Aug 2nd, 2014
Dear editors,
Thanks again for the reviewer’s opinions for our manuscript. For
answering their questions, we have collected more clinical information
and revised our manuscript. We are very grateful for the reviewers’ time
and effort. Thank you for your consideration. The following are the
detailed point-to-point answers for all of the questions. The red or blue is
newly inserted, the strike through is deleted.
Best Regards,
Weiwei Feng
Review 1:
This manuscript reports a case of leukemoid reaction (LR) attributed to a
cervical carcinoma relapse in a patient with a concurrent vaginal infection
by ESBL. The quickly tumor growth accompanied by fever and high
leucocytosis deserved doctors ‘attention. However, infection is a most
common cause of LR, especially when high fever is present; thus,
authors’attribution of the LR to the malignant cause may need further
justification. Issues:
Major issues:
1.- An abscessified malignant mass with vaginal anaerobic
microbiota that is not drained enough could justify the quick tumor’s
growth and the persistent fever and leukocytosis after one month of
antibiotic treatment. I would recommend taking into consideration
this option. It would be of interest to know about the evolution of the
initial purulent vaginal discharge.
Answer: The patient did have vaginitis, however, the vaginitis was not
severe enough to be the cause of LR. The evidence is the following:
1. The vaginal discharge revealed purulent cells on July 2nd (68 days after
the operation); repeated discharge culture showed ESBLs twice (Aug 5th,
Aug 17th) and negative results three times (Aug 2nd, Aug 12th and Aug
29th). We added the information in the text (line 95-96).
2. Although an ulcerous surface was found on the 60mm diameter solid
mass in the posterior vagina by gynecological examination, the MRI
showed a clear feature of homogeneous recurrent tumor. We inserted a
new MRI figure with detailed illustration (figure 2) and added the
explanation in the text (line 84-88).
3. In addition, the second bulky biopsy didn’t drain any abscess inside the
mass. We added the detailed information in text (line104-108).
4. The response to the antibiotics and chemotherapy was totally different.
One month of antibiotics treatment didn’t relieve symptom, however,
chemotherapy dramatically shrank the tumor and relieved fever and
leucocytosis subsequently.
2.- The only leukocyte count exceeding 50.000 was identified after
first paclitaxel+cisplatin. How strongly do you consider it to be a
tumor-related LR instead of a temporary worsening of the infection
secondary to chemotherapy?
Answer: After chemotherapy, despite the spiking fever and high
leukocyte count, the patient did not present any symptoms related to
worsening infection, such as pain and abscess. The possible reason for
LR is tumor necrosis, which is related to releasing multiple cytokines
(IL-1 alpha, IL-6, GM-CSF, G-CSF etc.) On July 30th, MRI scans
revealed small necrosis area inside the 63*65*58 mm tumor (Figure 2D).
Before chemotherapy, the necrosis area could enlarge since less blood
supply was in the central area with the growing of the tumor. After the
treatment with cytotoxic agents, the tumor might release more cytokines
temporary and resulted in spiking fever and high leukocyte count. Then
with the reducing volume of tumor, few cytokines were produced,
accompanied with improving condition.
3.- It would be interesting to know how the MRI defined the relapsed
mass: was it cystic or solid? Which density was it inside?
Answer: We reviewed the MRI results which showed a solid mass. The
density inside depended on the different imaging. We picked out four
representative pictures and added a new figure (figure 2) with detailed
illustration as the following:
“In this case, the giant oval mass (arrowhead) with homogeneous
isointensity signal was well demonstrated on T2WI (A, B). Note, the
balloon catheter (arrow) was placed into the bladder. On DWI(C), the
tumor (arrowhead) appears hyper-intensity signal compared with
hypointensity signal of background. On contrast-enhanced MRI (D), the
tumor mildly enhanced and the necrosis component (*) did not enhanced.
Note, the mass-rectum margin was not clear (arrow), indicating the
tumor invaded the anterior wall of rectum.”
Original figure 2 and 3 were changed to figure 3 and 4. We also inserted
the following in the text (line 84-88): “MRI scan confirmed a
homogeneous solid 68*63*58 mm mass located in the space between the
bladder and the rectum (Figure 1B and 2). MRI well displayed the tumor
itself and its margin. After injection of contrast materials, the relationship
between the tumor and surrounding tissues also was well appreciated on
serial MRI scans.”
Minor essential issues:
1.
I would suggest spelling ESBL and mentioning the specific
bacteria.
Answer: The specific bacteria was Escherichia Colli, ESBLs
(extended-spectrum β-Lactamase). (line 94)
2.
I would suggest using paclitaxel instead of the commercial
popular name
Answer: We replaced taxol with paclitaxel in the whole text.
3. SCCA marker is not routinely worldwide used. I would suggest
commenting in the Discussion about its sensitivity, specificity and
other causes of elevation.
Answer: We agree with reviewer’s suggestion. We added the
significance of SCCA in the discussion as the following (line 151-155):
“SCCA, defined as squamous cell carcinoma antigen, one of the most
popular diagnostic tumor maker of cervical cancer, has a sensitivity of
67-100% and specificity of 90-96% in recurrent cervical squamous
cervical cancer. The elevation of SCCA could also be occurred in
psoriasis, eczema, and severe kidney disease. In our case, SCCA was
elevated with the recurrence and subsequently decreased after
chemotherapy, which was in accordance with tumor burden.”
4. Expanding information from reference 13 in line 159 would be of
help.
Answer: Reference 13 is in German. We cited the information from the
abstract. However, we included a new reference 14 which provided
evidence from the cervical cancer. To support our finding, we cited the
important information from this article as the following (line 188-191).
“Nevertheless, Carus et al recently assessed tumour-associated CD66b(+)
neutrophils and CD163(+) macrophages by immunohistochemistry in
whole tissue sections of 101 FIGO IB and IIA cervical cancer patients
and found tumour-associated neutrophil count was an independent
prognostic factor for short recurrence free survival in localised cervical
cancer[14].”
Reviewer 2:
Minor Essential Revision
I would suggest treat LR and fever as a rare paraneoplastic syndrom
as it has been described elsewhere in the literature. Not mention at all
in their article.
Answer: We agree with the reviewer’s suggestion. We added the
following explanation in the second paragraph of discussion (line
161-164). “As in other carcinomas, we considered LR as a
paraneoplastic syndrome associated with cancer and attributed to
increased cytokine production. Fever is an integral component of
leukemoid reaction resulting from either release of endogenous pyrogens
or due to necrotic-inflammatory phenomena of the tumor.”
Discretionary revisions
I would suggest to clarify differential diagnostic of LR such as with
severe infection or CML
Answer: We mentioned the differential diagnosis of LR with severe
infection and CML in the first paragraph of discussion.