of propofol, and supraglottic devices were used for airway management (3, 10, 35-38, 40). Whenever the anesthetic regimen changed during the procedure for whatever reason, patients were excluded from the study.

Prophylactic antibiotic, Cephazolin 2 Gr IV, was administered within one hour before the incision. During the surgical procedure, fluid infusion at 1.5 ml/kg/h of normal saline and Ringer’s solution were used in both groups of patients; fluid infusion was maintained postoperatively for 12 h. Creatinine levels and urinary output demonstrated no significant difference in fluid balance between the groups. Patients were given intravenous prophylaxis with Cefazolin 2 g IV in the morning of POD1 and POD2. Drains were removed during the post-surgical follow-up and oral antibiotic was administered until removal. Non-steroidal anti-inflammatory drugs were forbidden after surgery. Thus, postoperative analgesia was achieved through an elastomeric device with tramadol (200 mg in 48 ml every 24 h at a rate of 2 ml/h). Postoperative pain assessment was made using a Visual Analogic Scale (0-10) for pain on POD 1 (VAS1) and POD 2 (VAS2) at the time of blood sample collection. All complications within 30 days of surgery were collected and Breast Modified Clavien-Dindo classification was applied (41, 42). Only the complications rated as ≥2 were analyzed in the study.

Statistical analysis. All continuous variables are expressed as medians and interquartile ranges (IQR). Preoperative inter-group analysis was performed with the Mann-Whitney U-test for major continuous variables. Categorical data were reported as frequencies and percentages and p-values were calculated with Fisher’s exact test. Longitudinal repeated measures of total leukocyte, total lymphocytes, total T-lymphocytes, T-helper lymphocytes, T-cytotoxic lymphocytes, NK cells, and B-cell lymphocytes were recorded as absolute numbers and percentages. Difference and relative difference [Δx=PODx-baseline; Δ%x=(PODx-baseline/baseline)*100; respectively] were calculated for repeated measures and two-way analysis of variance test (Two-way-ANOVA) was applied to determine within-group, between-groups and interaction p-values. Prior analysis, Mauchly’s Sphericity Test was performed, and when p-value was <0.05, Greenhouse-Geisser correction was applied. The statistically significant cut-off value was defined as p<0.05. When variables showed a statistically significant difference in between analysis, the Mann-Whitney U-test was performed between-group on POD1 and POD2.

Results

Preoperative and surgical data. A total of 46 patients were considered for enrollment. We preferred to include in the study a greater than the predicted sample size due to the lack of randomization and the existence of exclusion criteria following enrollment or surgical procedure (e.g. anesthetic regimen; prosthetic contralateral symmetrization).

Following recruitment, 3 patients withdrew (no reason given). After allocation, 2 patients were excluded from the study because one patient had received contralateral symmetrization with prosthesis and another received volatile anesthetic agents. Consequently, the final study group population considered for the study consisted on 41 patients divided into two groups (textured group, n=23; smooth group, n=18). Demographic and operative data, considered confounding factors, are listed in Table I, showing no statistical difference when compared between groups (43).

View this table:
Table I.

Demographic and operative data. All continuous data are shown as mean and range in brackets. Tissue expander volume and implant volume are shown as median and interquartile range (IQR). P-value was calculated with the Mann–Whitney U-test for continuous variables and Fisher’s exact test for categorical data.

Age and body mass index (BMI) analysis reported casual distribution between the groups (p=0.965; p=0.819, respectively).

Procedure analysis did not show a statistically significant difference in the symmetrization rate between the two cohorts of patients (p=0.201). Moreover, no difference was found in the chosen breast implants median volume (p=0.558), tissue expander median volume (p=0.819), and median number of surgical drains (p=0.742).

After surgery, no statistical difference was present in postoperative pain between POD1 (VAS1 p=0.741) and POD 2 (VAS2 p=0.694), nor when considering ≥2 Clavien-Dindo complications (p=1.000). Textured group experienced 2 complications: one case of seroma and one of post-operative mild anemia (POD2 hemoglobin 9.7 gr/dl). Both complications were conservatively treated (Clavien-Dindo II). In smooth group, one seroma occurred successively, requiring needle aspiration (Clavien-Dindo III).

Total leukocytes and lymphocytes subsets change. Table II shows a summary of the study results. Baseline data regarding leukocyte distribution and lymphocyte subsets did not show any statistically significant difference between textured and smooth groups. Table III exhibits differences, relative differences, and p-values of two-way-ANOVA.

View this table:
Table II.

Preoperative and postoperative responses of total leukocytes and leukocytes subsets, variables are shown as median and Interquartile range (IQR) in brackets.

View this table:
Table III.

Postoperative differences in total leukocytes and leukocyte subsets values are shown as difference from baseline as absolute number (Δ) and percentage (Δ%) in brackets. NK cell: Natural killer cell. Lymphocytes and lymphocyte subsets Δ were evaluated with two-way-ANOVA for repeated measures. *statistically significant.

Within-group analysis. Within-group analysis showed statistical results for total leukocytes in the textured group and smooth group (p<0.001 vs. p=0.001, respectively). Both groups showed a statistically significant increase on POD1 (textured group p<0.001; smooth group p=0.003) when compared with baseline data, and subsequent decrease toward baseline values on POD2 (Figure 2).

Figure 2.
Figure 2.

Absolute number of total leukocytes in the early postoperative period. All Values are shown as median with 95%CI. POD: Postoperative day; 95%CI: 95% confidence interval.

Conversely, in the textured group the total lymphocytes demonstrated a significant drop at POD1 with subsequent partial rebound on POD2 with a statistically significant value in the within-analysis (p=0.002). The drop on POD1 was not demonstrated in total lymphocytes of the smooth group with a flat curve (p=0.572) (Figure 3).

Figure 3.
Figure 3.

Absolute number of Total Lymphocytes in the early postoperative period. All Values are shown as median with 95%CI. POD: Postoperative day; 95%CI: 95% confidence interval.

Difference and relative difference of T-lymphocytes showed a trend similar to that of total lymphocytes in both groups. The within-group analysis of T-lymphocytes showed that absolute and relative differences were statistically significant in the textured implants (p=0.001), but not in the smooth group (p=0.637).

T-helper lymphocyte trends are displayed in Figure 4. Within-group analysis displayed a statistically significant distribution in the textured group only (p<0.001). Conversely, T-cytotoxic lymphocytes, NK cells, and B-lymphocytes did not exhibit a statistically significant difference in within-group analysis.

Figure 4.
Figure 4.

Absolute number of T-helper Lymphocytes in the early postoperative period. All Values are shown as median with 95%CI. POD: Postoperative day; 95%CI: 95% confidence interval.

Between-group analysis. Two-way-ANOVA between-group analysis was carried out to underline the early immunological difference between textured and smooth groups. In total leukocytes, similar trends with a peak on POD1 and subsequent fall were found in both groups (Figure 2) with no statistically significant difference (p=0.640). Neither total lymphocytes (p=0.247), nor T-lymphocytes (p=0.302) (Figure 3) showed different trends between groups.

Notably, absolute and relative differences in T-helper lymphocytes demonstrated a statistically significant trend in the between-group analysis (p=0.045). T-helper lymphocytes registered a larger drop on POD1 among the textured group in comparison with the smooth group, as shown in Figure 4. The Mann-Whitney U-test did not demonstrate a significant difference on POD 1 in T-helper lymphocytes [1058.05 (799.5-1348.5) vs. 748.60 (541-880), p=0.967 and 48.11 (41.5-53) vs. 42.80 (42-43.6), p=0.938, respectively]. A statistically significant difference was found on POD 2 in absolute numbers and percentages between groups [1,031.54 (798.25-1,126.75) vs. 622.80 (493-716), p=0.018 and 47.43% (41.75-54.25) vs. 42.20% (38-45), p=0.040, respectively]. No further statistical difference in the between-analysis was found regarding the other subsets (T-cytotoxic lymphocytes, NK cells, B-lymphocytes), as presented in Table III.

Discussion

T-helper lymphocytes are the central mediator of adaptative immune response by producing effector cytokines, playing a crucial role in adaptive immune responses to infective, autoimmune or allergic diseases (44, 45). The systemic response to surgical stress through hypothalamic-pituitary-adrenal axis activation could determine an impaired immune function and specifically T-helper lymphopenia with a nadir between 2 hours and 2 days (2, 4, 5).

Despite postoperative lymphopenia being widely proposed as a risk factor for postoperative complications (4), only recently has data demonstrated how postoperative lymphopenia represents an independent risk factor for infectious and not-infectious early postoperative complications (5, 32). Moreover, in oncological procedures early postoperative lymphopenia was described as a potential predictor of ipsilateral breast cancer recurrence (46), and lower five-year disease-specific survival rates in colorectal cancer (33, 47).

Several surgical and anaesthesiologic protocols have been designed with the purpose of reducing the impact of surgical and anaesthetic trauma in many surgical specialties (3, 9, 35, 36, 40, 48). However, despite a growing trend towards breast conserving surgery (34, 40, 49), mastectomy plus reconstruction is still required in some patients, leading to specific complications, such as BIA-ALCL (16, 19, 22, 50).

The emerging problem of BIA-ALCL has demonstrated that breast implants surface and it’s bacterial colonization could determine subclinical inflammation, T-helper monoclonal expansion and subsequent development of BIA-ALCL’s pathogenesis (37, 51, 52). The pathogenesis of BIA-ALCL underlies an amplified immune response, especially in textured implants, with features of a chronic allergic reaction in a susceptible patient (53). Despite these immunological theories, crosstalk between mesenchymal peri-prosthetic cell and T-helper/BIA-ALCL cells is still poorly understood (54).

Our results are consistent with existing theories and previous data from the literature. In fact, we demonstrated that early crosstalk between host and textured breast implant surfaces determines an early immunological impairment of the T-helper population. In our cohort, T-helper subsets in the textured group displayed a decrease on POD 1 with statistically significant value at two-way-ANOVA between-analysis when compared with smooth implants. Interestingly, this reduction takes place despite the expected increment of total leukocytes count exhibited at POD 1 as a physiological response to surgical trauma (1).

We hypothesized that this behavior may be triggered by a higher chemotactic stimulus driven by periprosthetic M1-M2 macrophage immune response against textured prosthesis (55, 56). These cells attract T-helper cells toward the periprosthetic microenvironment (57) and direct their terminal differentiation into Th2 subsets eliciting an amplified immune response with features of a chronic allergic reaction (53). We postulated that this recruitment could eventually determine systemic depletion of T-helper population in our samples with higher risk of postoperative complications (5, 32, 58), and potential immunological impairment (59, 60).

We are aware that our research has some limitations. First of all, this study has a non-randomized design. Grouping allocation was intraoperative, decided by plastic surgeon. This may have introduced a potential selection bias. However, we think that lack of randomization was an ethical choice, driven by the risk of a detrimental effect on patients’ aesthetics and quality of life outcomes. Nevertheless, we achieved two well-matched study groups. In particular, demographic, and preoperative variables as age, BMI, contralateral symmetrization, number of drains, and complication rates did not differ between the two populations. Other postoperative variables that could affect postoperative lymphocyte response like postoperative pain or early complications were evaluated with no significant impact. Additionally, confounding variables such as anaesthetic regimen, postoperative analgesia, and previous implant tissue expander were selected to reduce as much as possible any other confounding factors. Second limitation was the small sample size, which could have affected the power of our study. However, the sample size was calculated prior to recruitment to assure a statistically acceptable power in detecting intergroup differences. Third limitation of the current analysis is the sole quantitative assessment without information about lymphocyte activity as well as circulating inflammatory markers and endocrine response. However, data regarding lymphocyte activity or inflammation biomarkers, such as cytokine or chemokine, are rarely evaluated in the postoperative clinical practice.

Although many other factors could have altered our results, the well-matched baseline data led us to postulate that breast implants surface could have played a major role in postoperative lymphocytes impairment through lymphocyte periprosthetic recruitment.

Implant based breast reconstruction can produce excellent aesthetic results with reduced operating times compared to microsurgical reconstruction. Our prospective study demonstrates that textured implants result in an early immunological impairment with a T-helper cell reduction. In conclusion, if confirmed in a larger study, our current findings regarding impaired immunological function in the early postoperative period may have practical relevance in frail patients.

Acknowledgements

The work was financially supported by Italian Ministry of Health (Grant N° CUP E84E19002740006).

Footnotes

  • Authors’ Contributions

    Study conception and design: Vanni Gianluca, Materazzo Marco, Buonomo Oreste Claudio; Collection of data: Tacconi Federico, Pellicciaro Marco; Analysis of data: Vanni Gianluca, Materazzo Marco; Interpretation of data: Buonomo Oreste Claudio, Vanni Gianluca; Article draft: Materazzo Marco, Vanni Gianluca, Ambrogi Vincenzo; Critical revision: Amir Sadri, Ambrogi Vincenzo; Critical revision of literature: Amir Sadri, Materazzo Marco.

  • Conflicts of Interest

    The Authors declare no conflicts of interest regarding this study.

  • Received February 9, 2021.
  • Revision received February 23, 2021.
  • Accepted February 24, 2021.

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Breast Textured Implants Determine Early T-helper Impairment: BIAL2.20 Study
GIANLUCA VANNI, MARCO MATERAZZO, MARCO PELLICCIARO, SADRI AMIR, FEDERICO TACCONI, VINCENZO AMBROGI, ORESTE CLAUDIO BUONOMO
Anticancer Research Apr 2021, 41 (4) 2123-2132; DOI: 10.21873/anticanres.14984
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